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PMC3952285_01

Male

A 24-year-old male presented with a 15 days history of persistent swelling of upper lip that ulcerated 2 days ago. He denied any history of trauma, fever, cough, weight loss, and drug or tobacco usage and his past medical and dental history was non-contributory. The patient was thin built with normal vital signs. There was no lymphadenopathy. A diffuse, non-tender swelling of lower lip with mild eversion of the lip was present [Figure 1]. A reddish pink granular lesion involving the vermillion border, labial mucosa, floor of the mouth, and the mandibular anterior gingiva was seen. The lesion had patchy areas of brown crustation, bleeding and purulent discharge [Figure 2]. A provisional diagnosis of Chelitis granulomatosis was made with a differential diagnosis of Baelz disease, tuberculous granulomatosis, sarcoidosis, a deep mycosis, primary syphilis, leishmaniasis, Squamous cell carcinoma, and non-Hodgkin's lymphoma. Plain chest radiograph and complete hemogram were within normal range. Serologies for syphilis and Leishmania, Mantoux test, and Enzyme-linked immunosorbent assay (ELISA) for HIV gave a negative result. An incisional biopsy from the lesion was undertaken that revealed numerous necrotizing epitheloid granulomas with Langhans type giant cells. Ziehl-Neelsen staining showed multiple rods like acid fast bacilli, confirming the diagnosis of primary labial tuberculosis [Figures 3 and 4]. The patient was started on anti-Koch's therapy in consultation with the physician with culture report awaited. Culture report obtained after 6 weeks confirmed mycobacterium tuberculous infection. Anti-Koch's therapy administered in this case consisted of four drug regimen, that is, rifampicin, isoniazide, ethambutol, and pyrazinamide for 6 months. The patient was regularly followed-up for next 6 months. The lesions regressed significantly within 15 days of beginning of the therapy and healed completely within 2 months [Figure 5].

granulomatosis, labial, oral, tuberculosis

PMC4847605_01

Female

A 43-year-old married Syrian woman presented at the age of 40 with distortion of central vision in the right eye. Choroidal dystrophy was suspected in Damascus (Syria) (Figures 1 and 2). Rheumatology and infectious workup was negative (syphilis, tuberculosis, anti-double-stranded DNA, anti-single-stranded DNA, rheumatoid factor). CNV was also detected in the macular area in Dubai (United Arab Emirates) and intravitreal injections were advised. She subsequently received three monthly intravitreal ranibizumab injections in Barcelona (Spain) (Figure 3A and B). Past ocular history revealed myopia of 2.5 D as per patient recollection. She had undergone bilateral refractive surgery (excimer laser 5 years ago followed by laser in situ keratomileusis [LASIK] 3 years ago). Medical history was negative. There was a strong family history of myopia and no parental consanguinity. Fifteen months after initial right eye involvement, the patient expressed the same symptoms in the left eye, such as seeing broken lines and asymmetric faces. She was advised to undergo treatment for CNV in the macular region. She received one injection in Beirut (Lebanon), and subsequently, three monthly injections in Dubai to the left eye. She reported further worsening of vision after each injection. Consultation in London (UK) revealed a best-corrected visual acuity of 20/80 in the right eye and 20/30 in the left eye. Dilated fundoscopy revealed bilateral areas of vertically linear atrophy, more extensive in the right eye, without subretinal fluid or hemorrhage by optical coherence tomography. Fundus autofluorescence imaging revealed areas of reduced autofluorescence corresponding to these areas of atrophy. The reported clinical impression then was myopic chorioretinal degeneration versus lacquer crack-associated myopic degeneration. She was advised to have regular checkup without intravitreal injections as long as the macula stays dry. The patient was frustrated because of both inability to pinpoint a definite diagnosis and gradual decline in vision bilaterally. Nine months later, she initially presented to our clinic with 20/200 visual acuity. Fundoscopy revealed definite widening of the vertical macular choroidal rupture bilaterally (Figure 4A and B). Stippled changes in the retinal pigment epithelium were observed. Peau d'orange appearance was not present. The patient was emmetropic without keratoconus on corneal topography. Axial length measurement with the IOL Master (Carl Zeiss Meditec AG, Jena, Germany) was 27.35 mm in the right eye and 27.31 mm in the left eye. Keratometry readings were 38.6 D in the right eye and 38.2 D in the left eye. The skin of the neck had tiny pinkish papules suspicious for early goose flesh (Figure 5). Two separate dermatology consultations and skin biopsies did not favor the diagnosis of pseudoxanthoma elasticum. Even further widening of the choroidal rupture occurred 9 months after presentation. Our working diagnosis was lacquer crack from high myopia (without pseudoxanthoma elasticum) (Figure 6) possibly initiated by LASIK and exacerbated by ocular rubbing and intravitreal injections (Figure 7). The patient was instructed to avoid ocular rubbing, head-down position, and intravitreal injection (unless an exudative component was present) and to have prior paracentesis before any future intravitreal injections.

bruch’s membrane rupture, lasik, angioid streak, choroidal neovascularization, choroidal rupture, high myopia, lacquer crack

PMC10109244_01

Female

87-year-old female resident ("Resident 1") - additional fall mitigation strategies included use of a pressure alarm on bed and wheelchair, and use of a rolling walker. Early in the morning hours, the resident walked out of her room into the hallway with no assistive device wearing the smartbelt. She grabbed onto a medication cart which then rolled, causing the resident to lose her balance and fall towards her right side. The irrecoverable fall motion caused the smartbelt airbags to deploy prior to her hip striking the floor. A nurse sitting at the end of the hall witnessed this fall. The smartbelt triggered alarms that the fall and airbag deployed. The resident was immediately approached and given attention for injury assessment by the staff nurse. The resident had no complaint of pain and was assisted to her feet and walked back to her bed. The resident's son expressed his gratitude and sense of assurance for having the device on his mother.

falls, fall injury, hip injury, intervention, older adults, wearable technology

PMC10109244_02

Female

88-year-old female resident ("Resident 2") - additional fall mitigation strategies included use of a pressure alarm on bed and wheelchair, and use of a wheelchair. In the early evening, the resident experienced a fall onto the floor while attempting to rise unassisted to standing from being seated in her wheelchair while wearing the smartbelt. The smartbelt detected an irrecoverable serious hip-impacting fall motion, deployed the airbags and triggered alarms to bring attention. Nurses found the resident on the floor with the wheelchair behind her. The nursing staff completed a physical assessment including checking for range of motion. No injuries were reported, and the resident had no complaints of pain or discomfort. The resident was helped to her feet and returned to her wheelchair.

falls, fall injury, hip injury, intervention, older adults, wearable technology

PMC10109244_03

Female

94-year-old female resident of memory care unit ("Resident 3") - additional fall mitigation strategies included use of a wheelchair. In the early evening, the resident fell during an attempt to self-transfer from her wheelchair to her bed while wearing the smartbelt. The smartbelt detected an irrecoverable serious hip-impacting fall motion, deployed airbags and sent alerts of the fall. The nursing staff discovered the resident on the floor of her room, provided a physical assessment with no injuries reported and helped the resident to her bed.

falls, fall injury, hip injury, intervention, older adults, wearable technology

PMC10109244_04

Female

83-year-old female resident ("Resident 4") - no additional fall mitigation strategies. In the early morning hours, an unwitnessed fall occurred while wearing the smartbelt in her room. The smartbelt detected an irrecoverable serious hip-impacting fall motion, deployed airbags and sent alerts of the fall. Nursing staff reported no injury following physical inspection. Post-hoc analysis of motion data captured by the smartbelt indicated a distinct pattern of gait with increasing postural sway prior to the fall, suggesting that the resident attempted to walk from her bed across the room prior to losing her balance and falling onto her side.

falls, fall injury, hip injury, intervention, older adults, wearable technology

PMC10109244_05

Female

91-year-old female resident of memory care unit ("Resident 5") - additional fall mitigation strategies included use of a pressure alarm on bed and wheelchair. One morning, the resident stood up from the memory unit dining room chair and fell. The smartbelt deployed airbags prior to the individual striking the floor and sent alerts that the fall had occurred. The resident was immediately given attention by nursing staff for physical assessment and found to have no injuries. Family members expressed to the facility team that they were very pleased that she sustained no injuries from the fall.

falls, fall injury, hip injury, intervention, older adults, wearable technology

PMC10109244_06

Female

78-year-old female resident ("Resident 6") - participant had a past medical history of Parkinson's Disease, low BMI and frequent falls who was on hospice care in addition to the fall risk factors noted above. Additional fall mitigation strategies included use of a pressure alarm on bed and wheelchair. In the very early morning hours, an unwitnessed fall occurred while wearing the smartbelt in her room. It was believed that the resident was attempting to make her way to the restroom from her bed, lost her balance and fell sideways very quickly onto the floor. The smartbelt deployed the airbags and sent alerts to the care team. Upon assessment, a minor injury of an elbow scratch was discovered. She was helped to her feet and returned to bed. The Memory Support Director in the unit reported her belief that the smartbelt "saved the resident's hip." During the 23-month time period after implementation, there were 2 incidents of airbag deployment not related to a serious hip-impacting fall. The first incident occurred when a participant with dementia became agitated, wriggled out of the smartbelt, and tossed the device across the room. The second incident involved a participant, described by staff as being a "fidgeter," slipped the device past their hips, leading to airbag deployment as the device fell to the floor. Neither of these incidents resulted in participant injury. Lastly, staff at the center did not report any instances of participants sustaining a fall which resulted in a major hip injury.

falls, fall injury, hip injury, intervention, older adults, wearable technology

PMC5624160_01

Female

This is the case of a 55-year-old African American female, with past medical history of hypertension and illicit drug use, who presented with worsening productive cough. The patient stated that the cough had been ongoing for the past 5 months but had worsened in severity over the last 2 weeks prior to admission. She complained of associated fever and chills for two days, sore throat, and copious white sputum. She denied shortness of breath, wheezing, and pleuritic chest pain. She also denied having hemoptysis. Patient denied having had any recent exposure to sick individuals. She is a 40-pack-year smoker, drinks alcohol socially, and admits drug use. Upon admission temperature was 98.1 F, blood pressure 112/61, heart rate 92 beats per minute, respiratory rate 18 breaths per minute, and saturation 99% in room air. Physical examination was significant for left lower lobe rhonchi without wheezing or rales. Laboratory studies were significant for elevated leukocyte count of 13.0 x 103/muL with a negative procalcitonin level. All other laboratory values were within normal limits. Urine drug screen was positive for opiates. Chest X-ray revealed left-sided infiltrative pattern (Figures 1(a) and 1(b)). A CT scan of the chest (Figures 2(a) and 2(b)) showed left-sided pneumonia involving the lingula and posterior basal segment and endobronchial occlusion of the posterior segment of the left lower lobe, possibly foreign body, not present on prior chest X-ray. Patient is subsequently scheduled for bronchoscopy. Prior to bronchoscopy, the patient disclosed additional information about her social history. She stated that 5 months prior to the admission, she was abusing cocaine and during an altercation with law enforcement she attempted to ingest a vial of cocaine. Bronchoscopy was performed, which revealed a significant circumferential inflammation of the left lower lobe segment and a foreign body noted in the postbasal left lower lobe bronchus. The foreign body was successfully removed with biopsy forceps, revealing a synthetic vial measuring 3.2 x 0.7 x 0.7 cm (Figure 3). Following bronchoscopy, the patient's cough improved significantly. She denied having shortness of breath, wheezing, and fever. Patient was sent home with oral antibiotics along with her home medications.

PMC4363670_01

Male

A 46-year-old Guinea-Bissau born male, living in Portugal for 16 years, was admitted to our institution because of vomiting, hiccups, weight loss (about 16 kg), occasional nocturnal sweating, and dry cough, lasting for 1 month. He had a past medical history of recurrent episodes of intestinal worm infection and excessive alcohol consumption (100-120 g/day). He was screened for tuberculosis due to prior contact with pulmonar tuberculosis. Laboratory blood tests were normal except for a high sedimentation rate (79 mmh). A bilateral bronchial reinforcement was observed on chest X-ray. Mediastinal enlarged lymph nodes and a nodular lesion at inferior left pulmonary lobe were noted on chest CT (computerized tomography) scan. A brain CT showed a small corticosubcortical ring-enhancing lesion in the right frontal lobe. He was diagnosed with HIV-1 infection (323/8,3% T-CD4 + lymphocytes/muL) and HBV chronic infection (AgHBs positive, Ac anti-HBc positive, and AgHBe negative). Inspection revealed good general condition, with papular lesions scattered throughout the body. On brain MRI a single round lesion with 7 mm was seen, with perilesional oedema, suggesting tuberculoma (Figures 1(a)-1(b)). Cerebrospinal fluid (CSF) cytochemical evaluation was normal. Bronchoscopy showed nonspecific inflammatory findings. Bacteriological and mycobacteriological (direct and cultural examination) analysis of respiratory products tested negative. Bronchial histology showed inflammatory infiltrate, with no granuloma or neoplastic tissue. Patient was discharged from hospital clinically stable, with no signs of infection. One month later he manifested persistent deterioration of general condition, with vomiting, abdominal pain in the right upper quadrant, myalgias, and fever. Laboratory tests revealed leukocytosis, C-reactive protein 12,2 mg/dL, and sedimentation rate >120 mmh. On chest CT scan a bulky right adrenal gland mass was disclosed. Abdominal sepsis was considered and treatment with intravenous (IV) ceftriaxone (1 g bid) was empirically started. Blood, urine, and stool cultural exams were negative, as well as Schistosoma spp. and Taenia solium serology. He completed a 14-day cycle of antibiotic treatment with clinical and analytical improvement. He was also treated with oral fluconazole (200 mg id) during 14 days for esophageal candidiasis. One week after ceftriaxone suspension a worsening of headache and inaugural seizures were observed. MRI brain-scan presented multiple well-defined annular lesions. Nocardia versusfungal abscesses was hypothesized (Figures 1(c)-1(d)). Empirical treatment with IV ceftriaxone (2 g bid), liposomal B amphotericin (4 mg/Kg id), and valproic acid was started. Adrenal mass was punctured; culture of purulent material revealed Nocardia spp. Characterization of bacterial species and antimicrobial susceptibility testing were not possible, neither by microbiologic methods nor by protein chain reaction (the sample was deteriorated when it arrived at reference laboratory; in Portugal, characterization of Nocardia spp. and antimicrobial susceptibility testing are made at reference laboratory, National Health Institute, Dr. Ricardo Jorge). ACTH and cortisol were within normal limits. As skin nodules persisted, a skin biopsy was performed; histology revealed superficial acute folliculitis and no microorganisms were seen with special stains; microbiological study was missed. The diagnosis of disseminated nocardiosis with brain, adrenal, and possibly lung and skin involvement was assumed. Based on literature, IV treatment was started with cotrimoxazole 1440 mg 8/8 h, amikacin (dosage adjusted to the serum levels), and ceftriaxone (2 g bid); liposomal B amphotericin was stopped. Two months later the patient showed clinical and laboratory improvement. His CD4 + cell count was then 207 (7,1%)/muL and viral load was 491640 cp/mL (genotypic resistance test was negative); HBV viral load was 777873717 UI/mL. An antiretroviral scheme with HBV activity was initiated with lopinavir/ritonavir (LPV/RTV) and tenofovir/emtricitabine (TDF/FTC). Four weeks later there was deterioration of renal function (GFR 69,2 mL/min). Amikacin was stopped. As renal failure went on worsening (GFR 37,7 mL/min), TDF/FTC was replaced by abacavir/lamivudine (ABC/3TC) and then cotrimoxazole was also stopped. Attempting to maintain a sulfonamide on the antibiotic regimen, dapsone was introduced. A significant transaminases elevation (AST 513 U/L; ALT 622 U/L with normal bilirubin) was interpreted as hepatotoxicity and dapsone was discontinued. The possibility of reactivation of HBV infection regarding the replacement of TDF/FTC for ABC/3TC was also considered. HBV viral load was still detectable (782 UI/mL), but at a lower level, so entecavir was added. Treatment with IV ceftriaxone (2 g bid) was kept for 1 year. Reassessment with Brain-MRI showed remaining lesions (Figures 1(e)-1(f)) and abdominal-CT scan showed resolution of adrenal abscess; HIV viral load was on the threshold of detectability (54 cp/mL) as well as HVB viral load (16 UI/mL). Currently, six months after stopping ceftriaxone, the patient is asymptomatic and presents a good recovery of renal function (GFR 80 mL/min). He is under valproic acid (800 mg bid) and antiretrovirals, with virologic suppression of HIV and HBV and improvement of immune status (306/12% T-CD4 + lymphocytes/muL).

PMC7193124_01

Male

A 39-year-old Taiwanese male painter had a history of alcohol consumption (approximately 90 units of alcohol per week for more than 6 years) and smoking (30 pack-years), but no illicit drugs use. Initially, he was brought to our hospital on 31 August 2018 with hemoptysis, yellowish thick sputum, a retrosternal burning sensation, and a 2-month history of progressive cough. No fever, chest pain, dyspnea, or tarry stool was found. He denied any previous medical history and he also denied previous travel history. At the emergency department, physical examination revealed a heart rate of 102 beats per minute, blood pressure of 133/82 mm Hg, respiratory rate of 20 breaths per minute, oxygen saturation of 89% on room air, and temperature of 37.0 Celsius. There was no lymphadenopathy or splenomegaly. There were left lower lung crackles on chest auscultation, and the neurological examination was normal. A chest radiograph showed a cavitary lesion in the left lower lung area (Fig. 1A). Chest high-resolution computed tomography revealed a cavitary mass with air-fluid level over the left upper and lower lobes (Fig. 1E); therefore, lung abscess was diagnosed. For community acquired pneumonia, these are many types of pathogens which could induce pneumonia with parenchymal cavitary lesion, including Gram negative bacteria such as Klebsiella pneumoniae and Haemophilus influenzae, Gram positive bacteria such as Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae, atypical bacteria such Mycoplasma pneumoniae and Legionella pneumophila, pulmonary tuberculosis, fungal infection, and parasite infection. The patient was admitted to our ward on 31 August 2018. The initial white blood cell (WBC) count was 10.33 x 1000/muL, C-reactive protein was 97.8 mg/L, and eosinophilic percentage was about 0.8%. Based on the laboratory data, bacterial infection was suspected. In addition, due to previous alcoholism history, Gram negative bacterial infection was highly suspected, especially Klebsiella pneumoniae. According to 2019 American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) for pneumonia treatment guide suggestion, beta-lactam with fluoroquinolone combination therapy is considered as a standard regimen for severe inpatient pneumonia. In our patient, the chest CT revealed lung abscess lesion over the left upper and lower lobes. Lung abscess is a relatively more severe pattern of pneumonia. In addition, the patient had used to drink alcohol for a long time, and immunocompromised status should be considered. According to ATS & IDSA guideline, combined treatment with Curam (amoxycillin + clavulanate potassium) and levofloxacin should be suitable in this situation. Therefore, we prescribed intravenous amoxicillin 1000 mg/clavulanic acid 200 mg every 8 hours and levofloxacin 750 mg per day for initial treatment. The serum mycoplasma IgM titer was 0.443 OD ratio which excluded mycoplasma infection. In addition, three sets of tuberculosis acid fast stains showed negative results on 04 September 2018 afternoon, and therefore pulmonary tuberculosis infection was excluded. The sputum culture report became available on 03 September 2018, and confirmed Klebsiella pneumoniae infection, which was sensitive to all of the antibiotics except ampicillin. Besides, chest radiograph on 6 September 2018 showed persistent cavitary lesion with newly developed peripheral infiltration at left lower lung field (Fig. 1B). Therefore, we changed the antibiotics from amoxicillin/clavulanate to inhaled colimycin (colistin base 2MU (66.8 mg) = 2.0 MIU colistimethate sodium (CMS) (160 mg/vial)) every 8 hours, but we retained levofloxacin as a synergistic agent for severe pneumonia treatment. The patient's chest radiograph on 13 September 2018 showed both the cavitary lesion and peripheral infiltration at left lower lung field had improved one week after change of antibiotics (Fig. 1C), and the lung lesions were almost completely resolved after four weeks of treatment (Fig. 1D and F).

alcoholism, inhaled colistin, lung abscess

PMC2838361_01

Female

The proband, an adopted six-year-old girl, and her four-year-old sister were brought to a pediatric cardiologist for evaluation, largely at the insistence of the natural maternal grandmother (MGM), who had maintained contact with the adoptive parents. At the time of the initial evaluation, the proband's family history, obtained through the natural MGM, was notable for hypertrophic cardiomyopathy (HCM) in her maternal uncle (diagnosed on autopsy following SCD at age 15), maternal grandfather (s/p ICD for HCM), and two maternal great aunts (SCD at age 16 and 36) (Figure 1). At the time of the maternal uncle's death, the cardiac status of the proband's mother was deemed "normal." On initial evaluation, the proband was asymptomatic with a normal physical exam, a normal electrocardiogram (ECG) and a normal echocardiogram. Given their significant family history for HCM, the proband and her sister were followed at 1-2 year intervals. At 8, 11, and 13 years, the proband was largely asymptomatic. The electrocardiograms showed no evidence of ST changes, left ventricular hypertrophy (LVH), or T-wave changes. The echocardiograms were completely within normal limits. She remained a very active child playing soccer and basketball without any exercise intolerance. At 13 years, the proband experienced a syncopal episode lasting a few minutes that was attributed to a vasovagal event. Her ECG and Holter monitoring at the time did not show any abnormalities. At 14 years, the proband continued to be athletic and denied any symptoms. Her physical exam and echocardiogram were normal. However, the proband's ECG did show nonspecific ST-T wave changes (Figure 2(a)). At this time, genetic testing was discussed with her and her adopted parents, but the family opted to defer testing. At 15 years, the proband's ECG showed right bundle branch block, right posterior fascicular block, and Q waves in the lateral and inferior leads (Figure 2(b)). Subsequent cardiac evaluations, including an exercise stress test, echo, and MRI, however, were normal, without any signs of myocardial ischemia or hypertrophy. The proband denied any symptoms or exercise intolerance. At 17 years, the proband's echocardiogram showed very mild concentric LVH (thickness 1.1 cm, Z-Score of 2), with evidence of diastolic dysfunction (maximal E : E' ratio=12). An exercise stress test did not reveal any evidence of ischemia or ectopy, and Holter monitoring was unremarkable. At this time, the proband was restricted from participating in competitive athletics, and genetic testing was performed (see below). An MRI performed two weeks later showed normal overall left ventricular mass at 67 g/m sq and normal interventricular septal and posterior wall thickness, but also revealed a prominent 2.7 cm thickening of the anterior wall at the base of the left ventricle (Figure 3).

PMC9051404_01

Female

A 32-year-old female presented to her primary care physician with tender erythematous nodules on her bilateral lower extremities four weeks following her second Moderna COVID vaccination (Figure 1). She had a past medical history of Ehlers-Danlos syndrome, psoriasis, 3 possible first-trimester pregnancy losses, and chronic diarrhea. There were no other family members with similar conditions. Serologic testing for SS-A, SS-B, JO-1, RF, CCP, ANA, DNAse B, TG2, PR3/MPO with reflex to ANCA, protein electrophoresis with immunofixation, complement C3c and C4c, tuberculosis, and hepatitis B and C was negative. A punch biopsy was reported by a community pathologist to be consistent with leukocytoclastic vasculitis. Additional testing for HIV antigen/antibody and Lyme disease was negative. Vascular studies revealed no abnormalities. As her clinical presentation did not match a small vessel vasculitis, a provisional diagnosis of cutaneous polyarteritis nodosa (PAN) was made by a community rheumatologist in the setting of ulcerating retiform purpura consistent with a medium vessel process. Treatment with 50 mg oral prednisone daily, 0.6 mg colchicine twice daily, and daily wound care with Medihoney for suspected cutaneous PAN was ineffective. Her dose of prednisone was decreased to 40 mg. One week later, the patient reported "a feeling of gravel" on her legs. At this time, her legs contained many necrotic ulcers and nodules, requiring debridement under anesthesia at an outside institution. Cultures showed extended spectrum beta-lactamase (ESBL)-producing E. coli and she was started on intravenous (IV) vancomycin and fluconazole, with collagenase and xeroform wound care. In early September, the patient was admitted to our institution for pain control and wound management, with her prior antibiotic regimen stopping 3 days prior. Estrogen based hormones were stopped at this time, and she was started on ertapenem 1 g IV and fluconazole 400 mg daily with wounds dressed in sulfamylon cream. Alternative diagnoses were discussed at this time due to lack of response to treatment of medium vessel vasculitis, including pyoderma gangrenosum. Repeat autoimmune and infectious testing was negative. A colonoscopy showed no evidence of inflammatory bowel disease. Magnetic resonance imaging (MRI) of her chest, abdomen, and pelvis was negative for vasculitis. The initial outside punch biopsy was reviewed, and the pathology findings were reclassified as thrombotic vasculopathy instead of vasculitis. Repeat punch biopsy revealed subcuticular necrosis with fibrin thrombi within blood vessels. No significant immunoglobulin (Ig) G, IgA, IgM, or C3 deposits were identified via direct immunofluorescence. Testing for coagulopathies was positive for prothrombin variant G20210A. The remainder of her thrombophilia evaluation, including testing for cold agglutinins, JAK2 with reflex, paroxysmal nocturnal hemoglobinuria, antithrombin III deficiency, factor V Leiden, platelet factor 4 antibodies, antiphospholipid labs, platelet count, and protein C and S levels were normal. The patient started taking warfarin due to concern of vasculopathy and was transitioned to apixaban once negative antiphospholipid antibodies were confirmed. Her antibiotic regimen was altered to 3 g IV ampicillin-sulbactam and 100 mg micafungin daily after a wound swab grew Klebsiella. In October, a diagnosis of cutaneous PAN was no longer favored due to evidence of ulcers eroding further into adipose tissue despite patient's steroid treatment (Figure 2). The patient's steroid treatment was tapered. After being on prolonged antibiotic treatments, the patient developed diarrhea secondary to clostridium difficile infection. Oral vancomycin was added, and she underwent two surgical debridements to lessen the load of necrotic tissue. Her anticoagulant regimen was switched to a heparin drip prior to the first procedure. By the end of October, it was discovered the patient was resistant to heparin. At the end of this month, the patient was transferred to the intensive care unit for sedation due to uncontrollable pain. By the beginning of November, the patient received her third debridement. The most likely cause of the patient's progressive necrotic ulcers at this time was thought to be a thrombotic vasculopathy. A review of the literature found a case series on subcutaneous thrombotic vasculopathy similar to the patient's presentation. The possibility of an autoimmune reaction following COVID vaccination was discussed by the hematology and immunology teams at this time. A larger incisional biopsy at the edge of a developing lesion on her flank was performed. She was started on therapeutic enoxaparin, 81 mg aspirin daily, dipyridamole 75 mg four times daily, and pentoxifylline 400 three times a day in addition to treatments with IV immunoglobulins. Despite appropriate 1 mg/kg twice daily dosing of enoxaparin, the patient's anti-factor X activity level was subtherapeutic requiring escalation to 1.5 mg/kg twice a day. In addition, the patient was given 1 g IV solumedrol and transitioned to prednisone. The biopsy results came back as diffuse small vessel thrombosis with rare small vessel calcification, suggesting a thrombotic vasculopathy (Figure 3). Despite the less conspicuous tissue calcification present in the patient's biopsy, calciphylaxis was considered as a diagnosis. The low risk of IV sodium thiosulfate was weighed with the potential benefits, and it was started twice weekly. Over the next 2 weeks, the patient experienced improvement in pain - however during this time she started oral ketamine and received a hydromorphone PCA. In mid-November, the patient had a spontaneous retroperitoneal bleed resulting in discontinuation of therapeutic anticoagulation. By the end of November, pentoxifylline was restarted with prophylactic enoxaparin. Wounds continued to progress (Figure 4), most notably on patient's bilateral flanks. The decision was made to stop intravenous immunoglobulin and initiate plasmapheresis in attempt to reverse any unknown immune-mediated processes. Her bilateral legs were debrided again early December 2021 to decrease necrotic tissue burden. She is now on argatroban due to difficulty with enoxaparin dosing, has received 7 treatments of plasmapheresis, and is receiving IV sodium thiosulfate 25 g five times weekly. A recent tissue culture was positive for Stenotrophomonas maltophilia, Mucor, and Candida parapsilosis, and her antibiotic regimen consists of 100 mg minocycline twice daily, 1 g imipenem/cilastin intravenous every 8 h, 5 mg/kg IV amphotericin B every 24 h as tolerated, and oral 125 mg vancomycin four times daily. Her prognosis remained guarded, with differential diagnoses including idiopathic subcutaneous thrombotic vasculopathy, non-uremic calciphylaxis sin calcifications, or an autoimmune response to her COVID vaccination. She reported depression, and high levels of pain despite a rigorous pain control regimen. She chose not to see the lesions on her bilateral lowerextremities since November as she believed it would worsen her mental health. Although it was difficult at times to havehope, she and her family continued to search for answers and have aggressive treatment goals. She wanted to share her story with the medical field in hope other providers would be able to provide insight to help her, and future patients with similar afflictions. In early February, the patient was transitioned to comfort care and passed away surrounded by her family.

covid, calciphylaxis, polyarteritis nodosa, thrombophilia, ulcers, vasculopathy

PMC8634327_01

Female

A 52-year-old woman presented at the emergency room (ER) in a regional hospital with progressive dyspnea, a dry cough and fatigue during several weeks despite taking oral antibiotics because of a suspected pneumonia. Three days prior to presentation she had experienced a severe dull thoracic and epigastric pain accompanied by nausea and vomiting that had resolved spontaneously. Besides taking ferrofumarate and cholecalciferol for iron-deficiency anemia and vitamin D deficiency, she had no previous medical history. On presentation, physical examination revealed a regular tachycardia of 116 beats per minute (bpm), a blood pressure of 120/75 mmHg, an oxygen saturation of 100% while breathing ambient air, and a core temperature of 38.0 C (100.4 F). Cardiac, pulmonary, and abdominal examinations were unremarkable. There were no signs of deep venous thrombosis and the Wells-score was 4.5. The electrocardiogram (ECG) showed sinus tachycardia, normal electrical heart axis and normal PR- and QRS-intervals, but inverted T-waves in both antero- and inferolateral leads (Figure 1). A low hemoglobin level (5 mmol/L), elevated c-reactive protein (102 mg/ml), troponin-I (1036 ng/L, cut-off is <20) and NT-pro-BNP (366 ng/L, normally <100) levels were the most prominent abnormal laboratory results. Computed tomography angiography of the thorax (CTA) ruled out pulmonary embolism, but demonstrated pericardial and pleural effusion. Subsequent transthoracic echocardiography (TTE) confirmed circumferential pericardial effusion of ~4.5 cm with signs of haemodynamic compromise (dilated and poor collapsing inferior caval vein, early systolic right atrial (RA) collapse and >25% respiratory variation in peak mitral E-wave). Urgent evacuation of ~1 L of hemorrhagic fluid after pericardiocentesis immediately ameliorated symptoms. Investigation of this pericardial fluid did not reveal a tuberculous, bacterial, viral, or malignant etiology. A respiratory viral panel by polymerase chain reaction (influenzas A and B and respiratory syncytial virus) and a serum HIV antibody test were negative. After recurrent pericardial effusion was ruled out 1 week later, she was discharged home. While unconfirmed, a discharge diagnosis of post-infectious/post-viral pneumonia related pericardial and pleural effusion was made. Already 5 days later, she presented again with progressive dyspnea, coughing, and nausea. A further decrease in hemoglobin (4.7 mmol/L) was noted and TTE showed recurrent circumferential pericardial effusion (~3 cm) but now a dense structure suggesting thrombus in the pericardial sac (Figure 1). Coronary angiography (CAG) was performed after which coronary artery disease including dissection could be ruled out. She was transferred to a tertiary university center and received a blood transfusion. Additional viral serology (adenovirus, coxsackievirus, echovirus, borrelia burgdorferi, cytomegalovirus, Epstein-Barr virus, and parvovirus), immunological testing (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, complement screening, and M-protein), a tuberculosis test and blood culture analyses were normal. To re-assess the possibility of a malignant cause, a repeat CTA of the thorax and abdomen was performed. While macroscopic malignancies could be ruled out, the scan showed contrast extravasation into the pericardial space, suggesting active bleeding. After a multidisciplinary consultation between cardiologists and cardiothoracic surgeons, and given the observation that the patient remained hemodynamically stable, it was decided that urgent surgery was not yet indicated and that there was still sufficient time for additional diagnostic workup. On cine cardiac magnetic resonance imaging (CMR), left (LV) and right ventricular (RV) systolic function were preserved and pleural and pericardial effusion confirmed. During contraction, the LV apex remained remarkably "fixed" to the pericardium (Supplementary Video 1). On the delayed enhancement (DE) images, the high intra-pericardial signal again suggested contrast-extravasation into the pericardial sac, whereas an extensive, hypo-enhanced circumferential layer against the inner parietal pericardium suggested thrombus (Figure 1). No intramyocardial abnormalities were observed. It was concluded that ongoing, albeit slow, intra-pericardial bleeding was present. Since other diagnostic clues were missing at this time, an initial post-viral and subsequent recurrent traumatic or reactive pericardial effusion after pericardiocentesis were still considered causative and urgent surgery was yet indicated. Since focal bleeding from a traumatic ventricular lesion after initial pericardiocentesis could not be excluded, it was decided to first perform a limited thoracotomy via a left-sided submammary incision. After evacuating 2.5 L hemorrhagic pericardial fluid with thrombi, careful inspection did not reveal a focal bleeding site. Because of persistent bleeding, the incision was extended further but again no focal bleeding source was discernable. Instead, multiple active venous hemorrhages on the entire epicardium were visible and hemostasis was attempted by placing multiple fibrin sealant patches Tachosil (Baxter healthcare cooperation, Illinois, USA). In addition, multiple biopsies of the pericardium and pericardial fluid and thrombi were sent for pathological examination. The patient was subsequently transferred to the intensive care unit (ICU), but went into cardiogenic shock the following day. TTE showed recurrent pericardial effusion with a thrombus compressing the RA. A conventional emergency sternotomy was carried out. After thrombus removal, again diffuse hemorrhages were observed and a single bleeding focus in the RA was sutured. Unfortunately, within 3 days she had to be operated two more times to relief recurrent cardiac tamponade and a left-sided hemothorax. Repeatedly, extensive diffuse venous epicardial hemorrhages were found that were difficult to manage, causing her to remain hemodynamically unstable in the ICU. After 9 days, pathology of the pericardium revealed an epithelioid angiosarcoma. Given the disease extent and unfavorable prognosis, it was decided to refrain from additional aggressive therapy. She died the same day, 28 days after the initial presentation. A timeline is showcased in Figure 2. After obtaining consent from relatives, gross autopsy revealed a diffusely thickened residual pericardium with an irregular surface with multiple thrombi and hemorrhages. The pericardium was extensively adhered to ribs, myocardium, ascending aorta, and aortic arch. A nodular epicardial surface was found with diffuse hemorrhages and thrombi. The heart was only minimally enlarged (419 [normal 233-403] g). Microscopy showed an atypical vascular proliferation with focal papillary structures consisting of large epithelioid cells with high amounts of eosinophilic cytoplasm. The nuclei of these epithelioid cells were pleomorphic and hyperchromatic with numerous, sometimes atypical, mitoses. Because these epithelioid cells stained positive for the immunohistochemical vascular markers ERG, CD31 and CD34 but not for CD68, HHV-8 and keratin markers CK AE1/AE3, CK 5/6, and CK7, a diagnosis of epithelioid angiosarcoma was made. The angiosarcoma was predominantly localized in the pericardium and epicardium without deeply infiltrating the myocardium leading to epicarditis and pericarditis. A single longitudinal thickened lesion was found at the RA appendage that had been surgically sutured. Microscopic evaluation of this lesion revealed transmural invasion of the angiosarcoma (Figure 3). Additionally, lympho-vascular invasion with intracapillary tumor cells in the lungs (hemangiosis carcinomatosa) and focal invasion from the pericardium into the left lung was found, explaining the hemothorax.

cardiac angiosarcoma, dyspnea, hemopericardium, pericardial effusion, right heart sarcoma

PMC8383176_01

Male

The patient, a 65-year-old man, presented with swelling and pain in his right scrotum three months ago. He was first admitted to our hospital 5 years ago with a cough and fever. The CT scan of the abdomen showed multiple soft tissue densities behind the peritoneum and the serum IgG4 3200 mg/dL. The patient was definitively diagnosed with IgG4-RD as well as secondary retroperitoneal fibrosis by the gold standard of histopathology. He was in long-term remission after regular treatment with mycophenolate mofetil (1g Bid) and prednisone (0.6 mg/kg), followed by six months, four years, and a recent abdominal CT scan showed no progression of retroperitoneal fibrosis. He had no previous history of pulmonary or urinary tuberculosis and no significant family history. On examination, a mobile mass of approximately 2 cm in diameter was found in the right scrotum. The mass was hard and tender. No other positive signs were found. Laboratory tests showed erythrocyte sedimentation rate 69 mm/h (reference range 0-15 mm/h), C-reactive protein 29.9 mg/L (reference range 0-10 mg/L), complement C3 0.58 g/L (reference range 0.9-1.8 g/L), complement C4 0.03 g/L (reference range 0.1-0.4 g/L). Serological examination showed elevated IgG4 levels to 2070 mg/dL (reference range 6-130 mg/dL). Negative for prostate-specific antigen (PSA), tumor markers, and tuberculosis antibodies. Scrotal ultrasound demonstrating enlargement of the right testicle. Enhanced computed tomography of the scrotum showed a nodular hyperdense shadow with a diameter of approximately 23 mm on the right epididymis, with significant heterogeneous enhancement on the enhanced scan (Figure 1). After ruling out testicular tuberculosis and hydrocele due to retroperitoneal fibrosis secondary to IgG4-RD, given the potential risk of malignancy, he underwent a pathological biopsy by puncture of the right epididymis. Pathological biopsy of the right epididymis showed infiltration of plasma cells, lymphocytes, and a few neutrophils with occlusive vasculitis changes in the tissue (Figure 2A). IgG4+ plasma cells stained positive, with an IgG4/IgG ratio of more than 40% and more than 30 IgG4+ plasma cells per high-power field (Figure 2B). A diagnosis of IgG4-RD involving the testicles was made. Prednisone 30 mg/d was given for three weeks. No scrotum swelling or pain was observed at the follow-up after six months. The timeline of diagnosis, treatment, and prognosis for this case is shown in Figure 3.

igg4-related disease, clinical feature, glucocorticoids, testis, treatment

PMC4767091_01

Female

Here, we present the case of a 42-year-old female patient, American Society of Anaesthesiologists 1 and donor for renal transplant surgery of her husband. The preanesthesia visit did not reveal any co-morbidity on history and the physical examination was also within normal limits. The weight recorded was 50 kg and the height corresponded to 1.50 m, and the body mass index was calculated as 20.8 kg/m2. Blood investigations revealed hemoglobin of 11.5 g/dL, total leukocyte count of 8600 mm3, and platelet count of 156,000 mm3. Random blood sugar was 86 mg dL. Renal function tests and serum electrolytes were within normal limits. Electrocardiogram and chest X-ray done preoperatively were normal. The patient was taken to the operating room, and routine monitoring in the form of noninvasive blood pressure, SpO2 probe, and five-lead electrocardiogram were applied. The vital parameters had noted before induction were within normal limits. Intravenous access was secured with one 16-gauge (G) and one 18-G cannula. Anesthesia was induced with intravenous midazolam 1 mg intravenous (i.v.), fentanyl 100 mug i.v., propofol 100 mg i.v., and vecuronium bromide 5 mg i.v. The patient was mask ventilated by a mechanical ventilator to achieve normocarbia with O2, N2O, and isoflurane (0.9-1 minimum alveolar concentration [MAC]) for 3 min approximately. The trachea was intubated using endotracheal tube no 7.0 mm internal diameter. After confirming the position of endotracheal tube, the patient was mechanically ventilated with a tidal volume of 400 ml, respiratory rate of 12/min, and maintaining an ETCO2 between 32 and 35 mmHg, and an esophageal temperature probe was inserted. The patient was maintained on O2, N2O (50:50%), and isoflurane (MAC 1). Donor nephrectomy for the left side was completed in 3 h. At the end of the surgery, anesthesia was reversed, and breathing attempts were observed. Suddenly, the monitor displayed a drop in the ETCO2 to 5-6 mmHg. Immediately, the ventilator circuit was checked which was found to be in place and on chest auscultation, bilateral equal air entry was heard. Sudden bradycardia with heartbeat dropping to 32 beats/min (bpm) and a blood pressure reading of 90/50 mmHg was displayed on the monitor. Injection atropine 0.6 mg i.v. was given and a second dose repeated after 2 min following that arise in the heart rate to 120 bpm was observed, and a blood pressure of 90/60 mmHg was noted. On examination, patient's conjunctiva was pale. Surgeons were informed about the possibility of an intra-abdominal bleed. An emergency laparotomy was planned while resuscitation with crystalloids, colloids, and packed red blood cells was instituted. On surgical exploration, the renal artery pedicle (at the hilum of the kidney) ligature was found to have slipped away resulting in torrential amount of bleeding. The bleeder having been identified was secured, and a complete inspection of other possible bleeding sites was done. Meanwhile, hemodynamic status stability was ensured with inotropic support. A total of 5 liters (L) of crystalloids, 1 L of colloids, 4 units of packed red blood cells, and 2 units of fresh frozen plasma were transfused during the entire re-open laparotomy. The estimated blood loss was 2500 ml approximately, and urine output of 2800 ml was noted. Postoperatively, the patient was shifted to the Intensive Care Unit with inotropic support. It was decided to keep the patient mechanically ventilated on volume control mode of ventilation. All blood investigations including complete blood count, liver function tests, kidney function tests, arterial blood gas, coagulation profile, and chest X-ray were sent postoperatively. Extubation was planned to take place only when hemodynamic stability would be achieved without inotropic support. Next day, the patient's condition improved significantly. Inotropic support was switched off, and vitals were stable. The hemoglobin was 7 g/dL and other parameters were within normal limits. Two units of packed red blood cells were transfused on the 1st postoperative day. Weaning from mechanical ventilation was commenced and subsequently, postoperative day 3, extubation was planned with patients general condition have improved and a hemoglobin of 9 g/dL. The patient remained stable on postoperative day 5; the patient was shifted to the ward.

donor nephrectomy, hemorrhage, renal artery, vascular complication

PMC8383642_01

Female

A 70-year-old female consulted for 2-year evolution symptoms consisting of syncopal episodes, with loss of postural tone and without the presence of abnormal movements, relaxation of sphincters or other associated symptoms. She referred a frequency of approximately two to three episodes per year without consultation to the emergency services or previous study of the episodes. On the admission day to the institution, she presented an event of the same characteristics with mild traumatic brain injury (TBI) and facial trauma secondary to falling from her own height. For this reason, a simple skull computed tomography (CT) is carried out and a neurosurgery concept is requested. During the initial evaluation, the patient is found in a Glasgow Coma Scale (GCS) as follows: GCS of 15, acceptable general condition, with vital signs within normal limits, with craniofacial trauma stigmas, bradypsychic, cranial nerves without alterations, preserved muscle strength in all 4 limbs, without sensory deficits and without the presence of pathological reflexes. Significant vasogenic edema in the extension of the left frontal lobe with volume effect and deviation of the midline to the right is evidenced on the skull CT (Fig. 1). Findings highly suggestive of tumor lesion without clear limits in it were considered. The study was extended with simple and contrasted brain nuclear magnetic resonance imaging (MRI) in order to characterize the lesion. The initial diagnostic impression was a metastatic lesion; therefore, extension studies were requested in order to search for possible primary neoplasm, which were negative. Anti-edema management was started with intravenous 8 mg of dexamethasone every 8 h and anticonvulsant management was managed with 500 mg of levetiracetam every 12 h. The simple and contrasted MRI (Fig. 2) showed a lesion with well-defined intra-axial left frontal edges, isointense in T1 and T2 sequences, with homogeneous uptake of the contrast medium, without restriction to diffusion, associated with large perilesional edema, with deviation of the midline to the right and subfalcine herniation (Fig. 2). The patient underwent surgical intervention with prior skull CT-guided surgical site marking (Fig. 3). The procedure was carried out under general anesthesia, with a left pterional craniotomy. Through intraoperative ultrasonographic guidance, the tumor lesion was identified and delimited in the left inferior frontal opercular subcortical gyrus. A corticotomy was carried out through the fissure and after 0.5 cm of depth, the lesion was identified. A blunt dissection was conducted through the capsular plane and progressive devascularization was carried out, subsequently achieving complete exeresis of the lesion. Intraoperatively, a solid encapsulated violet-colored tumor was observed, highly suggestive of meningioma. During the postoperative follow-up, there were no motor or sensory focal neurological signs. Motor aphasia was evident, which resolved after the first 48 h. A control tomography was carried out, with evidence of postsurgical changes and decrease in vasogenic edema. The pathology report informs a lesion compatible with transitional meningioma, World Health Organization (WHO) grade I. The patient was discharged without sequels of neurological deficit, with the indication to continue the outpatient follow-up. In her first outpatient post-operative follow-up after 2 weeks, she remained asymptomatic, without neurological deficit and a healthy surgical wound.

intra-axial meningioma, intraparenchymal meningioma, meningioma

PMC9368318_01

Female

An 8-year-old Kachchi breed of dromedary camel was presented with abortion after the 9th month of gestation during her 2nd pregnancy. This camel belonged to a herd comprised of 350 dromedary camels in the Thar desert of Rajasthan, India. The herd is maintained in a semi-intensive husbandry system, mostly in outdoor facilities, and fed with a mix of pellet feed, hay, and ad libitum water. A history of sporadic occurrence of TB has been reported in this herd. Clinically, the aborted she-camel appeared healthy with a good body condition score and normal appetite and did not show any respiratory symptoms and fever at the time of the abortion. The she-camel was tested negative for brucellosis on Rose Bengal Plate Test. However, she tested positive in a single intradermal tuberculin test performed a day after abortion, showing marked swelling and a 2-fold increase in skin thickness at the injection site. After the abortion, the placenta and aborted fetus were examined for gross lesions. The expelled placenta was thickened, edematous, and multifocal to coalescing ecchymotic hemorrhages on the allantoic surface (Figure 1A). The fetus showed generalized subcutaneous edema, congestion, and a moderate amount of sero-hemorrhagic fluid in the abdominal and thoracic cavity along with generalized congestion of all internal organs, which is likely due to autolysis and hemoglobin imbibition. The striking finding in the fetus was the presence of multiple, white-yellow, solid nodules scattered over the lung, the pleura, and the liver which measured from 2 to 15 mm in diameter (Figure 1B). The lung was collapsed, severely congested, and had multiple small white-yellow tubercle nodules scattered on all lobes. These nodules were also found attached to the pleura and inner surface of the rib cage. The liver was found enlarged considerably, congested, and had multiple tubercle nodules (Figure 1C). The other organs viz., the heart, the spleen, the kidney, and the intestines showed severe generalized congestion without any evidence of tuberculous lesions. The tissue samples suspected to have TB lesions, such as the lung, the liver, and the placenta, were collected in 10% neutral-buffered formalin for histopathology, as well as in sterile vials for DNA extraction. For histopathology, tissues after fixation were embedded in paraffin, cut into 4-mum-thick sections and stained with hematoxylin and eosin. Selected sections were also subjected to Ziehl-Neelsen (ZN) staining. On histology, the lung and liver sections showed typical granulomatous lesions characterized by a central area of caseous necrosis and mineralization surrounded by scattered lymphocytes, macrophages, and/or occasional giant cells, and concentric layers of fibrosis (Figures 2A,B, 3A). Scarce acid-fast bacilli were observed on ZN-stained sections of the lung and the liver (Figure 3B). Histopathology of the placenta showed normal physiologic and/or autolytic changes of mineralization of the chorionic epithelium, necrosis of villous stroma, and hyperemic blood vessels. However, granulomatous inflammation and acid-fast bacilli were not observed. Tissues (placenta, fetal lung, and liver) were processed for DNA extraction using the PureLink Genomic DNA Mini Kit (Invitrogen). The DNA was subjected to PCR amplification of a 245bp region of IS6110 sequence specific for the MTBC, using primer pairs INS1 (5'-CGTGAGGGCATCGAGGTGGC-3') and INS2 (5'-GCGTAGGCGTCGGTGACAAA-3'). Briefly, a 25 mul reaction was prepared using 12.5 mul Gotaq green master mix (Promega), 1 mul each primer (10 picomoles), 5 mul of DNA, and 5.5 mul of nuclease-free water. The cycling conditions used were initial denaturation at 94 C for 5 min, followed by 35 cycles of denaturation at 94 C for 1 min, annealing at 65 C for 1 min, and extension at 72 C for 1 min. This was followed by a final extension step of 72 C for 10 min. The PCR-amplified products were visualized in 2% agarose gel and the purified PCR products were subjected to nucleotide sequencing for the IS6110 gene using Sanger sequencing based on the chain-terminating dideoxynucleosides method (Eurofins, India). These sequences were deposited in NCBI GenBank (accession numbers: MW393780 and OL436218) and aligned with the published sequences for phylogenetic analysis using the ClustalW tool and the Maximum Composite Likelihood method. This analysis involved 30 nucleotide sequences, and the evolutionary analyses were conducted in MEGA X. The DNA extracted from the lung and the liver showed amplification of the IS6110 region of MTBC by PCR (Supplementary Figure 1). The sequencing and phylogenetic analysis revealed that sequences in this study clustered with M. tuberculosis. On a managemental aspect, this she-camel was isolated and maintained away from the herd after abortion. After 1 year of isolation, the she-camel exhibited the clinical signs of chronic infection, including poor appetite, weakness, and progressive emaciation. Eventually, this she-camel died after 7 months of exhibiting symptoms. Considering the clinical history and the safety of the personnel, neither necropsy nor tissue evaluation was performed on this she-camel. Instead, the carcass was immediately disposed of by deep burying.

mycobacterium tuberculosis, abortion, camel, congenital tuberculosis, pathology, vertical transmission

PMC6335926_01

Male

A 16-year-old boy was admitted to a rural hospital in the Democratic Republic of Congo with a 1-month history of abdominal pain, headache, and nightly fevers, and a 1-week history of seizures. Physical examination included general weakness, low-grade fever (37.5 C), neck rigidity, and bilateral abducens palsy leading to double vision (Figure 1A and B), typical clinical findings consistent with tuberculous basal meningitis. The latter was supported by lumbar puncture showing white blood cells of 720 cells/mm3 (90% mononuclear) and elevated protein (Pandy test positive) but negative Ziehl-Neelsen stain. In 20% of meningeal tuberculosis cases, the cerebrospinal fluid cell count is between 500 and 1,500/mm3, and in 65% between 100 and 500/mm3. In addition, physical examination revealed spinal tenderness at T 10-11 with normal reflexes, sensation, and strength of lower extremities bilaterally. Abdominal and cardiopulmonary examination was unremarkable. Spinal X-ray showed destructive anterior spondylodiscitis at T 10-11 with a paravertebral abscess (Figure 1C), again typical findings for Pott's disease and explaining the abdominal pain. Simultaneous pulmonary tuberculosis or human immunodeficiency virus (HIV) infection were ruled out by chest X-ray and a HIV rapid test. Due to pulmonary tuberculosis already experienced as an infant and current extrapulmonary manifestation, an extended treatment scheme with rifampicin, isoniazid, ethambutol, pyrazinamide, and streptomycin (2SRHZE/RHZE/9RH), as well as initially beginning with corticosteroids (prednisone 1 mg/kg) was chosen. Within 2 weeks, the abducens palsy was resolved completely, the abdominal pain improved, and the spinal fluid cell count dropped to 23 cells/mm3. One month later, the patient was back to normal daily life, playing football with friends. Tuberculosis is still endemic in many low- and middle-income countries such as the Democratic Republic of Congo with a tuberculosis incidence of 323 cases per year per 100,000 inhabitants and a high number of undetected cases every year. This case illustrates that a good clinical examination, knowledge on the epidemiological background, and basic laboratory technology may allow diagnosis and successful treatment even without modern technologies such as polymerase chain reaction and magnetic resonance imaging/computed tomography scan in resource-limited settings.

PMC3261802_01

Female

The patient in this study was a 39-year-old Chinese woman who presented with a painful right breast lump on April 5, 2008. She had a history of schizophrenia for over 20 years and had been receiving risperidone (2 mg bid) for more than 3 years. She had developed a lump in her right breast a month before her visit and had noted a progressive worsening tenderness with erythematous changes around the lesion. She had no systemic symptoms nor did she have any known previous fungus or tuberculosis exposure. The patient had a gestational history of G0P0 and had amenorrhea for approximately a year. She had no history of any other breast disease or receiving any breast surgery, and her medical history was otherwise unremarkable. She had never consumed tobacco, alcohol, oral contraceptive pills nor did she have any family history of breast cancer. On physical examination, a 9-cm x 6-cm breast lump with localized redness over the right breast lateral aspect with an ill-defined margin was noted with no palpable lymphadenopathy at the axilla. There was no splenomegaly or hepatomegaly. She did not have fever, joint pain, airway or urinary tract bleeding. No other skin lesion was found. The patient's blood count was normal. Breast ultrasound images revealed a large ill-defined area with heterogeneous echoes in the right upper and lower outer quadrants, associated with increased vascularity. Micro-calcification and tissue edema were noted. No enlarged lymph node was noted in the right axilla, and there was no dilatation of the lactiferous duct. CXR didn't show any lung lesions. Mammography showed asymmetry with increasing radiodensity at the outer upper quadrant of the right breast with nipple retraction. Mastitis with edema and micro-abscess in the right upper and lower quadrants was suspected. However, inflammatory carcinoma could not be ruled out. All other laboratory and other radiological studies including C-reactive protein (0.8 mg/L) were normal except that the prolactin level was 84.5 ng/ml (normal, < 20 ng/ml); FSH, 4.6 mIU/ml; and LH, 6.0 mIU/ml. Although malignancy had not been excluded, the patient received a presumptive diagnosis of infectious mastitis and was treated with a 14-day course of keflex (first-generation cephalosporin), but there was no improvement. Therefore, core breast biopsy was performed, which revealed an adipose tissue with acute and chronic inflammation. Aspiration culture showed no evidence of bacterial or mycobacterial growth. In order to rule out previously missed diagnosis, another incision biopsy was performed 1 week later, and the pathology showed chronic inflammation with focal fibrotic changes in the fat tissues. Due to persistent drainage with erythematous swelling and in consideration of malignancy, the patient then was scheduled for simple mastectomy. Macroscopic appearance demonstrated a huge mass with an ill-defined margin of inflammatory tissue at the center with peripheral fatty necrosis and hematoma (Figure 1). Microscopic examination revealed chronic inflammation and macrophage, giant histiocyte, and epithelioid-like cellular infiltration, with cytologic features suggestive of a granulomatous process. The noncaseous granulomatous lesions were centered at the breast lobules. The lesions were characteristic with an empty space in the center and surrounded by microgranulomas and microabscesses. Some granulomatous lesions composed of confluent epithelioid cells and huge abscess were also seen (Figure 2A, B). Based on the histological features, the differential diagnosis included autoimmune response, undetected organisms, systemic granulomatous disease with breast involvement, granulomatous reaction in a carcinoma and foreign body reaction. There was no evidence of carcinoma or specific organism can be found. All cultures, Ziehl-Neelsen staining, PAS staining and GMS staining yielded negative results. Considering the patient's clinical history and all the laboratory findings, the diagnosis was interpreted as IGM. In suspect of the dopaminergic effect of risperidone to cause hyperprolactinemia and IGM, the prescription was shifted to prolactin-sparing second line agent (clozapine). The residual breast lesions resolved completely 3 months later and no recurrence was noted since then.

PMC6159233_01

Female

A 74-year-old female was referred to the respiratory clinic with incidental finding of a pulmonary nodule on chest X-ray. She did not have any other respiratory symptoms. She was a non-smoker throughout her life and had no exposure to asbestos or tuberculosis. Her past medical history was significant only for chronic lymphoedema and recent hip replacement. Subsequently , CT thorax was performed, which confirmed a 1.2 cm pulmonary nodule in the posterior segment of the left upper lobe. There was no cavitation or calcification and no discrete nodules were present in the remaining lung parenchyma. There was no mediastinal or hilar lymphadenopathy (Figure 1). On positron emission tomography scan, the pulmonary nodule was found to be non-avid (Figure 2). Her pulmonary function tests were normal with a normal gas transfer. She was also investigated for any underlying plasma cell dyscrasias to rule out nodular amyloid deposit: no evidence was found to support it as her serum and urinary electrophoresis was negative with normal immunoglobulin levels. Biopsy of the lesion was not feasible either by bronchoscopy or by CT-guided lung biopsy. The patient underwent wedge resection as she was keen to have a definitive diagnosis and did not want to have serial imaging as part of pulmonary nodule surveillance. Microscopy of the fluid sample from the wedge biopsy showed scanty lymphocytes. No pathogenic microorganisms were found. Mycobacterial and fungal cultures were also negative. Histology showed abundant eosinophilic material with scattered giant cell reaction. No necrosis or epithelioid granulomatous inflammation was seen. Lamellar fibrosis was evident (Figure 3). Masson's stain confirmed hyaline lamellar fibrosis whereas Congo red stain for amyloidosis was negative (Figures 4 and 5). These features are consistent with the diagnosis of PHG.

PMC3507022_01

Male

The patient was a 39-year-old man who was referred to our hospital because of headache, cough, and hemoptysis. The patient is a known case of WG for 2.5 years. His other complains were fever and chills. Dark bloody nasal discharge was also mentioned. Headache was localized on frontal and maxillary sinuses. It was permanent and not related to light and noise. In the frontal region, a pulsatile fashion was described. No exacerbating factor was mentioned. We found no nausea or vomiting history during those days. Firstly, there were bloody streams in sputum; however it changed to apparent hemoptysis in a few days. It occurred two times and was estimated about 200 cc each time. He had no previous history of smoking, addiction, any specific allergy, hypertention, diabetes mellitus, or hyperlipidemia. He afflicted a chronic anemia and admitted for pneumonia last year. Vaccination seems to be complete. No history of tuberculosis or any similar problem in the first-degree relatives had been recorded before. He received cyclophosphamide (100 mg BID), methyl prednisolone (50 mg QID), ceftriaxon (1 g BID), and azithromycine (250 mg per day). Two units of packed cells were administered after his last episode of hemoptysis. During his stay, he was conscious and obey, a little pale, and had mild coughing without any toxicity. He complained of blurred vision in eyes, nasal stiffness, rhinorrhagi, hearing loss, hematuria, perspiration, artheralgia in wrist and foot. On the examination of neck mobile, not firm, elastic lymph nodes was palpable. He had a saddle nose and septal perforation with many dark crusts was obvious in nasal examination. There was redness in his right eye. Vision and pupil reflex were normal; ophthalmologic examination revealed no ophthamologic involvement. In chest examination crackles in the upper part of lungs, and generalized expiratory wheezing was heard. Other physical examination revealed no abnormal findings. Spiral-computed tomography (CT) with contrast from the chest revealed multiple cavitary lesions with alveolar infiltration. In coronal sinus CT scan, a bilateral mucosal thickening in frontal, sphenoidal, ethmoidal, and maxillary sinuses was present. Bony erosion of the medial wall of both maxillary sinuses and nasal septum was seen [Figure 1]. His laboratory data contained WBC: 12000 (NEUT: 79%); hemoglobine: 9.1; urine sediment: RBC+, WBC+, WBC cast, granuler cast; C-ANCA was positive(1/40). As the patient had complained of hearing loss, a pure tone audiometry was done that showed left conductive hearing loss (40 db, air bone gap). A biopsy of the nasal septum with culture of crusts was done by the otolaryngologist. Nasal examination revealed necrotic materials [Figure 2]. The specimen was ready in 1 week; during this time the patient became ill, altered mental status, and drowsy. Pathology and culture revealed a necrotic material with nonseptated fungal hyphae, consistent with mucormycosis [Figures 3a and b], so amphotricine was administered immediately and an endoscopic sinus surgery (ESS) was done to accomplish the diagnosis and treatment. Massive necrotic fungal debris in his maxillary and ethmoid sinuses was brought out completely. The Eustachian tube was eroded in the left side (that justified his unilateral conductive hearing loss). Immediately after clinical and pathologic establishment of diagnosis of mucormycosis, prednisolone was tapered and administration of cyclophosphamide was stopped. On the other hand, intravenous immune globulin (IVIG) was started (2.5 g for 5 days). Besides, he was also taken vancomycine (500 mg BID), amphotricine (30 mg per day), tab coterimoxazole, tab acid folic, and atrovent spray. His cough and headache became better. The patient's mental status improved, and he did not remind any visits or surgery in 2 weeks before. He experienced a second sinus examination by endoscopic sinus surgery. He had complete remission of his fungal infection. Six-week administration of amphotericine was accomplished. At the time of discharge he complained of mild bilateral blurred vision and left conductive hearing loss.

immunoglobulins, intravenous, mucormycosis, paranasal sinuses, wegener granulomatosis

PMC4899931_01

Male

A 22-year-old male sustained blunt trauma to his anterior chest/sternum while playing recreational American football. He complained of persistent sternal pain, worse with deep inspiration and elevation of the left upper extremity against resistance, despite five days of rest and over-the-counter nonsteroidal anti-inflammatory medication. Radiographs of the bilateral SC joints (AP, bilateral obliques) obtained four weeks following the injury were negative (not shown). Selected images from an MRI of the SC joints obtained seven days after injury are shown in Fig. 1, A-D. Based on the imaging findings, a diagnosis of complete rhomboid ligament avulsion was proposed. The patient was placed in an upper-extremity sling, including a contralateral "figure of 8" harness for six weeks; physical therapy was gradually instituted beginning at four weeks of immobilization. Eighteen months following the original injury, the patient is asymptomatic and has complete range of motion of the left upper extremity.

ct, computed tomography, mri, magnetic resonance imaging, sc, sternoclavicular

PMC8202395_01

Male

A 50-year-old male patient was referred to our hospital, with a 4-month history of neck pain and gradually progressive weakness of all four limbs. Over the past 2 weeks, the patient noticed significant deterioration and became bed bound. The patient denies any previous history of trauma, malignancy, or medical history of note. Clinical examination revealed spastic quadriparesis of 3/5 with 80% decreased sensation of all modalities below C5. Sphincters were found to be intact. Plain X-ray cervical spine on anterior-posterior (AP) view showed a large lucent lesion replacing the C5 vertebra with loss of the left pedicle [Figure 1a]. The magnetic resonance imaging (MRI) of the cervical spine demonstrated a T1 and T2 isointense, expansile mass lesion involving the C5 vertebral body extending into the left pedicle but sparing neural foramina. On T2, small hyperintense intralesional cavity was noted in the anterior part. The lesion extended across the C5/6 intervertebral disc and into the anteroinferior part of the C4 vertebra. Significant cord compression with absent thecal sac against C5 was noted. The lesion enhanced homogeneously with gadolinium and appeared completely extradural [Figure 1b-d]. Based on imaging, metastasis, myeloma, and tuberculous granuloma were suspected. The patient underwent standard anterior cervical decompression and fixation. Peroperatively, tumor appeared as a well-encapsulated, firm, multinodular mass, yellow tan in color, 3 cm x 3 cm x 2 cm in size. There was a small necrotic part corresponding to the T2 hyperintensity. The lesion was excised in piecemeal fashion [Figure 2a] to completely decompress the cord. No clue of bone was found within the mass. At this point, differential was further narrowed to granulomatous lesion like tuberculosis. Histology revealed sheets of histiocytes with foamy cytoplasm and bland nuclei. Focal cholesterol clefts and multinucleated giant cells were also noticed. There was no cellular atypia. CD68 was positive and S100 was found to be negative [Figure 2b and c]. The serum calcium was normal, and lipid profile showed normolipemia. Clinical examination did not reveal any soft-tissue xanthomas. The patient was able to return to his normal activities 4 weeks after the operation. Postoperative imaging as per routine following anterior decompression and fixation consisted of plain X-ray cervical spine AP and lateral views [Figure 3a and b]. Postoperative computed tomography (CT) of the same area was planned at the 6-month follow-up both to see the integrity of fixation as well as to rule out the tumor recurrence, but the patient was not able to reach out for imaging because of pandemic restrictions. Currently, he is 1 year out of his surgery, with no reported complaint as per telephonic follow-up.

adult, bone xanthoma, cervical, lytic, spine

PMC6732605_01

Male

A 5-year old boy is presented by his parents to Pediatric Surgery Emergency of the Hospital Escuela Universitario (HEU) in Tegucigalpa, Honduras; with a 8-day history of pain in his right testicle, with sudden onset, continuous, intense enough to prevent him from wandering around, denying trauma backgrounds, followed by an increase of the volume with same amount of time; vomiting preceded by nausea, 3-day vomiting evolution with 4 daily episodes of alimentary content; concomitantly, 4-day history of high fever, without a timetable predominance, attenuated with acetaminophen. Physical examination of genitals showed an augmentation in size of the right testicle in comparison with the left one, inflammatory changes, tenderness, positive Prehn sign, bilateral cremasteric reflex present. Blood count showed leukocytosis with eosinophilia (Table 1). Sonogram reported a testicle of 1.8x1.0x1.1 cm, volume of 1.07 mL, with alteration on its axis and hypoecogenic areas with irregular appearance, no sign of abstraction of discharge to color Doppler, nor power Doppler; showed diffuse enlargement of the epididymis, edema and inflammatory changes on the scrotal bag; no hydrocele nor pyocele. Left testicle with normal size and form. The treatment was a right simple orchiectomy, finding necrosis of the testicle and pyocele. The biopsy showed a reddish-purple aspect and soft consistency testicle, followed by the spermatic cord, with macroscopic outbreaks of necrosis and softening zones. Histologic studies revealed the presence of a worm inside the testicular artery (Figure 1), surrounded by granulomatous inflammation with abundant eosinophils, testicular parenchyma showed wide discharges of hemorrhagic necrosis, eggs were not identified. Medical discharge was given 24 hours later with successful progress. Patient presented to the Pediatric Surgical Emergency department 10 days after his last admission with a 7-day history of not having bowel movements, treated with 2 enemas without stimulating defecation; also 5-day evolution abdominal pain, located in the epigastrium, irradiated to the right iliac fossa, intense, attenuated with ibuprofen, 4-day history of fever, subjectively high, predominant at night. 3-day vomiting history with 4 daily episodes of dietary content. During physical examination, abdomen was bloated with no umbilical scar deviation, to auscultation bowel sounds were absent, to percussion timpanums was confirmed, abdominal girth was 53 cm with tenderness and pain were located at the lower right quadrant, Blumberg and Rovsing signs were positive, no visceromegaly nor abdominal masses were found. Complete blood count presented increased WBC with eosinophilia (Table 1). A laparoscopic appendicectomy was performed finding inflammatory changes in cecal appendix with small pinpoint marks in terminal ileum, caecum and appendix. The cecal appendix biopsy reported secondary eosinophilical appendicitis infection by A. costaricensis, secondary vascular occlusion and coagulative necrosis subsequently. Cecal appendix showed similar changes to the testicle, with worm in the arteriolar lumen, A. costaricensis eggs were found in capillaries, stroma and cecal appendix wall.

PMC5379782_01

Male

A 32-year-old gentleman was referred for left frontal brain lesion for further management. He presented with headache, giddiness, and blurring of vision at left eye for the past 2 months. All symptoms progressively worsened over time. He has no other known medical illnesses nor complained of anything else. There is no significant family history of tuberculosis (TB) exposure or malignancy. History of smoker about 15 pack years, not alcoholic and denies other social issues. He has neither drug allergies nor drug adverse effects during his stay in the ward. On examination, his Glasgow Coma Scale (GCS) was full. He is orientated to time, place, and person. Vital signs were stable throughout admission. No palpable lymph nodes were observed. There were unremarkable cardiovascular, respiratory, neurological, and gastrointestinal system findings. Fundoscopy reveals left eye papilloedema. Karnofsky performance status (KPS) is 80% in which patient is able to perform normal activity with some difficulty due to symptoms such as headache, giddiness, and blurring of vision. Metastasis was made as one of the differential diagnosis from the computed tomography (CT) brain findings. Screening was done by means of CT thorax-abdomen-pelvis for distant metastases and lung lesions were found. Bronchoscopy revealed abnormal lower tracheal mucosa and right hilar-carina region appears widened. Biopsy result was not suggestive as there is no diagnostic material received. He also later complained of left sided upper thigh pain radiating to the front and we noted left gluteal mass from which biopsy was taken and the result is mesenchymal tumor suggestive of alveolar soft part sarcoma. Patient was operated due to a good life expectancy as the left frontal brain lesion was solitary. Craniotomy with complete excision of tumor was done in December 2011. Intra-operative findings were vascularized tumor with a mix of solid-cystic-friable lesion and total excision was done. Results of diagnostic imaging are as below: Noted multiple hypodense lesions (cannon ball lesions) and huge radio opaque lesion at mediastinum [Figure 1]. Left frontal lobe mass with significant mass effect and small lesion at occipital lobe [Figure 2]. Right lower lobe lung mass (7.5 x 8 cm) extending to mediastinum, multiple lung metastases, normal CT abdomen and pelvis. Left gluteus mass is probably metastasis. T4 N2 M1, Stage IV Carcinoma. Conclusion made as advanced carcinoma of the right lower lobe with multiple lung metastases and left gluteal metastasis [Figure 3]. Results of histopathological examination are as below: No diagnostic material or inadequate for interpretation. Mesenchymal tumor suggestive of alveolar soft part sarcoma [Figure 4]. Features are compatible with metastatic tumor, request to correlate with gluteus mass biopsy result [Figure 5]. He is asymptomatic at his next review but repeated scan shows multiple new brain lesions in just 2 months post operative period. He is planned for palliative chemotherapy due to high recurrence rate and multi-systemic involvement. Left frontal lesion, right occipital lesion, right parietal lesion, and midline intraventricular lesion. Features show local spread to the surrounding brain tissue [Figure 6].

alveolar soft part sarcoma, brain metastases, central nervous system neoplasm, combined therapy, tumor recurrence

PMC5829423_01

Female

Clinical samples were collected from 514 total patients, of which 207 (40%) tested positive by ZIKV rRT-PCR or ZIKV IgM or both. Nine samples tested positive by both tests. Testing sera from 480 patients resulted in 107 positives for ZIKV by rRT-PCR and 109 positives for ZIKV IgM. Of the 102 urine samples, 12 tested positive for ZIKV by rRT-PCR. The one CSF sample tested negative by rRT-PCR. Table 1 summarizes the spatial and temporal occurrences of reported cases, the number of symptomatic and asymptomatic cases, the number of positive and negative cases for each parish and for the country. Also shown is the number of Guillain-Barre syndrome (GBS) cases identified by the Grenada Ministry of Health. The parishes on the main island are listed in decreasing order of population size with the neighboring island of Carriacou listed last. The parish population data are based on the 2011 Grenada Census data. The outbreak began in the last week of April in St. Andrew Parish when a 28-year-old female tested positive for ZIKV by rRT-PCR. Her reported symptoms included rash, fever, headache, joint pain, body pain, lymphadenopathy, nausea or vomiting, and diarrhea. This patient is considered the index case for the country. To make relative comparisons among geographic areas across the country, an indicated attack rate was calculated for each parish as the proportion of positive samples collected from a parish scaled to the size of the parish. With a population of 25,722 people and 36 positive cases, St. Andrew Parish had an indicated attack rate of 14 cases of ZIKV infection per 10,000 people. Of the 36 positive cases, 18 were rRT-PCR positive and 18 were ZIKV IgM positive. The positive cases collected in St. Andrew Parish were 17% of the total ZIKV-positive cases identified in this study. St. Mark Parish, in the northwest of the country, was the next to report its first case, during the week of May 8. St. Mark Parish has a population of 4,086 with 12 positive cases reported, of which eight tested rRT-PCR positive and four tested ZIKV IgM positive, giving an indicated attack rate of 29 positive cases per 10,000 in the population. St. Mark Parish had 6% of the ZIKV-positive cases identified in this study. St. George Parish, in the southwest, with a population of 36,823, was the next to report its first case in late May. With 117 positive cases of which 66 were rRT-PCR positive and 51 were ZIKV IgM positive, St. George Parish had an indicated attack rate of 32 per 10,000 people in the population. St. George Parish had 57% of the ZIKV-positive cases identified in this study. With the highest population density in the country, St. George Parish was also the focus of infection during the outbreaks of DENV in 2001-2002 and CHIKV in 2014. After St. George Parish, three other parishes reported their first cases within two weeks of each other: St. Patrick Parish in the week of June 5, St. David Parish in the week of June 12, and St. John Parish in the week of June 26. These three parishes combined had 16% of the total positive cases identified in this study. Carriacou, located northeast off the coast of St. Patrick Parish, and accessible only by a ferry or plane, was the last parish to have its first diagnosed case of ZIKV, which was reported during the week of July 3. Carriacou had only 4% of the total positive cases identified in this study. The countrywide-indicated attack rate during the outbreak was 20 per 10,000 people with peak transmission occurring in the week of June 26 with 26 cases, of which 21 were rRT-PCR positive and 5 were ZIKV IgM positive. The reported date of symptom onset was used as the week of indicated infection. When the symptom onset date was not available, the date of sample collection was used as a conservative infection date. Figure 1 shows the spatial distribution of all ZIKV-positive cases with the highest concentration in St. George Parish in the southernmost area, which is the most urban area. Figure 2 presents graphically the temporal distribution of ZIKV-positive cases during the outbreak by week. The rRT-PCR-positive cases are shown in dark blue and the ZIKV IgM-positive cases are shown in light blue with the GBS-positive cases identified by the Grenada Ministry of Health shown in green. The ZIKV vector, A. aegypti, is known to be an endophagic urban dweller that clusters around population centers. In past outbreaks in Grenada of other arboviruses carried by the same mosquito species, specifically the DENV (2001-2002) and CHIKV (2014) outbreaks, cases tended to cluster in population centers. This was observed again during the ZIKV (2016) outbreak. St. George Parish, which is the most densely populated parish with 36% of Grenada's population, had 57% of the positive cases identified in this study. St. Andrew Parish with 25% of the population had 17% of the reported positive cases. St. Mark Parish and St. George Parish, despite having, respectively, the lowest and highest populations, had the highest indicated attack rates. It is reasonable to conjecture that this could be because these parishes had early cases of the disease, and thus, there was ample time for the virus to circulate within their immunologically naive populations.

PMC3872324_01

Female

"A" was a 35-year-old female, admitted to the unit with severe TBI following a road traffic accident 10 months previously, who had undergone bi-lateral frontal craniotomies to reduce cranial swelling. Both her SMART and MATADOC assessments gave a diagnosis of VS. Medication adjustments, spiking temperatures, and general poor arousal levels were thought to be impacting on her response levels. The experimental session took place during this assessment period, i.e., when arousal was reduced. "A" displayed a range of behaviors suggestive of discriminatory responses in relation to LM, EI, and WN. In relation to EEG, significant post hoc peaks for LM and EI were observed for temporal, frontal, central, parietal, and occipital regions across bandwidths. Figure 6 illustrates the theta and alpha EEG responses for each stimuli in the R temporal region, highlighting the dominance of EI in theta, and LM in alpha. Furthermore Figure 7 highlights the marked significant increase in frontal beta for LM, which contributed to a significant theta:beta ratio [F(4, 356) = 47.0, p < 0.001] with a marked decrease for LM [F(1, 89) = 133.8, p < 0.001]. "A" had her eyes open with no body movement throughout the session. Interestingly, she displayed eye movement only for LM and WN with significantly more counts for LM (48 compared to 38, t-test p = 0.001). Her HR ANOVA showed marked significant change [F(4, 36) = 1373, p < 0.001] due to the striking increases for mean HR for LM (91 BPM, SD: 2) and WN (86 BPM, SD: 1.2) compared to BLS (68 BMP, SD: 0.69), DM (67 BPM, SD: 1), and EI (65 BPM, SD: 0.9). HRV (RMSSD) also showed significant change [F(4, 36) = 101.2, p < 0.001] due to decreases for LM [F(1, 9) = 141.2, p < 0.001] and WN [F(1, 9) = 154.4, p < 0.001]. LF and HF change was also significant [LF: F(4, 36) = 11, p = 0.012, HF: F(4, 36) = 11.8, p < 0.001] accounted for by increases in LF for LM [F(1, 9) = 9.8, p = 0.012] and WN [F(1, 9) = 23.8, p = 0.001] and decreases in HF for all stimuli compared to BLS. In summary, "A" displayed significant behavioral responses LM, autonomic responses for LM and WN, and EEG amplitude increases in the R temporal and frontal regions across bandwidths for both music therapy stimuli.

eeg, assessment, brain injury, diagnosis, disorders of consciousness, minimally conscious state, music therapy, vegetative state

PMC9712176_01

Female

A 5-month-old female infant was admitted to the First Affiliated Hospital of Shantou University Medical College due to recurring fever and productive cough for 2 weeks unresponsive to cephalosporin and penicillin in a local hospital. She was born full-term with a weight of 2.7 kg (3 < P < 10). BCG vaccine, routinely administered at birth in China, was given at 2 months of age because of meconium aspiration pneumonia after birth. She had been hospitalized locally for 7 days for generalized small papules and pustules at 4 months and recovered gradually after supportive treatment. No tuberculosis contact was noted. Her non-consanguineous parents and only older brother were all healthy. There was no family history of similar or genetic diseases. Her total white blood cell count, neutrophil count percentage, and C-reactive protein were apparently elevated along with a low to normal lymphocyte count; chest radiograph showed bilateral infiltrations (thymus shadow not mentioned) before her current admission. On physical examination, her weight was 5.2 kg (<P1). Several enlarged axillary lymph nodes were palpable bilaterally. Her oral mucosa was intact. Coarse breath sounds and rhonchi were audible bilaterally. Throat swab was positive for parainfluenza virus (PIV) and respiratory syncytial virus (RSV) by PCR assays, while routine cerebrospinal fluid analysis/culture and blood HIV testing were all negative. Chest CT revealed bilateral parenchymal and interstitial infiltrations, multiple enlarged lymph nodes in the mediastinum and right axilla, and hypoplasia of the thymus. The patient was treated sequentially with intravenous ceftriaxone, piperacillin/tazobactam, and vancomycin, but her symptoms were not relieved. From her blood samples, the sequences of M. tuberculosis and P. jirovecii were mapped through next-generation sequencing. Acid-fast bacilli were found in the concentrated smears of the sputum aspirate and gastric aspirate; M. tuberculosis and P. jirovecii were not isolated after culturing. The subtypes of M. tuberculosis failed to be identified prior to antituberculosis therapy. To clarify the source of tuberculosis infection, her older brother, parents, and grandparents underwent chest X-ray examinations and purified protein derivative (PPD) skin tests, which were all negative. In addition, low numbers of T cells and natural killer (NK) cells and increased B lymphocytes from lymphocyte subset analyses confirmed T-B+NK- immunodeficiency ( Table 1 ). Subsequent gene sequencing identified two heterozygous missense mutations in the Janus homology 7 (JH7) domain of the JAK3 gene of the patient, each inherited from her parents ( Figure 1 ). The paternal mutation C.301A>G at nucleotide 301 encoded by exon 3 changed amino acid 101 from arginine to glycine (i.e., p.Arg101Gly), and the maternal mutation C.331G>A at nucleotide 331 encoded by exon 4 altered amino acid 111 from glycine to arginine (i.e., p.Gly111Arg). These two mutations were predicted to be pathogenic by Sorting intolerant from tolerant (SIFT) (both <0.05, deleterious), PolyPhen2_HVAR (paternal: 0.997, maternal: 0.992; both probably damaging), PolyPhen2_HDIV (both >0.957, probably damaging), and Rare exome variant ensemble learner (REVEL) (paternal: 0.809, maternal: 0.655; both pathogenic). Consequently, her treatment strategy was switched to rifampicin, isoniazid, and ethambutol for tuberculosis, intravenous immunoglobulin to enhance immune functions, and further trimethoprim/sulfamethoxazole for PJP, after which improvements in symptoms (cough and fever) and lab results (e.g., decreased serum lactate dehydrogenase) were noted. After being hospitalized for 28 days, the patient improved but was discharged upon request of her parents who were satisfied with the timely diagnosis and treatment. During our follow-up, the patient continued antituberculosis treatment routinely at the assigned local tuberculosis prevention clinic and died without hematopoietic stem cell transplantation (HSCT) or autopsy at 13 months of age mainly because of severe infections in addition to hepatic injury (autopsy is culturally unacceptable and therefore uncommon in China). Her other laboratory results are shown in Table 1 . Written informed consent for laboratory examinations and submission/publications of this work was obtained from her parents. This study was approved by the Ethics Committee of the First Affiliated Hospital of Shantou University Medical College.

jak3 deficiency, mycobacterium tuberculosis, pneumocystis jirovecii, case report, severe combined immunodeficiency

PMC7555605_01

Female

A 53-year-old female was referred to our department with complaints of a slight dry cough and enlarged pulmonary nodules [computed tomography (CT) value: 15 Hounsfield units (HU)] with slight peripheral enhancement, which were under close monitoring after cytoreductive surgery for a BOT. Seven years prior, she had suffered from progressive abdominal distention. Abdominal contrast-enhanced CT (Figures 1A,B) and a thorough check-up revealed a giant pelvic-abdominal cyst with an uneven density (7 HU) with peripheral and internal septal enhancement. The giant cyst extended from the pelvic cavity to the level of right renal pelvis, measuring 20 x 40 cm, with ascites. Meanwhile, chest CT showed multiple bilateral cystic nodules without obvious enhancement (Figures 2A-C). The patient's serum carbohydrate antigen 125 (CA-125) and CA-19-9 levels were increased to 69.15 U/ml (0-35 U/ml) and 369.4 U/ml (0-37 U/ml), respectively. Other serum tumor markers [carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), neuron-specific enolase (NSE), and cytokeratin 19 fragments] were within normal ranges. For final diagnosis of the mass in the abdomen, exploratory laparotomy was planned. Before laparotomy, to determine the nature of the nodules in the lungs and the detailed staging of the mass, the patient underwent percutaneous biopsy, and the histopathological results indicated only fibrosis and degeneration of the lung tissue but no evidence of metastasis from the ovary. Repeated percutaneous biopsy for another nodule was performed to avoid a missed diagnosis of metastasis, and the histopathology confirmed the previous results showing clear cystic fluid but not metastasis. Subsequent laparotomy revealed a cystic mass with a smooth surface and an intact capsule on the right ovary and ascites. Intraoperative frozen section revealed an ovarian mucinous borderline cystadenoma (MBOT). Exfoliative cytological examination revealed no evidence of implantation in the ascites. Thus, staging surgery (bilateral salpingo-oophorectomy (BSO), hysterectomy, appendectomy with omentectomy, and the adjacent lymphadenectomy including para-aortic lymph nodes, and pelvic lymph nodes) was performed. The final pathology confirmed the diagnosis of ovarian mucinous borderline cystadenoma, intestinal type, with the intestinal epithelium rich in goblet cells and the stratification of cells showing light to moderate atypia in a papillary structure (Figures 1C,D) with no involvement of the left ovary, omentum, and bilateral adjacent lymph nodes. Thus, the FIGO stage at diagnosis was incomplete stage due to the obscure diagnosis of the lung nodules. After resection of the tumor, the serum CA-125 and CA-19-9 levels of the patient declined to normal values of 27.5 and 18.09 U/ml, respectively, which is consistent with the reported correlation between preoperative CA-125 levels and increasing FIGO stages of BOTs. Then, the patient was followed closely for the pulmonary nodules on CT scans (Figures 2D-F) and for possible asymptomatic recurrence of the BOT and malignant transformation arising from the BOT. During the following 7 years, CA-125 was within the normal range after the risk-reducing cytoreductive surgery, and the size and morphology of the pulmonary nodules were stable. For this admission in our department at the end of the seventh year during the monitoring of the disease, the patient presented with cough and clear sputum without hemoptysis or any other symptoms. Chest CT showed a new irregular nodule at the dorsal segment of the right inferior lobe, and a cavity was observed in the largest original pulmonary nodule (Figures 2G-O). The patient's serum CA-125 and CEA levels were elevated to 68.9 and 66.50 U/mL (normal range 0 ~6 U/ml), respectively. Abdominal CT scan revealed no obvious abnormality or ascites. Thus, transbronchial lung biopsy (TBLB) targeting the new consolidation was performed. The histopathology result indicated papillary mucinous adenocarcinoma, while immunostaining suggested malignant transformation arising from the BOT [Cytokeratin(CK)(+), P63(-), CK5/6(-), Napsin-A(-), Transcription Factor-1(TTF-1)(-), Cluster of Differentiation(CD)56(-), Ki-67(15%), CA-125(focal+), Estrogen receptor (ER)(-), paired box gene 8(PAX8)(-), CK7(+), CK20(-), Caudal type homeobox transcription Factor 2(CDX2)(-), and P16(-)] (Figures 3A-F). Breast cancer susceptibility gene (BRCA) mutation was not observed in the tissue of the lung biopsy. After four cycles of chemotherapy [AUC (area under the curve): 5 mg/ml/min of carboplatin and 65 mg/m2 of docetaxel per cycle] with 3-week intervals were completed, the pulmonary solid metastasis progressed with the development of pleural effusion and pleura thickening (Figures 2P-R). Ultrasonic-guided transcutaneous pleural biopsy revealed metastatic adenocarcinoma (Figures 3G-J). The patient passed away 4 months later.

borderline ovarian tumor, metastasis, pleural biopsy, pulmonary cystic nodules, transbronchial lung biopsy

PMC4573412_01

Female

A 48-year-old multiparous woman (with four normal vaginal deliveries and one cesarean section) was referred to the gynecology clinic because of enlarged myomatous uterus and persistent heavy vaginal bleeding. She underwent a subtotal hysterectomy and unilateral salpingo-oophorectomy in a hospital in Yazd (Iran). Intraoperatively severe bleeding occurred and dense cervical adhesions to peripheral tissues were found. Pathology report indicated benign leiomyoma. After a few months, an abdomino-pelvic CT scan was performed because of flank pain that revealed bilateral hydronephrosis. The patient was referred to the Gynecology Oncology clinic of Bahman hospital in Tehran. Pelvic and rectovaginal exam and colposcopy were performed. Biopsy report was negative, after which mycobacterium tuberculosis test showed negative results. Under general anesthesia, multiple deep cervical biopsies revealed no malignancy again. The slides were reviewed by another "referral" pathologist who reported atypical lymphoid infiltration, consistent with malignant lymphoproliferative disorder, in parametrial biopsies (Figs. 1). Immunohistochemistry confirmed the diagnosis. The stony appearance of the cervix and a concomitant frozen pelvis strongly supported the diagnosis of cervical malignancy.

biopsy, cervix, lymphoma, malignancy

PMC8535441_01

Male

A 55-year-old man was diagnosed with stomach lymphoblastic lymphoma at the IB stage (Ann Arbor staging system) 2 years ago. He received six cycles of standard-dose R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone). Positron emission tomography-computed tomography (PET-CT) scan showed multiple mass with elevated metabolic activity in the cervical and peritoneal cavities, right clavicula fossa, mediastinal region. Bilateral renal tumor invasion was also detected (Deauville score 5). Progressive disease was considered and rebiopsy of the renal mass was performed. Pathology indicated relapse of the primary disease. The patient then received three cycles of R-IMED/DHAP (rituximab, ifosfamide, methotrexate, etoposide,dexamethasone, cytarabine, and cisplatin) therapy. Posttreatment PET-CT reanalysis suggested partial remission as the metabolic activity of the stomach was significantly repressed (Deauville score 1). The patient had previous history of HBV infection, and blood test on initial admission indicated positive results for HBsAg, antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B e antigen (anti-HBe), while the serum HBV DNA level was undetectable. His results for human immunodeficiency virus (HIV) and anti-hepatitis C virus (HCV) antibody detection were negative. As for his liver function, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were within the normal range, and no abnormal ultrasound findings were identified suggesting chronic hepatitis. On admission to our clinical center, the patient was required to receive anti-HBV prophylactic treatment with entecavir (0.5 mg/day) during his entire treatment. Lymphoma of the patient progressed after multiline chemotherapy. In order to control his present conditions, we selected CAR-T cocktail therapy with anti-CD19 and anti-CD22 CAR T-cell infusion. The patient was enrolled in our trial and agreed to receive CAR-T treatment. Informed consent was provided by the patient. Peripheral blood mononuclear cells (PBMCs) were harvested and CAR T cells were constructed and cultured for 14 days by Bio-Rad Corporation (Hercules, CA, USA). Then, standardized FC (fludarabine and cyclophosphamide) regimen was conducted for lymphodepletion (25 mg/m2 fludarabine and 20 mg/kg cyclophosphamide on days -4 to -2). Sequential infusion strategy was planned as follows: anti-CD19 CAR-T infusion 2 x 106/kg on days 1 and 3 and anti-CD22 CAR-T infusion 2 x 106/kg on days 0 and 2. The patient gradually developed cytokine release syndrome (grade 1), with peak ferritin level of 952.1 mug/L and interleukin-6 (IL-6) level of 118.50 pg/ml ( Figures 2A-C ). Lentiviral copy surveillance conducted with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) suggested that CAR T-cell expansion reached a maximum point +9 days post-infusion (copy numbers for CD19 27297 and CD22 6212) ( Figure 2D ). Although this patient continuously received entecavir (0.5 mg, q.d.) antiviral treatment, he suffered from vomiting and stomach discomfort +11 days post-CAR-T infusion. The liver function assay indicated elevated ALT and AST levels, combined with increased levels of total bilirubin (TBIL) and direct bilirubin (DBIL) ( Figure 2E ). After exclusion of other potential causes of acute liver injury, we examined his HBV DNA copy level, and the results indicated that HBV reactivation was highly possible (+16 days HBV DNA, 2.58 x 102) ( Figure 2E ). Therefore, we quickly implemented combinatory rescuing anti-HBV treatment with entecavir and tenofovir. Reexamination suggested that the patient's HBV DNA and abnormal liver function recovered on +24 days.

car t, antiviral therapy, hepatitis b virus, lymphoma, reactivation

PMC8535441_02

Female

A 46-year old woman was diagnosed with diffuse large B-cell lymphoma 6 months ago (stage IIB). The MRI scan indicated that the lymphoma invaded her liver, pancreas, stomach, and right kidney. She received one cycle of R-CHOP, three cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, oncovin, cyclophosphamide, and hydroxydaunorubicin), one cycle of large-dose methotrexate (MTX), and one cycle of R-DHAP plus Bruton's tyrosine kinase (BTK) inhibitor chemotherapy. Posttreatment evaluation indicated that the remaining tumor (13 mm x 10 mm) resided in her lower common bile duct. This patient had previous history of HBV infection and took entecavir treatment before chemotherapy initiation. On her first admission into our center, serum test indicated that she had positive results of HBsAg, anti-HBe, and anti-HBc. The results for hepatitis C virus (HCV) and HIV antibodies were negative. Her HBV DNA level was undetectable. Her initial liver function test result was quite abnormal as serum AST was 121 U/L and ALT was 190 U/L. Her TBIL level reached 223.9 mumol/L, and the DBIL level was 212.1 mumol/L. We then performed magnetic resonance cholangiopancreatography (MRCP), and the results demonstrated tumor nodule localizing in the lower common bile duct, with notable dilation of the bile duct and pancreatic duct. As her tumor caused serious obstruction, percutaneous transhepatic cholangial drainage (PTCD) was conducted and her liver function quickly recovered. Because the patient had suffered rapid progression of lymphoma and obstructive jaundice during chemotherapy, chemotherapy resistance was considered. In order to control her pancreatic tumor progression, we performed CAR-T cocktail therapy with anti-CD19 and anti-CD22 CAR-T therapy. Her CAR-T culturing and lymphodepletion chemotherapy were the same as those of case 1. Sequential infusion strategy was planned as follows: anti-CD19 CAR-T infusion 2 x 106/kg on days 1 and 5 and anti-CD22 CAR-T infusion 2 x 106/kg on days 0 and 2. The patient developed mild nausea, vomiting, and fever post-infusion, with peak ferritin level of 2,583 mug/L and IL-6 level of 197.7 pg/ml ( Figures 2A-C ). Lentiviral copy surveillance conducted using qRT-PCR suggested that CAR T-cell expansion reached a maximum point +10 days post-infusion (copy numbers for CD19 6541 and CD22 3602) ( Figure 2D ). Her liver function remained steady under entecavir treatment until +14 days post-CAR-T infusion. Blood test on +14 days indicated elevated ALT (53 U/L)/AST (66 U/L), with mild elevations of TBIL (22.5 mumol/L) and DBIL (20.7 mumol/L) ( Figure 2E ). After ruling out possibilities of obstruction of the PTCD tube and a retest of HBV copy (+14 days, 2.25 x 102 IU/ml) ( Figure 2E ), reactivation of HBV was suspected. We quickly implemented combinatory rescuing anti-HBV treatment with entecavir and tenofovir. As a result, her HBV DNA copy and her AST/ALT levels returned to normal at +21 days.

car t, antiviral therapy, hepatitis b virus, lymphoma, reactivation

PMC2800004_01

Female

The patient is 62-yr-old woman with skin changes which started 3 yr ago with diffuse erythematous, slightly infiltrated plaques on her trunk and extremities, with no clear borders, associated with moderate pruritus. Because she had been suffered from hypothyroidosis for 20 yr, at the first dermatological examination, she was misdiagnosed and her skin changes were thought to be in relation with the endocrine disorder. First, she was treated with topical potent corticosteroids (Betametasone valerate 0.1%, triamcinolone acetonide 0.1%, fluocinonide 0.05%), in 1 to 2 weeks repeated courses, over five months, without effect. In next six months her skin changes became more extensive, erythrodermic with scaling and showed tendency for generalization, and then her diagnosis was erythroderma, also thought to be secondary to her hypothyreoidism. Pruritus was persistently present and intensive. In that time, she began with systemic corticosteroid therapy in medium doses (40 mg/day of prednisone). In first month of therapy her skin changes improved, and erythema and pruritus became less intensive, but every time with reduction of dose of steroids, she had an exacerbacion. Sistemic corticosteroid therapy lasted almost one year with pauses and with doses between 20 and 40 mg of prednisone daily. Biopsy specimens were taken several times, but on microscopic examination there were only signs of nonspecific inflammation. Suddenly, she came to a hospital with widespread skin eruptions which had developed during previous few weeks. Examination showed generalized erythema and scaling of the whole body and face with large hyperkeratotic plaques on her trunk and limbs and crusted lesions on her scalp and external ears (Fig. 1, 2). Also, she had fever and raised body temperature. Laboratory examination showed an elevated sedimentation rate (46 mm) and leukocgtosis with eosinophilia (1.3x109/L). The haematologic (urea, creatinine, hepatic enzimes, glukose level) and urine analyses were normal. Pruritus was very intensive, so she could not sleep. At this time crusted scabies was suspected and microscopical examination of scrapings from the hyperkeratotic lesions from trunk (we did not examined tips of fingers and toes) showed numerous mites and eggs (Fig. 3). In that time we did not perform biopsy, because we made diagnosis. She was treated first with 1% lindane (one application, left on skin 24 hr) with remarkable improvement. After treatment no live mites were found on microscopic examination, but after three days we repeated antiscabiotic treatment first with 25% benzyl benzoat and then with 10% precipitated sulphur ointment (for three consecutive days). At the follow up controls after one, three and six months she had no signs of skin disease. Maybe the reason of these serious infection is that patient lives in poor hygiene and socioeconomic conditions, she lives alone,without any human care. We have not data about affected neighbors. There had been outbreak of scabies among the staff (2 doctors, 5 nurses), and 14 patients who were in clinic in the same time.

diagnosis, sarcoptes scabiei, therapy

PMC4901839_01

Male

A 4-year-old boy was brought to the Emergency Department (ED) from a rural area with complaints of fever, headache, and weight loss. He was suffering from these symptoms for the past 4 months, which had worsened in the past week. His brother informed that the child had been unwell since infancy with several episodes of respiratory infection and has had several hospital admissions. Recently, he had started complaining of severe persistent diffuse headaches along with nausea, vomiting, and anorexia. He also suffered from low grade fever intermittently over this period of time. Physicians in his locality who had treated him with antibiotic courses for chest infections started him on antituberculosis (ATT) drugs 2 months back after an MRI, which suggested meningeal enhancement and small ring enhancing lesions. He had no history of seizures or loss of consciousness. One of his brother had passed away at the age of 8 years who was considered to suffer from disseminated tuberculosis. On examination, the child was listless, emaciated, and extremely irritable. He had left-sided weakness in both the upper and lower extremities. An urgent computed tomography (CT) scan of the head showed multiple rings enhancing the left parietooccipital region, with significant surrounding edema and mass effect [Figure 1a]. His white blood cell count was 17900/uL, with neutrophils 77.4% and lymphocytes 15.7%. Hemoglobin was 10.9 and erythrocyte sedimentation rate (ESR) was 88 mm/h. We involved pediatric physicians and infectious disease specialists to perform a neuronavigation-guided craniotomy for the excision of these abscesses along with the walls, which contained thick purulent material. Microscopic examination revealed granulomas with fugal hyphae [Figure 2a and b]. Presence of Aspergillus was further confirmed on culture. Postoperatively, he was successfully extubated and shifted to the intensive care unit for postoperative monitoring. His weakness also improved. Considering his chronic cough and repeated chest infections, we obtained a tracheal aspirate for examination, which was positive for Mycobacterium tuberculosis polymerase chain reaction assay. Considering the history, we screened the child for immune deficiency disorders. Nitroblue-tetrazolium (NBT) was found to be negative, which established the diagnosis of CGD. Intravenous (IV) voriconazole was commenced at 6 mg/kg/dose every 12 h for 2-3 days, which was later switched to 6 mg/kg/day orally. Five-drug ATT treatment was restarted for the management of pulmonary TB. He was also given broad-spectrum antibiotics. Pneumococcal and meningococcal vaccines were administered as prophylaxis, and co-trimoxazole was included in the regimen for the prevention of pneumocystis carinii pneumonia. The child showed slow improvement, however, the treatment course was complicated by fever, seizures, and hyponatremia. Repeat CT scans did not show residual or recurrent abscesses [Figure 1b]. After stabilization of the medical condition, he was discharged. About 10 days after discharge, his family brought him to the ED with complaints of drowsiness. CT scan showed hydrocephalus [Figure 1c]. A temporary cerebrospinal fluid (CSF) diversion was performed, followed by a ventriculoperitoneal shunt once the CSF culture was reported negative. The child was again discharged after stabilization. He died 4 months later at home in respiratory distress. The child could not be brought to us, and hence no autopsy was performed to determine the actual cause of his death.

cerebral abscess, chronic granulomatous disease, tuberculosis

PMC9186469_03

Female

Twin A displays asynchrony in attention, behavior, and motor tonus, and her behavior lacks any coherent build-up of arousal or anticipation (Figure 2). The attempt at play with Twin A lacks structured phrases or a narrative arc - it is not a game at all. Twin A's behavioral style does not promote or modulate, in her father, the typical impulse to engage with graceful rhythmicity. Already (remember the twins are only 11 months old, way in advance of diagnosis, with the parents retrospectively reporting no concerns) the father has tacitly and completely adapted his interaction style. Wanting, naturally, to make his daughter happy, the father has dropped all attempts at social build-up with Twin A reverting, instead, to frequent moments of purely physical stimulation (the "monster belly blow"). Sadly, this natural adaptation will likely perpetuate asynchrony and asocial behavior in Twin A as she develops. The father, like many parents and practitioners, needed encouragement and therapeutic tools with which to tailor specialized attempts to connect with his daughter with autism. Support for social timing should facilitate perceptual discrimination, timing, and contiguity of sensory input (for instance, reducing audio "noise" and latency). It should facilitate the temporal integration of multimodal information for just-ahead-in-time motor planning, and the just-ahead-in-time prediction of an other's communicative acts. It should facilitate the rhythm and phrasing of play. It should facilitate alignment of the movement/sound patterns of client and practitioner into good enough synchrony. Co-regulatory SMS should include a wide range of synchronous experience and involve a variety of narrative arcs in which partners travel together through different types and levels of arousal and back to calm. Social timing and reciprocity are by no means seamless in TD infant interaction. Playful partners flow in and out of levels of synchrony. Sometimes partners share Simultaneity15, (traveling alongside each other, directly in-sync), experiencing concurrent occurrences of specific behaviors in parent and child, such as the co-occurrence of social gaze, vocalizing together, the matching of arousal level, or the coordination of parent affectionate touch with infant social gaze. Sometimes partners share Complementarity (the behavior of one partner complimenting the other's in timing and quality, while relating to the same pulse). In complementarity, behaviors often coalesce into repetitive "configurations", creating early rhythmic structures with inherent temporal expectations; expectations which can then be challenged and extended in playful teasing-around-timing (e.g., peepbo" vs. "pee....p-bo!" vs. "pe-ee........p-bo!"). This is particularly a feature of more sophisticated (bidirectional) mutual synchrony whereby each partner shares a more influential role. Such playful reciprocal "double-take" of expectations, during preverbal play with, and without objects, may facilitate appreciation of the "double meanings" required for symbolic play. Sometimes, partners are out of sync. found that infants regularly experience interactive miscoordination, yet mismatch is typically repaired close-on-instantaneously (review:). "This constant oscillation between momentary miscoordination and interactive repair marks the essence of human dialogue, to which infants are sensitized in their earliest interactions" (, p. 341) It is, in part, through the developing ability to recover synchrony when it goes off track, that TD infants may learn robust, flexible socio-communicative skills. For people with Autism(Therapeutic Needs), of course, the initial priority is enabling good-enough synchrony and helping to repair it where needed. People with Autism(Therapeutic Needs) experience pervasive sensory disruption and fracturing. When this experience is acute, most often accompanied by heightened arousal levels, interaction is unfeasible. As practitioners we can help with a structured environment: minimal and consistent across all sessions; clean; low light levels; low levels of ambient sound; minimize smells; private (no disturbances); unconditional opportunities for time-out and rest. Long-term consistency of practitioner is also essential. A period of acclimatization may be a crucial precursor to potential playful interaction. In this period, practitioners should prioritize client-led sensitivity; sensitively mirroring while adding nothing; maintaining low levels of arousal; observing the client's needs, including the need for short-duration engagement, time-out and rest. As practitioners, we can be sensitive to when trust and simplicity become established - and feel carefully for those moments when our tentative input becomes feasible rather than damaging. helped children with autism gain improved fine motor control of their hand movements. They used a co-adaptive child-computer interface (visuo-spatial and auditory) to augment each child's spontaneous movement experience and substitute corrupted kinesthetic information. The aim was to give existing heterogenous movement patterns a chance, seeing these patterns as meaningful adaptations with personal momentum and rhythmicity. The study (and the trust) worked. "... This new concept demonstrates that individuals with autism do have spontaneous sensory-motor adaptive capabilities. When led to their self-discovery, these patterns of spontaneous behavioral variability (SBV) morph into more predictive and reliable intentional actions. These can unlock and enhance exploratory behavior and autonomy in the individual with autism." Infants with Autism(Therapeutic Needs) often appear to channel the potential momentum of social engagement into interactions with the non-human environment. Disconnected from interaction, the infant's rhythmicity often appears in loops of repetitive behavior: movements and/or sounds [often referred to colloquially as "stimming" ]; relational patterns; or configurations of object-play. The loop is a self-completing pattern, with impulse and energy within either the beat pattern of repetitive movement or sound, or the discrete behavioral steps in a section of object-play. Each beat/step is essential to the pulse of the loop, to its momentum and sense of completeness. If present, we, as practitioner, can piggy-back on that pulse. If looping regularity is not apparent, we can find ways of integrating a pulse and moving from there. In musical experience16, the presence of a beat enables the perception of rhythm and compels movement. Why is this? Pre-motor organization engages a network of cortical regions [pre-motor cortex, supplementary motor area (SMA), and pre-SMA], which loop information via critical subcortical bodies (including the basal ganglia, brainstem and cerebellum), and route information through the IPL. The SMA, basal ganglia, and the cerebellum comprise an, "extended cortico-subcortico-cortical functional network providing specific timing and entrainment sensitivities" (, p. 156), in the processing of auditory rhythm - the beat perception/generation network. Biological oscillators in these respective regions provide overlapping yet different time-signature ranges, and therefore differing functions, which complement each other in the full creation of rhythmic experience. This beat perception/generation network shares significant structural and functional overlap with the pre-motor organization network. Oscillatory function within the pre-SMA, the SMA, and the basal ganglia in particular is integral to both beat generation and pre-motor organization. The basal ganglia and the pre-SMA/SMA are richly connected through striato-thalamo-cortical loops and are involved in the prospective timing of future movements. "A role for the basal ganglia and SMAs in beat induction is consistent with their involvement in motor prediction (the spontaneous response to hearing a beat is often to move at the time when the next beat is predicted)" (, p. 902). The potential for beat-based SMS facilitation relies, of course, on intact beat-perception. Across simple and complex meter conditions, pre-SMA, basal ganglia, and cerebellar dysfunction in autism appears to be functionally specific, leaving beat-perception largely intact. The anatomically and functionally specific nature of basal ganglia dysfunction in particular may likely allow for a window of beat-based support. presented moments of potential prediction error (when a sound occurred earlier than expected in a regular series) to individuals with ASD (recruited via a multi-level assessment to factor out possible confounding variables; 6-21 years.). As discussed in section "Prediction, social timing, individual motor planning, and social motor synchrony in early autism," hypersensitivities, sensorimotor "noise," relative latency, and disrupted multimodal integration all have the potential to set people apart in time and disable just-ahead-in-time prediction. In section "Autism and Auditory-Temporal Processing" in particular, we outlined the case for predictive delay and/or asynchrony in autism in response to isolated sonic events. However, when presented within simple or complex rhythms, prediction error was completely absent - no difference was found in ERP response patterns between individuals with ASD and neurotypical controls. Importantly here, our concept of rhythm is information-rich; full of temporal and non-temporal cues (potentially multimodal) to guide participants to on and off-beat moments in time, intention, and action. This is crucially different from the clinical tick-tock of the metronome. A meta-analysis of "tapping studies" (), included six studies which examine unilateral (simple) movement response patterns17 (i.e., basic tapping) as a synchronization response to "auditory stimuli". All but one of these, result in ASD subjects performing worse at synchronization than TD controls (as expected, see sections "Autism and Synchrony" and "Autism and Auditory-Temporal Processing"). One study,, was exceptional - demonstrating no significant difference between ASD and TD performance, and concluding non-verbal rhythm synchronization is intact for children with ASD. On examination, all of the preceding five studies presented auditory stimuli as a "paced beat" (a straight tick-tock generated by computer or metronome). presented audio recordings of woodblock rhythms (complex, medium, and simple meters). We suggest this stand-out feature, in relation to the stand-out result, is not coincidence. explored the impact of dyadic drum playing on children with HFA, concluding that the presence of rhythmic cueing and sensitive tempo adjustment correlated with improved measures of social skills. Recruiting this information-rich rhythmical interaction as an intervention over time, facilitated synchrony between children with ASD and neurotypical partners. After the intervention, participants showed decreased asynchrony when tapping with a partner at adjusted tempi, and showed greater engagement in joint attention and action. developed a synchrony training program in which children with ASD were shown a progression of meaningless arm movements, with associated melodic/rhythmic scaffolding, and were asked to imitate the movements. Over 6 weeks, the children improved across increasingly difficult task variants in measures of synchrony and imitation (ibid.). demonstrated that, over 8 weeks, children with ASD benefited from a rhythm-based movement intervention, displaying improvements in body coordination, imitation/praxis, and interactive synchrony. In a study designed to compare music versus non-music interventions, ASD groups were assessed before and after on measures of social communication and resting-state functional connectivity of fronto-temporal brain networks. Over 8 - 12 weeks the music intervention group (where improvisational approaches, involving song and rhythmic scaffolding, were used to target social communication and sensorimotor integration) scored significantly higher on a measure of pragmatic communication (P = 0.01). Significantly (P < 0.00001), post-intervention resting-state brain connectivity was lower between auditory and visual regions in the music compared to the non-music groups, showing a reduction in disruptive over-connectivity (known to be prevalent in autism, ibid.; + see). The human ASR is a neurophysiologically fast and direct response to certain sudden, unexpected auditory stimuli. ASR latency - the time from presentation of the startling stimulus until neural response - provides an index of neural processing speed. As discussed in section "Autism and Auditory-Temporal Processing," individuals with autism demonstrate prolonged unmodulated ASR latency as compared with age-matched TD controls (though without controls for LD, *). Understanding the conditions which modulate latency is important for us here as, if we can minimize relative TD-autism latency difference, we can improve alignment for synchrony. When startle stimuli were presented with pre-stimulation and/or with habituation18, latency differences and auditory hypersensitivities (shown via ASR amplitude) became non-significant (ibid.). Clearly, predictive information - through context and familiarity - matters. Rhythmic Relating will build on the pulse inherent in the client's movement, sound, or object-play and augment it with clarifying qualities and tailored multimodal cues. This client-centered rhythm will provide a flow of predictive information and compelling pulse - clarifying the practitioner's communication and providing a framework to facilitate sensory contiguity, discernment, prediction and just-ahead-in-time planning. Recently an innovative computational approach to the automatic categorization of music (X-System) has proved successful in predicting emotional, arousal, and mood responses to music. Certain specific psychoacoustic qualities produce extremely direct, evolutionarily pertinent responses in humans. These include ASR-stimuli and acoustic activation contours. have used the term brain stem turbulence to describe these sounds, with reference to the degree to which these sounds constantly change in ways which activate and move us. The ASR operates along a pathway leading directly from the cochlea, along cranial (auditory) nerve VIII by way of the lateral lemniscus, to the caudate reticular nucleus. From here, there are descending projections to spinal and limb motor neurons, provoking the "jump" or "blink" effect. Acoustic activation contours are evolutionarily significant sounds indicative of the positioning and movement of the human body in space and time (from sudden approach, to slowly moving away). This may extend from separation cries, or the hissing of snakes, to rapidly approaching sounds, glides, falling, fast crescendos, bursts of sound and the like. It is very likely that these sounds are recognized by innate systems early in auditory pathways (; re: the Inferior Colliculus,). There is clear evidence of these pathways ascending to emotional systems, as well as a descending, emotional "feedback" pathway from the amygdala. Music plays with the use of turbulence, specifically taking the "dangerous" edge of activation and, through context, timing, and expectation, leveraging that energy for joy, wonderment, and anticipation. Moments of relative acoustic startle can provide defining beats and turning points. Acoustic activation contours can, individually, stimulate changes in mood and energy, and, used as repeating rhythmical structures, they can define the mood of extended moments or of a whole piece of music. Turbulence compels response through movement. Turbulence is neurophysiologically direct vitality communicated instantaneously via sound. Sensitive use of turbulence may provide people with autism with a palette of sounds which represents their most-direct audio experience (relatively decreased latency and increased signal-to-noise ratio). This sensitive use will include tailored multimodal experiences, time given for familiarity and habituation, and modulated volume within an information-rich rhythm. Most clients with Autism(Therapeutic Needs) will find loudness intolerable (stimuli > 80 dB - which is akin to shouting, twice as loud as conversation), and some may be hypersensitive to particularly high-pitched sounds at normal-to-mid-range volumes. For many clients then, we could start quietly, experimenting with relative acoustic startle and low-volume acoustic activation contours. As such, we may be able to use turbulent rhythmic structures (accents and contours) to add guiding information and energized pulse into interaction with a client with Autism(Therapeutic Needs). Turbulence may also help us share emotion, mood modulation, and co-regulation. Akin to its use in music, when turbulence is presented sensitively within interactive social rhythms (defined by structure, predictability and safety - i.e., the absence of threat) the mobilization (fight/flight) potential of turbulence is likely to become the stuff of joy, anticipation, and play. Here, we introduce the concept of a tonescape: a "landscape" of interactive possibilities, spanning a wide range of modulated turbulence and synchrony; a landscape full with a variety of co-regulatory narrative arcs, leading partners in and out of varying levels of arousal and emotional tone. The tonescape can bring opportunities for small-step co-regulation and layered SI. The range of modulated turbulence in the tonescape, reaches from the poignance of peace shared, to the wonderment of subtle variation (playful, fluid, unexpected, an emotional "hide-n-seek"), to the raw joyous anticipation of "peek-a-boo." Activation contours are short expressions of quality which stimulate an (inter)active state change. They are single events, often multimodal, communicating vectors of intention in movement and sound, containing "...the felt experience of force... with a temporal contour and a sense of aliveness, of going somewhere" (, p. 3). Activation contours can be the building blocks of a developing game - shared experiences in repetition or combination. They can be tools for the embodied reflection of vitality. They can be recruited as stand-alone events, promoting interest and motivation if things feel stuck. And they can also be integral to rhythmic synchrony scaffolding (see later) as up-beat guides to an on-beat shared moment. Activation contours come in a huge variety and subtlety of types. Here we describe seven of them - possibly the most prevalent in interaction19, and those which we have found most useful to consider in practice: Up-Swish - an upwards inflection guiding toward a moment in time, space, expressed energy, and emotional tone. Down-Swoosh - a downwards inflection guiding toward a moment in time, space, expressed energy, and emotional tone. Stretch - a consciously elongated up-swish or down-swoosh. Burst - an instantaneous, exploding energy often in an outward, interactive vector. Quick-fade - the opposite of the burst, an instantaneous imploding, withdrawing vector. Waver - a wavering vector in either an up-swish, down-swoosh, or an even plane. Pulse - a pulsing vector in in either an up-swish, down-swoosh, or an even plane. Activation contours can be expressed in any sensory modality or combination of modalities. When envisioning combination possibilities, we have found the following constructs useful (some single-, some multi-modality): Volume - volume change (including silence). Proximity - positional change (relative to the other player). Embodiment - whole-body, postural change. Intensity - change in the level of energy invested. Pitch - audio pitch change. Timbre - vocal emotional-tone change. The "Monster belly blow" game (section "What Does Disrupted Bidirectional Social-Motor-Synchrony Look Like in Play?") involved the father using a rising vocal inflection (Up-swish in volume, pitch, timbre) whilst looming in toward his daughter (Up-swish in: proximity), then a falling vocal inflection (Down-swoosh in volume, pitch, timbre) whilst looming away (Down-swoosh in proximity), and the "Belly blow" (Burst in volume, intensity, and timbre). Other examples are, an energetic star jump (Burst in embodiment and intensity), pulling a client along a smooth floor, cradled in a blanket, with a sideways waggle [Stretch (with interspersed Waver) in proximity, embodiment, intensity] bouncing with a client on a trampoline [Pulse (vestibular) in intensity, embodiment]. Here we introduce the concept of Rhythmic Synchrony Scaffolding: the use of rhythm (in any modality or combination) to match, accent, cue, augment, and develop the client's pulse in movement and sound. Within music, beats can be easy to perceive, very difficult to perceive, or overtly non-existent. For us, a lock-on beat (useful in scaffolding rhythmic experience) is one that maximizes the properties which promote perceptual ease. These properties can be temporal or non-temporal. The temporal properties of a rhythm can induce the spontaneous feeling of a beat. For a lock-on beat, it is helpful to keep a regular pattern with a simple meter, i.e., one with short duration intervals, and simple integer ratios. Simple meter patterns, as opposed to complex ones, have been shown to improve synchronization dynamics. In western music tradition, all time signatures (or meters) are constructed in patterns of 2 and 3 s. Our simplest meters are: 2/4 [evenly accented; defined by a march; example, the Imperial March (Darth Vader theme) in Star Wars]; 3/4 (accented, strong-weak-weak, strong-weak-weak; exemplified by a waltz); 4/4 (accented, One-and-Two-and, One-and-Two-and; examples: the straight "money-beat" which opens Michael Jackson's Billie Jean, or defines Mozart's, "A Little Night Music" and Pachelbel's Canon in D major). In beat perception, the basal ganglia-cerebellum partnership displays different patterns of activation on attempted perception of simple or complex meters. Using a lock-on beat will engage the basal-ganglia/pre-motor-area relationship, as: "...functional connectivity between part of the basal ganglia (the putamen) and cortical motor areas (the pre-motor and SMA) is higher during perception of beat rhythms compared to non-beat rhythms" (, p. 35, italics added). Lock-on beats will also simplify cerebellar processing demands and limit the demands of beat generation on the basal ganglia. In rhythm tracking studies involving patients with brain lesions, "... for cerebellar patients... negative effects were... specific to the rhythm played at a fast tempo, which places high demands on the temporally precise encoding of events. In contrast, basal ganglia patients showed more heterogeneous responses at beat frequency specifically for the most complex rhythm, which requires more internal generation of the beat" (, p. 156, italics added). We can also simplify lock-on through choice of periodicity. Many potential rhythms have several levels of periodicity present. For example, in "twinkle, twinkle, little star," one can tap regularly to every syllable, every other syllable, or every fourth syllable, and still be synchronized to the music. Initially, we can choose to accent a well-spaced level of periodicity (for instance, the fourth syllable in the above example). The temporal accents present in certain rhythmic patterns can act as just-ahead-in-time guides, allowing players to land on a moment of emphasis. The feel of this is "the act of raising or lifting," followed by "setting down" - like lifting a foot before making a step then placing it down with precision. The raising acts as an upbeat, anticipating and guiding the on-beat. In prosody, this is well exemplified by the iambic pentameter with an even pulse: da-Daah, da-Daah, da-Daah, da-Daah... In music, the "da-" becomes the upbeat guide to the "Daah." In terms of non-temporal support, focal beats within a pattern can be accented with intensity accents. These are single beats, emphasized by a change of intensity in pitch, volume, and/or timbre. Intensity accents can make impacting use of relative acoustic startle. Activation contours, with their turbulent, directional energy, can help guide a player to the beat, with just-ahead-in-time advance warning. Guiding a movement toward an intended goal (moment in time; point in space; specific purpose) involves such motor prediction. TD individuals use perceptual force-time curves (with a felt sense of expected time-to-closure) to organize the effective use of force in actions, and to couple these actions with the actions of another. In an arm-extension (for example, in expressive gesture, reach-to-grasp, or tap-to-a-beat), the motor image is a force-time curve of energetic enervation: rising on initiation, increasing to reach, falling in expectation to land on point-of-contact, or body-space goal with intention-specific appropriate force. We are proposing that activation contours can serve as guides for perceptual-motor force-time curves, helping us land on beat and act in synchronous time-scales (e.g.,). have shown that children with HFA have difficulties in perceiving vitality-form differences between two contiguous stimuli (smallest change detected at >100 ms apart). This suggests that, "during action observation, children with ASD need greater stimuli variations than TD children to detect their differences in terms of vitality forms" (ibid. p8). We can support clarity in contiguity through clear isolated communicative acts. Children with autism can often recognize extreme vitality, while lacking distinction of the more nuanced vitality-forms characteristic of everyday interaction. Playful interaction gives us the platform to use big, distinct gestures when needed - to initiate and to clarify - and then to build toward sharing more nuanced actions. Any one vitality-form can be recognized via either visual or auditory expression. Indeed, have concluded, "...it may be plausible that visual information is not sufficient for children with ASD to encode vitality forms correctly and that the use of alternative (additional) perceptual information may help vitality form perception" (p. 8, italics added). Dependent on the client's level of language comprehension, we can support vitality recognition through explicit labeling of the other contextual intention-dimensions: goal and emotion. We can verbalize what we are doing and our goal; we can verbalize what the client is doing (using their name in third-person) and their goal, if apparent. We can verbalize our emotions; we can verbalize the client's gross emotional state (happy, sad, angry, excited), if apparent. A recent study by focuses on a bidirectional approach to motor dissimilarity in social contexts. Emphasized here, is the fact that TD adults demonstrate deficits in recognition of ASD vitality-forms even after information feedback. This bidirectional finding suggests that we should avoid our neurotypical-centric interpretations of vitality-forms and, until we have spent time tuning in to our client's expressions, we should begin with simple mirroring, observation, and trust-building. Using structural magnetic resonance imaging, *) found that neuroanatomical systems that process speech and song are more effectively engaged by song than by speech, for children with ASD. We can use a melodic "story-teller's" voice (light and playful variation in pitch, timbre, volume, overall mood tone - a conscious avoidance of monotone) and/or we can literally sing our communication. As is the case for short-interval parsing for ease of lock-on in beat perception, short spoken units support ease of rhythmic parsing in language comprehension. Whole utterances in a mother's baby-talk to very young infants tend to be short (about 0.5-0.75 s). They are typically repetitive and with rhythmic intonation and undulating pitch. The regular, simplified rhythms undoubtedly help the infant to synchronize (ibid.). As we sensitively move on from acclimatization, beginning to add elements to our client's rhythmic and sensory experience, we should do so only in small increments. We should add, remove, or adapt, just one layer at a time - Layering the Senses. We need to be careful to observe which, and how much sensory input the client can tolerate and engage with. As functional integration occurs, we can extend sensorimotor experience in small-steps, layering in and out of the client's thresholds of sensory vocabulary and tolerance. Piggy-backing on intact beat-perception pathways in autism, support for social timing should recruit tailored, information-rich rhythmic parameters to engage and clarify interactive pulse and relatable vitality. These lock-on parameters include beat specificity, periodicity, temporal and non-temporal accenting (including relative acoustic startle), and the use of activation contours (turbulent acoustic, and multimodal) as guides for perceptual-motor force-time curves. SMS support should facilitate good-enough synchrony as a basis for shared experience - enabling small-step co-regulation and a layered approach to sensorimotor integration. Initial and on-going environmental priorities should be acclimatization, simplicity, sameness, calm, short duration interaction, and rest. Interactive priorities should be: starting with the client's spontaneous movement, sound, or object-play20; isolating, accentuating, and simplifying initial focus behaviors; scaffolding with rhythm; leveraging movement (including touch) and sound in combination to maximize rhythmicity; leveraging acoustic turbulence to encourage movement-response and to simplify processing load; then extending co-regulatory experience and sensorimotor integration through small increments within a varied tonescape. We acknowledge the pervasive nature of timing and sensorimotor disturbance in autism. We are open to the possibility of rhythm-mediated SMS entrainment in interaction, yet expect that (as was found by) such support will take the form of temporary scaffolding. The aim here then, is to facilitate small-step co-regulation and sensorimotor integration within a zone of proximal synchrony. Rhythmic Relating offers a skill set21 that can be flexibly applied, as and when feels useful, when supporting playful interaction with a client with Autism(Therapeutic Needs). The skill set can be used independently, or in support of the play progression we present in Section "The rhythmic relating play progression: building games together (from movement, sound, or object-play)." The benchmark here is the essential quality of co-creating, and passing through experiences together - synchrony for its own sake. There are no interactive expectations, fixed rules for progression, tick lists or programs. Rhythmic Relating is about facilitating realistically short moments of playful synchrony whilst respecting overwhelm, and the need for rest and withdrawal. Phrases of playful interaction might be led by the client, sometimes the practitioner, often (and ideally) both in co-creation. In practice, the question of who is leading, is of far less significance than the sense of togetherness in synchrony. If the phrase is practitioner-led, then what is important is that the client is actively experiencing in relative synchrony. Or, if the phrase is client-led, then the practitioner should be actively following, ready to respond and develop. As practitioner, we can keep in mind this rule of thumb: follow-lead-follow. We follow the client's momentum, yet we feel free to take an initiating lead when it feels appropriate, then follow again when the client picks up the flow in response or lets us know that we have missed the mark - always careful not to coerce the client. Please refer to the overview of the Rhythmic Relating skill set (Figure 3). In what follows, we outline a series of reflective engagement skills which range from Selective Mirroring (Initial) (with close affiliation to simple imitation), through to a fully embodied, multimodal reflection of the client's vitality in Mirroring (Vitality). The range represents our small-step priorities: initial simplicity, low arousal, sameness, isolation and accentuation of one particular aspect of the client's movement/sound/object-play; then playful development; with extension of co-regulation and sensorimotor integration through sensitively layering the senses. In deciding which skill to use and when, it is important for the practitioner to act from a place of embodied observation, attempting to immerse themselves in how the client is experiencing and communicating. Isolated, simple mirroring may be perceived as a welcome simplicity, clarity, and validation to the client with Autism(Therapeutic Needs). Or it risks being perceived as judgmental and patronizing. We need to spend time attuning to find what is helpful, and always remain sensitive to adjusting, based on felt-sense feedback from the client's embodied communication. We isolate a selected aspect of the client's movement or sound to mirror. We might select a behavior, gestalt, or motif for its clear, repeating nature, or because it is marked by a noticeable emotion, mood tone, or level of arousal. We want to hone in on this behavior, bring awareness to it, accentuate its affective and expressive tone (we might exaggerate or diminish our reflection for emphasis), and minimize other elements of our behavior to allow this to stand out. Here we can use big distinct movements and/or clear amplified sounds as appropriate, later, progressing toward more nuance. When developing a game, we will need to be able to modify our interactive responses without losing connection with the client. While matching the overall quality of the client's behavior, we can play with modifying our mirrored movement or sound, one aspect at a time. Here are some aspects to consider. In movement22 : effort (pace, weight, fluidity); mood (emotional/energetic tone); structure (use of body as a whole vs. in parts; place of initiation of movement; placement/movement of limbs in relation to torso; upper-lower body relationship; left to right body relationship; contralateral body relationship; place of initiation of movement); space (proximity - near, mid, far reach; height level changes). In sound: volume (use of accents, crescendo vs. decrescendo); pitch (contours of sounds); timbre (breathy, soft, or vibrato voice or sound); form (musical motif or pattern); tempo (fast vs. slow and changes in between); articulation/length of sound (legato, staccato, tenuto). While maintaining the overall style, we can also play with either exaggerating or diminishing a mirrored aspect of the client's behavior. We use our kinesthetic empathy, all our observation skills, to feel our best-approximation of the whole-body/whole-sound vitality-form being communicated by the client in any one moment, in series, or in a repeating rhythm. Vitality-forms (including stillness and inaction); psychoacoustic dynamics (including silence); and/or extended patterns of vital quality, can be "mirrored" in various ways - the energy, shape or contour of vitality being re-communicated in essence. When we mirror vitality, we often use activation contours. We can match the energy and intensity of the client's behavior without imitating or overinvesting in the particular emotional tone. This enables a safe, congruent way to connect, without fueling negative emotional patterns. Vitality can be mirrored as: - An alternate expression within the same modality, for example: a client's slow, rhythmic hand clench-and-release matched by a whole-body contract-and-open; a client's anxious moan matched by mixed-pitch bubbling sounds (up-swish contour in pitch and volume, with a high level of turbulence, matching the energy contour but without replicating or fueling the anxiety); a client's violent jump matched by large body movements flowing from the core (matching the energy release without turning up the anger). - A cross-modal expression23 (matching with a different modality), for example: the arc of a client's arm movement matched by a down-swoosh contour in pitch and volume; the pulse of a client's vocalization matched by a foot tap; a client's sad vocalization matched with a sensitive whole-body folding; a client throws a pillow energetically at the wall, the arm movement matched in build-up by a playful vocalization (up-swish in pitch and volume) and then accompanied in the throw by a matching "whoooosh" (burst in pitch and volume). - A multimodal expression, for example: the client is energetically pushing a toy car back and forth, practitioner adds a swaying vocalization while swaying themself; the client is pouring sand from their hand into a sand-tray, practitioner adds a vocal activation contour (stretching down-swoosh in volume and timbre - full of granular turbulence) and strokes both hands down the client's arm. A sensitive mirroring progression (through selective mirroring (initial), and on to same modality, cross-modality, then multimodality mirroring (vitality), with playful selective mirroring (modified) along the way) is an important dimension of layering the senses. In conjunction with the layered use of rhythmic support skills, we suggest this progression represents a useful small-step approach to facilitating sensorimotor integration in playful interaction with clients with Autism(Therapeutic Needs). described how, in rhythmic/tonal grounding, the practitioner keeps a steady beat (simple meters - 2/4, 4/4, or 3/4 recommended) as a stable "anchor" for the client's expressions. This can be done by humming, singing, simple beatbox, repeating words, with a percussive "instrument" (drum, box, body, floor, soft shaker), or by playing a bass tone. In the early phase of interaction, this may provide a hyper-aroused client (for instance, anxious in a new situation) with a sense of rhythmical containment. Preferably, we will soon be able to pick up and match the pulse inherent in the client's current movement or sound, and our rhythmic grounding will morph into the practice of rhythmic synchrony scaffolding. Or, if we cannot find this pulse, we continue on with the possibility that our rhythmic grounding will become integrated into the client's behavior, adding pulse and regularizing heterogenous elements. The more complex the client's behavior, the less likely we will find that initial pulse - or at least, a pulse we can readily connect with via a regular beat. In this case, especially with loops of object-play, we suggest rhythmic grounding can bring a useful sense of containment and momentum and be a rhythmic foundation for other Rhythmic Relating skills (e.g., link in the loop and jazz gaps, see later). Rhythmic Synchrony Scaffolding (Initial) - is the use of rhythm (in any modality or combination) to match, accent, cue, augment, and develop the client's pulse in movement and sound. In rhythmic synchrony scaffolding we prioritize picking up and accenting the client's spontaneous pulse in movement, sound, or behavior patterns. We bring our expression into closer rhythmical alignment with that pulse. We make our behavior more obvious, describing intention with rhythmic accents, cues, and contours; describing what is to come, just-ahead-in-time. We may also bring clarity and energy to add to the existing pulse. Ideally, yet with sensitivity to the client's sensory preferences24, we will start with a simple modality combination25 : auditory pulse (humming, singing, simple beatbox, using percussive "instruments" [drum, box, body, floor, soft shaker], or playing a melodic instrument with percussive emphasis) and visual/movement pulse (repetitive movement from the practitioner, defined in space and proximity). We need, always, to be aware of our impact on the client. We need to start simply (and stay simple for as long as needed), to match and be led by changes in the client's interactive arousal levels, and not to push a sense of urgency or overwhelm with our added pulse. This is very much: follow-scaffold-follow. We can choose to accent a repeating aspect of the client's movement, sound, or object-play. We will use simple meters: 2/4, 4/4, or 3/4. We will choose a well-spaced periodicity for our accents. For instance, if a client is swaying left to right we could accent each sway (within a 3/4 meter); if a client is hand-flapping we could accent each fourth flap (within a 4/4 meter); if a client is repeating a spoken phrase we could accent the start, end, or a rhythmically significant mid-point of the phrase (within a 4/4 meter); if a client is walking around in a loop we could accent each second step (within a 2/4 meter); if a client is sliding on the floor, pushing a toy bear, we could accent each end-point of the slide (within a 4/4 meter). In selective mirroring we hone in on, accentuate, and bring awareness to a particular aspect of the client's movement or sound. In rhythmic synchrony scaffolding we could choose to accent that same aspect. We can improve our accenting with: - Temporal guiding information - the up-beat of, for instance, the iambic pentameter (remember, da-Dum, da-Dum, da-Dum, da-Dum - with the "da-" upbeat as guide). - Non-temporal guiding information - we can explore the use of relative acoustic startle for focal accents; tailoring our ground-zero-volume to each client's needs (often below average conversational volume i.e., <60 dB), employing the playful "shock" factor of immediate variation in pitch, volume, timbre; using drum-like bass tones; the hiss-factor of a high-hat-like-tone; the surprise of a higher-pitched machine-like pulse (e.g. a laser gun sound effect); "magical" pulses like bell and triangle tings. Here we can also bring in sound effects (animal noises, cartoon character refrains (Homer Simpson's "Doh!" as a perfect beat), machine and vehicle sounds, impressions) and focus words as accents. We can use activation contours as guides to direct the client toward on-beat timing and toward our accents. Perfect for turbulent activation contours are any sounds with lots of inherent movement: glides; crescendos (including "whhhooop"-like sounds); variations on playful hissing ("ssss," "ssshhh," blowing sounds); sounds with high levels of randomized internal movement (bubbling noises, raspberries, tongue wobbles); contoured spoken words (with movement in pitch, volume, timbre); contoured sound effects (cars vrroooom, animals squark, woof, growl - and if you can manage an elephant trumpet...!); and cartoon characters are literally designed for this, Scooby-doo's "Jshiiiicks! for example. Here are two examples. Firstly, using 4/4, with high-energy acoustic startle to accent the two and four: one and "POW" and three and "POW" and..., tiiiIIISSSSHHHH "POW," the contour uses a turbulent up-swish pattern rising in pitch, volume, and adding timbre, all guiding toward the "POW" accent. Secondly, using 3/4 with playful, fairy-tale acoustic startle to accent the strong beat with a magical "TIIING": TIIING te te, TIIING te te, TIIING... SSSHhhhh, TIIING, te, te, the contour uses turbulent down-swoosh, falling in pitch and volume, toward a whispery timbre, guiding intriguingly to the "TIIING" accent. We can experiment with sticking with the same patterning for some time, leveraging support from familiarity and habituation. Once we have established a scaffolding pattern in which our focal accent is a selected aspect of the client's behavior - for example, a vocalization - we could adjust the rhythm to bring our reflection of their vocalization into closer synchrony with our shared forward-moving pulse (and therefore, complementarity). This can function as rhythmic repair of rhythmic irregularity. This can also evolve into co-vocalizing, where we mirror elements of the client's vocalization, bring it into a rhythm, and make up "songs" (verbal or non-verbal) as a development. We have found the practice of co-vocalizing to be a useful step toward turn-taking. Our use of a link in the loop (see below) relies on establishing a shared rhythmic pulse (creating expectation and momentum) and then playfully "teasing" the client's expectation. More generally, this type of teasing-around-timing is a crucial early developmental ingredient when building and developing games (e.g., peepbo" vs. "pee....p-bo!" vs. "pe-ee........p-bo!"). As the richness of client-practitioner interaction develops, we may want to add layers of multimodality to our scaffolding (layering the senses). In addition to auditory and visual/movement pulse, this could include physical pulse (varying type, pressure and position of contact and touch), or facilitating proprioceptive and/or vestibular pulses for the client (through assisted movement - possibly using supportive equipment such as blankets, trampolines etc.). In our use of relative startle accents and activation contours we can add additional layers of multimodality and vary the range and tone of turbulence. We can play with modulating the tempo and volume of our scaffolding. To promote an orientation, or if things feel stuck, one option is to add an element to the loop. The aim is to do something with relevance to the client's movement, sound, or object-play, yet appropriately novel (the right level of different - noticeable, perhaps humorous, but similar enough not to jar). We repeat this simple action or sound with regularity, at the same point in a loop. If pitched and timed well, our action or sound can become part of the loop - an integrated link. We have become essential to the completion of the loop. Here are some examples: - With movement, client is running a circuit of the room, touching various points on the wall in a loop, practitioner adds rhythmic grounding and positions themself with their hand directly over one of these touch-points. - With sound, client is humming and swaying, practitioner adds rhythmic synchrony scaffolding and adds their own movement (an activation contour, quick-fade in embodiment, a whole-body withdrawing and shrinking small) every fourth bar of a 4/4 meter. - With object-play, client is sliding across the floor on their bottom, pushing a toy bear with their feet, practitioner adds rhythmic synchrony scaffolding and then creates a human-bridge (arched on all fours) for the client to pass through in their current trajectory. - With movement, client is rocking, practitioner adds rhythmic synchrony scaffolding and rocks in synchrony, then taps the client's right hand on every fourth rock. - With object-play, client is pushing a toy train around a track, practitioner adds rhythmic grounding and, each time the train passes the station, starts to chase the train with a toy car. The link can replace an accent or phrase within rhythmic grounding or within rhythmic synchrony scaffolding (with or without a preceding activation contour). Alternatively, without rhythmic support, we can use a stand-alone activation contour in the lead up to a link. Then, from there, we can facilitate an orientation from the client, by either withholding the link (a jazz gap - see below); or changing our action or sound (appropriate novelty). A jazz gap refers to a pregnant pause deliberately interjected into the rhythmic flow of communication. A jazz gap holds a silence longer than the natural on-beat demands. It has the energy of needing to be filled. A beat is expected, movement is compelled. We can play with the held duration of a jazz gap over a range up to around 6 s. If we push the duration much past this range, we lose the rhythmical impetus of the "here and now." "The current consensus in music psychology and cognitive neuroscience is that the ability to associate beats, or perform them meaningfully as a pulse, stops at around 6 s or 0.16 Hz... It is at this point that the mind and body can no longer "lock on" - either actively through playing, or passively through listening - to the rhythm as a pulse" (, pp. 18-19). We have not found studies which could provide equivalence for individuals with autism. As such, we will proceed with the tentative working assumption that the 6 s window is appropriate for the high-end of a sense of associated rhythm. Practically, it will be essential for the practitioner to retain their sense of the continued rhythm, and so the 6-s high-estimate remains entirely relevant to the therapeutic tool. We can use a jazz gap within rhythmic grounding or synchrony scaffolding. We simply replace an accent or short phrase. For example, in a straight 4/4 where the two and four are accented "TISH" sounds (employing relative acoustic startle): One and TISH and Three and TISH and One and [Jazz Gap...]. Or with the temporal accent of an iambic pentameter - da-Dum, da-Dum, da-Dum, da- [Jazz Gap...]. Or we can introduce a jazz gap within, or at the climax of an activation contour. For example, in a 3/4 swaying waltz: Dum, tuh, tuh, Click, tuh, tuh, Dum, tuh, tuh, Click, tuh, tuh, whooooaaahh...Click, tuh, tuh, Dum, tuh, tuh, Click, tuh, tuh, whooaaaah... [Jazz Gap]. We can also use a jazz gap to replace an established link in the loop (see above). Rhythmic Relating is about free-flow playful interaction. The play progression we describe, is a template which can be used flexibly. The progression may be useful in extending spontaneity toward experiences which facilitate co-regulation and SI. It may also provide a helping hand when things feel stuck. Please refer to the overview of the Rhythmic Relating Play Progression (in pictures) (Figure 4). Please refer to the overview of the Rhythmic Relating Play Progression (in words) (Figure 5). Applicable throughout - see Figure 3. See section "Acclimatization, Simplicity and Sameness". We ask ourselves, "what might it feel like to be experiencing this moment through the client's particular structuring of their movement, sound, stillness, and silence?" We aim to become sensitive to the pulse and quality of the client's behaviors. We try to tune into energy, effort, momentum, emotional color, potentially non-intuitive time-frames for response, and direction of focus. We are attempting to attune to possibilities of shared meaning that we might not initially recognize or understand. We start with the client's spontaneous movement, sound, or object-play. We attempt to connect with a particular aspect of their behavior - selective mirroring (initial) (section "Embodied Mirroring Skills" and Figure 3). If we are able to pick up on a repetitive, somewhat looping quality within the client's movement, sound, or object-play - use rhythmic synchrony scaffolding (initial) (section "Rhythmic Support Skills" and Figure 3). If not, we can use rhythmic grounding to add pulse (section "Rhythmic Support Skills" and Figure 3). In our rhythmic support, we should be led by the client's pulse and momentum where possible. If we are adding our own interpretation of pulse, we should be responsive to the possibility of rhythmic overwhelm (getting the momentum and mood wrong). If things feel stuck, we can wait and be with that uncertainty. There is often potential in space and patience. Or, as a possibility - use link in the loop (section "Orientating Skills" and Figure 5) and/or jazz gaps and activation contours (section "Orientating Skills" and Figure 5). In the Rhythmic Relating play progression, we have deliberately not defined a particular moment of initiation or specified an initiator. Instead, we are interested in the practitioner using the skill set, remaining sensitively open, and facilitating potential for bidirectional SMS. We consider the overt beginnings of an interactive phrase to be either, the point in which client/practitioner behavior shifts into closer alignment, or a moment of prosocial change in client behavior. Part of our practice is a continual tuning-in to possibly non-intuitive orientations from the client (Figure 6). We also recommend the highly powerful practice of reacting as if any orientation is an intentional initiation from the client. This practice is a safety-net, ensuring we don't miss opportunities, and also promotes positive feedback loops for learned interactive behavior. The simplest games tend to develop in a series of short phrases of playful interaction, each phrase building just a little on the previous, with the series tending toward a turning point (or peak) in a co-regulatory narrative arc (Figures 1, 4). Each phrase (Figure 7) starts with an orientation. Broadly, there are three possibilities at this point. The orientation itself could be a shift toward synchronous alignment, with the client's behavioral pulse somewhat locking into the attempts of rhythmic facilitation made by the practitioner. Then there are two possibilities that come from the use of activation contours and jazz gaps (within our rhythmic supports): the client may have been compelled to move, to do something new; or, if we have introduced a link in the loop, the client may pause as something specific is expected of us. As we are led into a shared period of developing synchrony, the type of orientation helps us respond and somewhat defines the terrain (the rough shape of the phrase to come: even, contoured, or pendulous): - An even phrase is marked by both partners traveling alongside each other, through an even pulse, in simultaneity (exactly in-sync): walking; jumping; rocking; blinking; sharing a regular sonic pulse; placing Lego bricks with regularity etc. After orientation and an extended moment of experiencing our even synchrony, we can pause and seek response (preferably), or respond ourselves through selective mirroring (modified) (section "Embodied Mirroring Skills" and Figure 3) and or rhythmic synchrony scaffolding (modified) (section "Rhythmic Support Skills" and Figure 3). Then, a further orientation, and the next iteration of the phrase. - A contoured phrase is one defined by an activation contour. Again, this experience is defined by simultaneity and traveling through the contour together. Either partner may be responsible for generating the activation contour, the other might be engaged in a relatively receptive fashion. What is important is that there is engagement and a sense of shared experience. After an extended moment of experiencing our contour together, we can pause for response. Contoured phrases tend to develop through increments of intensity and anticipation, tend to be repetitious in nature, building toward an overall crescendo peak (see section "What Does Disrupted Bidirectional Social-Motor-Synchrony Look Like in Play?"). The response, therefore, tends to be a subtle variation of "AGAIN"! However, there is also impact in occasionally breaking the expected rhythmic build-up through selective mirroring (modified) and/or rhythmic synchrony scaffolding (modified). - A pendulous phrase is one specifically defined by action, then response, in complementary synchrony within a shared time-frame - the simplest being the back and forth of turn-taking, the more complex being patterns of response delayed or staggered in time. We use a variation of imitation in movement or sound - selective mirroring (initial) - or a repetitious action in object-play (throwing a ball; sliding a soft toy; pressing a switch etc.) to develop a turn-taking dynamic. After an extended moment in this shared synchrony, we pause for response and the next phrase. We can develop the game with selective mirroring (modified) and/or rhythmic synchrony scaffolding (modified). We can facilitate sensorimotor integration, depth of relatable vitality, and a range of emotional and arousal experiences, all through our sensitive practice of layering the senses - mirroring (vitality) (section "Embodied Mirroring Skills" and Figure 3) and rhythmic synchrony scaffolding (extended) (section "Rhythmic Support Skills" and Figure 3). Over time, we explore a huge variety of co-regulatory narrative arcs (Figures 1, 4) across both simultaneity and complementarity in synchrony. Client and practitioner travel together in and out of the client's thresholds of emotional vocabulary, arousal, and tolerance. These co-regulatory arcs are like hills and mountains in the tonescape we travel through together (section "Recruiting Acoustic Brain-Stem Turbulence: Evolutionary Sounds That Move Us" and Figure 4). We co-create this tonescape, through cumulative experiences of turbulence, ranging widely from: - A sense of wonderment - light-footed variation in levels of turbulence in subtle playful combinations. Alternating between different types of activation contours. Moving across varying dimensions of quality. Finding a winding path to a turning point (peak) which could feel like a whispered moment of shared significance. - A building sense of raw joyous anticipation - high levels of turbulence. Sticking with the same phrase with similar activation contours, building the level of arousal incrementally. Moving forwards with increasing anticipation and momentum to a high-energy peak in release and usually laughter. - An increasing depth of shared peace - minimal yet playful turbulence. Just gently together. Moving toward a peak and extended conclusion in poignant silence. Please see the Examples in Practice (Figures 8-11) and Supplementary Material (Examples of Rhythmic Relating in Practice).

communicative musicality, rhythmic relating, autism, movement, sensorimotor integration, social timing, synchrony, therapy

PMC9218342_02

Female

An 83-year-old Chinese woman noticed a palpable mass in the left breast that had been there for 8 months. When the woman first came, there was a round mass about 3 cm in size in the inner upper quadrant and the outer upper quadrant of the left breast, without local pain, skin redness, swelling, ulceration, nipple bleeding, or discharge. She had histories of hypertension and diabetes for 7 years and was diagnosed with diabetic nephropathy, chronic kidney disease stage 4, and renal anemia for 3 months, and all the diseases were under treatment and control. She had no family history of tumor disease. Due to the patient's old age and multiple underlying diseases, no further treatment was performed. Eight months later, she felt a persistent dull pain in her breast for 10 days. The physical examination showed that the left breast was enlarged, and there was a firm, irregular mass, about 7 cm x 8 cm size in the left breast, with unclear boundaries and an acceptable range of motion without other changes in the breast. No mass was found in the right breast, and no enlarged lymph nodes were touched on the bilateral axillary and supraclavicular region. The laboratory tests showed that hemoglobin was 76 g/L, alkaline phosphatase was 554 U/L, and the serum tumor markers were all in a normal range. A calcified mass was found at the first examination of ultrasonography (US) and computed tomography (CT) plain scan and contrast enhancement of chest (Figure 1). The lesion was considered to be a degenerative fibroadenoma and was classified as a benign tumor according to Breast Imaging and Reporting Data System (BI-RADS) category 3. After 8 months, it was presumed to be highly malignant and graded as BI-RADS category 4C because of its rapid growth and more calcifications at the examination of US and CT plain scan and contrast enhancement of chest (Figure 1). Biopsy was performed according to the patient's preference, resulting in specimens showing to be a malignant phyllodes tumor of the breast with ossification or osteosarcoma. Then, 99mTc-MDP whole-body bone imaging was performed, and it showed that there was a mass-like abnormal radioactive concentration of Tc-99m outside the bone of the left chest, without other abnormal concentrations (Figure 2). Mastectomy and axillary lymph node dissection was performed on the left breast, and the histological results were observed (Figure 3). Microscopically, it showed a 7 cm x 8 cm x 8 cm regular mass in the central region with a clear boundary:the pectoralis major was invaded. The tumor was rich in osteoid tissues, heteromorphic osteoblast-like cells, multinucleated giant cells, and small foci of cartilage, which is consistent with osteosarcoma. Immunohistochemical analysis showed Special AT-rich-binding protein 2 (SATB2) (+), Vimentin (+), CK-Pan (AE1/AE3) (-), CK-Low Molecular Weight (CK-LMW) (-), CK-High Molecular Weight (CK-HMW) (-), CK56 (-), CK14 (-), P63 (scattered +), P53 (+-), S-100 (-), desmin (des) (-), Smooth Muscle Actin (SMA) (-), Cam5.2 (-), CD10 (-), CD34 (-), CD117(-), CD68 (scattered +), Estrogen receptor (ER) (-), progesterone receptor (PR) (-), Human Epidermal growth factor Receptor 2 (Her-2) (-), and Ki-67 (+, 60%). Axillary lymph node was negative (0/10). After the operation, she did not have any further treatment because of her venerable age. Four months later, she died of respiratory failure caused by multiple lung metastases (Figure 4).

extraskeletal osteosarcoma, extraskeletal osteosarcoma of the breast, osteosarcoma, primary osteosarcoma of the breast, thoracic oncology

PMC8500382_01

Unknown

Two feet were excluded from the analysis, the first due to the addition of a metatarsophalangeal fusion at the time of the index procedure and the second patient since only the initial intraoperative radiographs were available. This second patient had an early loss of fixation after a fall requiring revision to a Lapidus. Thus, data from the remaining 13 patients (14 feet) who underwent pre- and postoperative radiographic and clinical evaluation are presented in this study. These included 5 left and 9 right feet, all with incongruent MTP joints and moderate to severe hallux valgus preoperatively (Table 1). The average patient age was 56 years old (range 22-75). Seven of 13 (54%) patients underwent additional procedures at the time of hallux valgus correction (Table 1). Radiographic evaluation included assessment of hallux valgus angle (HVA), 1-2 intermetatarsal angle (IMA), proximal first metatarsal inclination angle (PFMI), and radiographic union (Figure 3). These measurements were made on digital weightbearing anteroposterior radiographs preoperatively, at the first postoperative visit and at the time of most recent follow-up. Final radiographic and clinical analysis occurred at an average of 7 months (range, 3-19 months) postoperatively. Measurements were made by 2 orthopedic foot and ankle fellows blinded to each other's measurements. Each evaluator's measurements were then averaged with those of the other evaluator . Both hallux valgus angle and 1-2 intermetatarsal angle have shown high intraobserver and interobserver reliability across multiple studies. PFMI was selected as a measure of first TMT joint obliquity. PFMI was measured as the angle between a line perpendicular to the axis of the second metatarsal and a line parallel to the proximal articular surface of the first metatarsal, which is easier to visualize than the articular surface of the medial cuneiform (Figure 3C). Clinical evaluation consisted of an assessment of clinical alignment, weight-bearing status, return to shoe wear, and complications. Radiographs were reviewed to evaluate healing of the osteotomy. Statistical analysis consisted of calculating means and ranges for preoperative, postoperative, and final HVA, IMA, and PFMI. Comparison was made between preoperative and immediate postoperative radiographic values to determine whether satisfactory intraoperative correction of the hallux valgus deformity was obtained. Additionally, comparison was made between immediate postoperative and final follow-up radiographs to determine if the intraoperative correction was maintained during the postoperative period. A Student paired t test was performed to determine if there were statistically significant differences between the means of pre- and postoperative measurements and between the means of postoperative and final measurements (Table 2). There was no commercial support or other external funding provided for this study. A medial midsagittal incision was made from the midproximal phalanx to the naviculocuneiform joint. An inverted-L capsulotomy was made at the MTP joint, with care taken to avoid injury to the dorsomedial cutaneous nerve. The medial eminence was resected in line with the long axis of the first metatarsal. A second, 2-cm longitudinal incision was made dorsally in the 1-2 interspace at the level of the hallux MTP joint. The adductor tendon was sharply released from its insertion on the base of the proximal phalanx and the lateral aspect of the fibular sesamoid. The transverse metatarsal ligament was identified and divided followed by capsulotomies of the metatarsosesamoid joint and lateral MTP joint to restore appropriate sesamoid station and MTP joint congruency. Attention was then turned to the medial cuneiform, where a dorsoplantar periosteal incision was made medially at the level of the second TMT joint. Two small Hohmann retractors were placed plantar and dorsal. Care was taken to avoid releasing the first TMT joint capsule, which could destabilize the joint and lead to failure of the correction. An osteotomy was made parallel to the TMT joint through approximately three-fourths of the width of the bone (Figure 4A). Care was taken to avoid completing the cut through the lateral cortex to prevent overlengthening of the first ray. The osteotomy was then carefully wedged open using a distractor. Once the correct IMA alignment had been obtained and the sesamoids had been reduced, a measuring guide was used to measure the osteotomy gap. A nonlocking osteotomy plate (Arthrex Low Profile Opening Wedge, Naples, FL) is then inserted into the osteotomy and fixated with 2.4-mm bicortical screws in all 4 holes. The osteotomy site was then filled with bone graft or bone graft substitute. A suture anchor was then placed centrally in the metatarsal head and the sutures were placed through the plantar medial capsule and tied in a mattress fashion securing the sesamoids into a reduced position and anchoring the joint capsule to the metatarsal head. A pants-over-vest capsulorrhaphy was then completed, with the hallux MTP joint held in a reduced position. A final fluoroscopic examination was performed confirming reduction of the hallux metatarsophalangeal joint, sesamoid position, and osteotomy fixation (Figure 4B). A sterile dressing and short-leg bivalved fiberglass cast were applied postoperatively. Patients were seen at 2 weeks postoperatively for suture removal and recasting for an additional 2-4 weeks. At 6 weeks, patients were transitioned to a postoperative shoe and allowed to begin progressive weightbearing for 1 month, using a silicone toe spacer during the day and a bunion splint at night. At 10-12 weeks postoperatively, patients were allowed to return to wide toe box shoes with continued use of a toe spacer and night splint for an additional 3 months.

bunion, forefoot osteotomy, hallux valgus, metatarsus primus varus, midfoot osteotomy, opening-wedge osteotomy, proximal first metatarsal inclination angle

PMC6008285_01

Male

A 60-year-old male with a 20 pack year smoking history and diabetes mellitus type 2, with no known asbestos exposure, underwent a chest and abdominal X-ray due to chest and abdominal pain complain which was significant for bilateral pleural effusions. Chest computed tomography (CT) revealed multiple bilateral pleural masses and mediastinal lymphadenopathy (Fig. 1A1B). A pleurocentesis and close pleural biopsy was performed but the results were non-diagnostic. An EBUS-TBNA and EUS-B-FNA was therefore performed using a conventional C-EBUS (Olympus). Under EBUS guidance, a pleural mass adjacent to the lower segment of the esophagus was identified (Fig. 2). EUS-B-FNA was performed of the pleural mass using a 21-gauge needle. Subsequently, mediastinal lymph nodes 4R and 7 were sampled with C-EBUS-TBNA with no immediate complication and no ultrasonographic signs of vascular damage. The patient was observed for one hour in the recovery room then for the following 12 hours without evidence of complications. The specimens were examined cytologically, histologically and immunohistochemically (Fig. 3). The morphologic and immunostaining findings were consistent with clear cell carcinoma.

PMC5465414_01

Female

The patient was a 30-year-old Vietnamese woman with no relevant medical history who was studying in Japan. She presented with common cold symptoms for 2 weeks and a fever of about 38C, followed by right hemiplegia. These prompted consultation and subsequent admission to our hospital. The patient had undergone fertility treatment at a private obstetrics-gynecology clinic and was about 19 weeks pregnant. She had hyperemesis with a poor nutritional status, however, no weight gain during pregnancy was observed. The general physical findings were as follows: height 157 cm, weight 52 kg, body mass index 21.1, blood pressure 116/57 mmHg, heart rate 128/min, respiration rate 30/min, body temperature 38.0C, and oxygen saturation of 95%. There were no pertinent thoracic or abdominal findings, except for the signs of pregnancy. The neurologic findings were lucid consciousness, spontaneous pain in the posterior cervical region, nuchal rigidity, right central facial palsy, right hemiplegia (Brunnstrom stage I in the arm and fingers, Brunnstrom stage II in the leg), hyperreflexia of the right upper and lower limbs, and right leg sensory deficit. Blood inflammatory markers showed a white blood cell count of 6,920 /muL and C-reactive protein of 3.42 mg/dL. Blood biochemistry results indicated mild liver dysfunction (aspartate aminotransferase 43 IU/L, alanine aminotransferase 46 IU/L) and undernutrition, with albumin at 2.3 g/dL. There were no abnormal findings related to the kidney or pancreas function. Testing for human immunodeficiency virus was negative. The cerebrospinal fluid (CSF) findings were as follows: pale yellow color, initial pressure 290 mmH2O, final pressure 150 mmH2O, cell count 100 /muL with a lymphocyte-to-polymorphonuclear leukocyte ratio of 67:33, protein 229 mg/dL, sugar 11 mg/dL, and positive Ziehl-Neelsen staining. Cranial magnetic resonance imaging (MRI) on diffusion-weighted images revealed acute cerebral infraction of the left putamen; magnetic resonance angiography (MRA) revealed stenosis of the left middle cerebral artery (LMCA) (Fig. 1a and b). Ground glass opacities in both lung fields were noted on chest radiograph and computed tomography (CT) (Fig. 1c and d). Cerebral infarction secondary to vasculitis from tuberculous meningitis and miliary tuberculosis were suspected. Fig. 2 shows the clinical course of the patient's hospitalization. Treatment was started with dexamethasone (19.6 mg/day) and four anti-tuberculosis drugs: INH (200 mg/day), rifampicin (RFP) (450 mg/day), ethambutol (EB) (750 mg/day), and pyrazinamide (PZA) (1.2 g/day). Because bacterial meningitis could not be ruled out, meropenem (6 g/day) was also administered. Taking into consideration the patient's pregnancy, acute cerebral infarction was treated with continuous heparin infusion at 10,000 units/day. Based on positive tubercle bacilli DNA on polymerase chain reaction and positive culture for Mycobacterium tuberculosis, the patient was given a definitive diagnosis of tuberculous meningitis. After five days of treatment, liver dysfunction ensued. When the liver dysfunction improved after a week, the administration of the four drugs was continued, with PZA being replaced by levofloxacin (LVFX) (500 mg/day). The fever and right hemiplegia promptly improved. Although Ziehl-Neelsen staining was performed only once and showed positivity and susceptibility to all anti-tuberculous drugs, the presence of Mycobacterium tuberculosis in the CSF was sustained for up to one month, despite the administration of anti-tuberculosis drugs. On hospital day 25, at 22 weeks and 1 day of gestation, the patient gave birth to a stillborn. Examination of the uterine contents revealed tubercule bacilli, confirming an intrauterine infection. After the stillbirth, the fever and meningitis signs recurred. Despite treatment with 5 anti-tuberculosis agents (with the addition of streptomycin at 1 g/day) and restarting dexamethasone administration (19.6 mg/day), no improvement in the signs of meningeal irritation was observed. On hospital day 33, aphasia and right hemiplegia appeared; on hospital day 37, right abducens nerve palsy developed. Repeat cranial MRI revealed recurrent cerebral infarction on the left parietal lobe; MRA showed peripheral occlusion of the horizontal segment of the LMCA. Findings indicative of inflammation of the cranial base and lateral sinus thrombosis were also observed (Fig. 3). These were treated with edaravone and heparin; administration of aspirin (100 mg/day) was also continued to prevent recurrence. However, the meningitis symptoms persisted and did not improve despite increasing the INH dosage from 300 mg/day to 500 mg/day. Therefore, intrathecal administration of 100 mg of INH 3 times per week was started. Furthermore, 15 mL of CSF was intermittently drained by lumbar puncture to relieve intracranial pressure. The signs of meningeal irritation started to improve after starting intrathecal INH. Serial cranial MRI indicated resolution of the venous sinus thrombosis and reduction of the inflammatory findings in the cranial base (Fig. 4). On hospital day 98, the visual acuity on the left decreased, suggesting left optic neuritis caused by inflammation of the cranial base. As the possibility of optic neuropathy could not be ruled out, EB was discontinued. Intrathecal INH administration was tapered to once a week and eventually was discontinued as the patient's symptoms improved. The patient was discharged for home on hospital day 191. Three anti-tuberculosis drugs (INH, RFP, and LVFX) were continuously administered for 1 year. The residual neurologic deficits were mild aphasia, decreased visual acuity on the left side, and hypoesthesia in both legs, which was suspected to be secondary to INH. Nevertheless, the patient was able to independently engage in her activities of daily living. Cranial MRI 2 years after onset showed that the occlusion in the horizontal segment of the LMCA was unchanged; therefore, the administration of aspirin (100 mg/day) was continued to prevent the recurrence of cerebral infarction. Approximately 2.5 years later, the patient returned to her home country. She was able to walk without assistance and carry out her usual duties and activities.

cerebral infarction, intrathecal isoniazid, pregnancy, tuberculous meningitis

Radiologic imaging findings in a 30-year-old woman with refractory tuberculous meningitis. (d) On chest CT, there were diffuse ground glass opacities in both lung fields. MRI: magnetic resonance imaging, MRA: magnetic resonance angiography, CT: computed tomography.

PMC3633019_01

Male

A 58-year old male was referred to our outpatient consultation centre with complaints of shortness of breath, dry cough and fatigue over the previous two months. He also reported anorexia and involuntary weight loss for the same period of time. His primary care physician had treated him with antibiotics, but no response or improvement in symptoms were noted. The patient's past medical history included an episode of pesticide poisoning 35 years ago for which no information was available and occasional gout that responded to anti-inflammatory medication. The patient was an ex-smoker of 80-pack years and a moderate drinker. No known allergies were reported. His occupational history included working as a stacker in a warehouse for 20 years, with moderate dust exposure, and following this, as an administrative worker for 20 years. He was regularly exposed to a parakeet (Melopsittacus undulatus), chickens, and cats. The patient was unaware of any exposure to tuberculosis patients, recent trips abroad or family history of respiratory disease. On physical examination, he was in good general condition, but crackles were heard in both lung bases. No other changes were noted. The patient's chest X-ray showed bilateral diffuse interstitial infiltrates with a predominant reticular pattern and no spared areas (Figure 1). This was followed by a high resolution computed tomography (HRCT) scan of the chest that showed several areas of subpleural cystic lesions and traction bronchiectasis affecting all lobes, but having an upper and middle level predominance and being much more extensive in the right lung. There were also multiple mediastinal enlarged lymph nodes and an enlargement of the pulmonary artery (3.2 cm diameter) and right cardiac cavities (Figure 2). Cardiac tests were performed, including an electrocardiogram and echocardiogram, and no other signs of cardiac disease were found. Blood tests, including those for auto-antibodies and IgG immunoglobulins (to parakeet and fungal proteins) were negative. Lung function tests suggested moderate restriction (percentage predicted forced vital capacity [FVC], 57.5%), low diffusion capacity ([DLco] 36% of the predicted value) and resting hypoxaemia (PaO2, 69.7 mmHg). The decision was made to perform bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. Upon examination, the bronchial mucosa showed moderate signs of inflammation, but no other morphological changes. Bronchoalveolar lavage showed an increase in the total cell count (300 cells/microL), and increased percentage of lymphocytes (28%) and neutrophils (12%). The CD4/CD8 ratio was 0.2. Transbronchial biopsy showed no specific findings. A transthoracic biopsy was then performed, but the results were also inconclusive. The patient was referred for surgical lung biopsy. The pathology of the surgical specimen was compatible with a pattern of usual interstitial pneumonia (Figure 3). At this time no definite diagnosis could be made, as the clinical, radiological and pathological findings were compatible with both chronic hypersensitivity pneumonitis and IPF. Nevertheless, treatment with prednisolone, azathioprine and acetylcysteine commenced. The patient was also instructed to avoid any contact with the parakeet. Despite the treatment, the patient got progressively worse, and has been referred for lung transplantation. Chronic hypersensitivity pneumonitis and IPF can present with the same clinical and radiological manifestations. A careful clinical evaluation is therefore fundamental, and the surgical pulmonary biopsy is usually helpful in performing the differential diagnosis, but not in this case. A UIP pattern can be seen on biopsy (and/or CT) in both IPF and chronic HP. The addition of BAL can give a decisive contribution to the diagnostic procedures. A cut-off level of 30% for lymphocytes in BAL demonstrated a favorable discriminative power for the diagnosis of IPF. In this case, despite careful evaluation, no definite diagnosis could be achieved. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

HRCT scans showing honeycombing and traction bronchiectasis affecting all lobes of the lungs, enlarged mediastinal lymph nodes and enlargement of the pulmonary artery (3.2 cm in diameter) and the right cardiac cavities.

PMC5994311_01

Female

A 32-year-old Greek woman, para 1, at the 22nd week + day 3 of gestation, was referred to the A&Es with a 1-week history of abdominal discomfort and persistent vomiting. The woman had HbH disease (thalassemia intermedia) with a - a 3.7/Hb Icaria a genotype. She was splenectomized at the age of 6.5 years and she maintained a Hb around 8 g/dl without blood transfusions. Her medical history included incidents of superficial-vein thrombosis in 2005, 2008, and 2009 (with negative family history of thrombosis) for which she was receiving acenocoumarol. Since the confirmation of pregnancy she was receiving Salospir 100 mg p.o. and Enoxaparin 40 mg sc. Laboratory exams revealed moderate hypochromic microcytic anemia (Ht 28.1%, Hb 8.46 g/dL, MCV: 67.2, and MCH: 20.2), mild thrombocytosis (PLTs: 519 x 109/L), and leukocytosis: WBC 27 x 109/L (neu: 87%, lymph: 9%, and mono: 4%). The C-reactive protein was 11.4 mg/L. INR and aPTT were within normal limits but fibrinogen was high, 519.9 mg/L, and D-dimers were >5000 mug/L. The rest of the biochemistry showed the following: TBil: 1.50 mg/dl; dBil: 0.8 mg/dl; SGOT 110 IU/L; SGPT 176 IU/L; ALP 165 IU/L; gamma-GT 46 IU/L; and ferritin: 63 ng/ml, indicative of hepatic impairment. An abdominal ultrasound revealed portal vein and spleen-vein thrombosis. The patient underwent a thrombophilia testing which was negative for hereditary thrombophilia (FV Leiden, FIIG20210A) as well as for anticardiolipins antibodies. Because of the site of the thrombosis (visceral), latent myeloproliferative neoplasms (MPN) were also excluded (she was negative for the JAK2V617F mutation). The patient was treated with enoxaparin 60 mg bd, sc, and Salospir 100 mg p.o. o.d. Transaminases were normalized two weeks later and a new abdominal ultrasound, performed two months later, showed chronic portal vein and chronic spleen-vein thrombosis. At the 35th week + day 3, the liver enzymes and the rest of the biochemistry were as follows: SGOT 466 IU/L, SGPT 931 IU/L, ALP 220 IU/L, gamma-GT 41 IU/L, TBil: 1.80 mg/dl, Ht 38%, Hb 10.2 g/dL, WBC 12.3 x 109/L, and PLTs: 487 x 109/L. The abdominal ultrasound showed no new findings. With the clinical suspicion of partial HELLP syndrome (the patient had only elevated liver enzymes) an urgent caesarian section (C-section) was performed. Anticoagulation bridging with heparin was used perioperatively. During the C-section, the patient developed hypertension episode [blood pressure: 190 (systolic)/ 110 (diastolic) mmHg] and she was treated with hydralazine. The premature newborn was 1810 gr but healthy and stayed in the neonatal ICU for 7 days. Mother's liver enzymes were normalized within five days after the delivery and the patient was discharged. The patient is now on long-term anticoagulant therapy with acenocoumarol. The imaging of splenic veins is unchanged.

PMC6178166_01

Male

A 37-year-old Caucasian male with a past medical history of alcohol abuse was referred for inpatient admission after being found to have pancytopenia. He had subjective fever and productive cough with yellow sputum a few weeks ago, which resolved after a few days without treatment. He visited his primary care physician and laboratory exam showed pancytopenia, thus leading to the referral. He also endorsed generalized weakness, progressive right eye blurry vision, and chest tightness for the past few weeks. There was no skin rash, joint pain, hair loss, heartburn, and Raynaud's phenomenon. Physical exam was only remarkable for cervical nontender lymphadenopathy. Upon admission, he was febrile with a maximum temperature of 101.2 F. Laboratory exam was notable for white blood cell 1,900 counts/muL, hemoglobin 7.2 g/dL, hematocrit 21.2%, platelet 19,000 counts/muL, sodium 126 mmol/L, and creatinine 1.44 mg/dL. Urinalysis showed elevated white blood cells, dysmorphic red blood cells, and proteinuria. Further work up showed that he had elevated ferritin 6542 ng/mL, high triglycerides 327 mg/dL, marked decreased complement levels (C3 14 mg/dL and C4 3 mg/dL), elevated ESR 137 mm/hr, strongly positive for antinuclear antibody (ANA, 1 : 640), and anti-double-stranded DNA antibody (anti-dsDNA, >1 : 1280). Anticardiolipin antibody (IgM and IgG) and beta-2 glycoprotein I antibody (IgG) were also positive. Direct antiglobulin test (Coomb's) was positive. Urine studies showed microalbumin to creatinine ratio of 1958 mg/g and protein creatinine ratio of 7.04 mg/mg consistent with nephrotic-range proteinuria. Transthoracic echocardiogram showed normal ventricular function but moderate circumferential pericardial effusion. Abdominal ultrasonography showed hepatosplenomegaly with evidence of cirrhosis. Based on the above findings, he was diagnosed with systemic lupus erythematosus, pericarditis, and lupus nephritis. Pulse steroid with methylprednisolone 1000 mg daily was started for 3 days, followed by oral prednisone 60 mg daily. His fever and chest pain resolved, and his blood cell counts and creatinine improved after the treatment. He subsequently underwent bone marrow biopsy which showed increased histiocytes with focal evidence of hemophagocytic cells consistent with macrophage activation syndrome considering his clinical presentation. Renal biopsy was also performed and confirmed diffuse proliferative and membranous lupus nephritis (Class IV/V) along with focal segmental glomerulosclerosis NOS type. He also underwent ophthalmology evaluation, and funduscopic exam with fluorescein angiogram showed cotton-wool spots with retinal hemorrhage consistent with retinal vasculitis. His laboratory examination continued to improve, and he was subsequently discharged from hospital one week after admission. Mycophenolate mofetil was started in addition to steroid upon discharge. Repeat transthoracic echocardiogram three weeks after treatment showed marked decrease in pericardial effusions. His disease remained stable while on mycophenolate mofetil with prednisone gradually tapered from 60 mg to 10 mg twelfth week after discharge. His vision acuity remained stable, and repeat funduscopic examination showed improvement of his retinal lesions. Detailed laboratory examination in the hospital and on follow-up visit is presented in Table 1.

PMC9149194_01

Male

A 67-year-old man was evaluated at the emergency department because of fever (up to 38,9 C), general fatigue, rhinorrhea and dyspnea for four days, without cough, thoracic pain or sore throat. The patient had a history of severe chronic obstructive pulmonary disease (COPD) for which he underwent a bilateral lung transplantation eleven years ago. He also suffered from mild obstructive sleep apnea syndrome, type 2 diabetes mellitus and chronic renal insufficiency, with an estimated glomerular filtration rate (eGFR) of 30 mL/min/1,73m2. The patient's therapy consisted of azathioprine, everolimus and methylprednisolone, as well as thrice weekly azithromycin and twice weekly dapsone to prevent Pneumocystis jirovecii (PJP) infection. Other medications included spironolactone, bumetanide, bisoprolol, atorvastatin, enalapril, moxonidine, prazosin, omeprazole, trazodone, zolpidem, gliclazide, magnesium, calcium and vitamin D. On physical examination, he appeared mildly ill, without fever. Oxygen saturation was 96% while breathing ambient air. Pulmonary auscultation revealed normal breath sounds and clinical examination was otherwise normal. Blood analysis showed mildly elevated inflammatory markers (C-reactive protein (CRP) 57.8 mg/L), stable chronic renal insufficiency (serum creatinine 2.49 mg/dL with an eGFR of 26 mL/min/1,73m2) and normal liver function. Chest radiography showed no abnormalities. A mild infectious bronchitis was diagnosed, moxifloxacin was initiated and the patient was admitted to the respiratory department. Two days after admission the patient developed high fever (39,1 C). Oxygen saturation was 93% while breathing ambient air. Clinical examination and pulmonary auscultation were normal. Blood cultures were taken and moxifloxacin was switched to piperacillin-tazobactam. Over the next four days the patient continued to develop daily fever. Blood cultures remained negative. Nevertheless, meropenem was started instead of piperacillin-tazobactam and a further work-up was performed. Chest computed tomography (CT) scan revealed bilateral ground glass opacities scattered over both lung fields (Fig. 1). Everolimus was discontinued and replaced by tacrolimus, due to concerns of possible pulmonary toxicity. Transbronchial biopsies (TBB) revealed mild (grade A2B0) acute cellular rejection, which was treated with high-dose intravenous corticosteroids followed by tapering. Bronchoalveolar lavage (BAL) fluid showed a concurrent positive PJP polymerase chain reaction (PCR) despite adequate prophylaxis. Because of the patient's underlying chronic renal failure primaquine and clindamycin were administered as first choice for PJP treatment, instead of trimethoprim-sulfamethoxazole. Soon after starting treatment fever disappeared and the patient's dyspnea improved significantly. Inflammatory markers returned to normal. Four days after initiation of therapy, however, dyspnea at rest reappeared. Oxygen saturation on pulse oximetry was 87% while breathing ambient air and chest auscultation revealed normal heart and breath sounds. The patient appeared mildly cyanotic, without signs of respiratory distress. Arterial blood gas analysis showed a pH of 7.49, a pO2 of 80.3 mmHg, a pCO2 of 29.5 mmHg, a bicarbonate of 22.4 mmol/L and a methemoglobin of 13.0%. Chest radiography did not show any new findings. A diagnosis of methemoglobinemia was made and a conservative approach was chosen. Supplemental oxygen through nasal cannula (2 L/min) was initiated. Three days later the patient appeared in moderate respiratory distress and seemed more cyanotic. Chest auscultation was clear, oxygen saturation on pulse oximetry was 86% with supplemental oxygen (3 L/min) and respiratory rate was 22 per minute. Repeated arterial blood gas analysis showed a dark brown color (Fig. 2), a pO2 of 100 mmHg, a pCO2 of 35.6 mmHg and a methemoglobin of 33.7%. Treatment with primaquine was discontinued and replaced by trimethoprim-sulfamethoxazole, despite the reduced eGFR. Oxygen flow rate was increased to 5 L per minute through nasal cannula. The next day, however, the patient continued to experience moderate respiratory distress and methemoglobinemia had even increased to 36.0%. We preferred not to treat with methylene blue due to concerns of possible serotonin syndrome, since the patient was also taking trazodone once daily. Ascorbic acid intravenously at a dose of 1 g four times daily was administered. Over the next days, the patient's shortness of breath disappeared completely, oxygen saturation on pulse oximetry improved and the patient's skin color and methemoglobin levels returned to normal (Fig. 3). The patient recovered completely and was eventually discharged from the hospital after 35 days, without need for supplemental oxygen.

cyanosis, methemoglobinemia, pneumocystis jirovecii, primaquine

CT of the lungs showing widespread scattered ground glass opacities.

PMC6339764_01

Female

A 48 -year-old Indian woman presented to the gastroenterology clinic with complaints of upper abdominal pain, heartburn, and unintentional 10-pound weight loss over a period of 6 months. Review of the system was negative for headache, nasal discharge, cough, chest pain, shortness of breath, sinusitis, joint pain, or skin rash. Past medical history is notable for hypothyroidism only. Family history and personal history is otherwise unremarkable. Her medications include levothyroxine 50 mcg daily. She underwent EGD, which revealed a solitary 1.4 cm ulcer in the gastric fundus. Biopsy of the ulcer revealed active chronic gastritis with lymphoid aggregates and nonnecrotizing granulomatous inflammation with multinucleated giant cells (Figure 1). Histochemical staining and culture results were negative for any bacterial, viral, and fungal infections. The biopsy was negative for gastric carcinoma. She was then empirically treated with proton pump inhibitors. Two months later, the patient presented to emergency room with cough, pleuritic chest pain, and hemoptysis. The CT chest showed two large necrotic masses (Figure 2): one in the right upper lobe with a cavitary lesion and the other in the mediastinum. She eventually underwent elective bronchoscopy with transbronchial biopsies and bronchoalveolar lavage (BAL). Right upper lobe transbronchial biopsy showed bronchial mucosa with acute and chronic inflammation (lymphocytes, neutrophils, eosinophils, and rare histiocytes) and small submucosal microabscess. Lung alveolar parenchyma was without significant histopathological changes. The biopsy was negative for any form of lung malignancy. The BAL was negative for pulmonary hemorrhage. No fungi, pneumocystis, or viral inclusion bodies were identified in BAL. Bacterial and fungal and mycobacterial cultures of BAL were negative as well. Infectious disease workup showed positive histoplasma serum antibody but histoplasma urine antigen was negative. Presumed diagnosis of histoplasmosis was made, and she was started on oral itraconazole as outpatient therapy. The patient did not respond well, and her clinical status continued to decline. She then presented to the emergency room with spiking fevers and recurrence of hemoptysis. She was admitted to the inpatient service and started on IV amphotericin-B per infectious disease service recommendations. During hospitalization, she complained of epigastric discomfort. CT abdomen showed opacity around the previously found gastric ulcer and fluid collection adjacent to the stomach and pancreatic bed. Repeat EGD showed further development of a sinus tract in the ulcer, leaking exudate, and necrotic debris. Biopsies of the ulcer again showed mild active chronic gastritis. No evidence of infection or malignancy was identified. During the hospital course, she developed arthralgia and maculopapular pruritic skin lesions on the right flank and both legs. After a week into the hospitalization, the patient developed severe shortness of breath and acute respiratory failure that required intubation and mechanical ventilation. CT chest revealed worsening of the previous right upper lobe cavitary lesion with pleural effusion. Skin biopsy showed leukocytoclastic vasculitis. Further workup showed positive ANA in the low titer (1 : 40, homogenous pattern). Specific antibodies, e.g., anti-dsDNA, anti-Smith ab, anti-SSA and SS-B, were negative. Complements, C3: 113 (90-180 mg/dl) and C4: 12 (10-40 mg/dl), were within normal limits. The C-reactive protein level was 86 mg/dl (normal < 0.5 mg/dl). Serum protein electrophoresis showed polyclonal acute phase reactant pattern. C-ANCA was positive with positive PR3: 7.21 (0.8-1.19 AU/mL). Anti-MPO antibody was negative. At this point, the diagnosis of GPA was established. She was treated with pulse methylprednisolone 1 g IV daily for 3 days and IV cyclophosphamide 750 mg/m2. During hospitalization, she received a course of sulfamethoxazole-trimethoprim (800-160 mg DS) tab PO twice daily for 5 days for urinary tract infection. She responded very well and was promptly extubated and discharged in two weeks. She was maintained on PO prednisone 1 mg/kg/day and IV cyclophosphamide 750 mg/m2 monthly for the next 6 months. At 3 months post-hospital discharge follow-up, she was completely asymptomatic. Repeat anti-PR3 titer was 3.6 (normal 0.8-1.19 AU/mL). There was a near-complete resolution of pulmonary masses on repeat CT (Figure 3) and complete healing of the ulcer on follow-up EGD. Prednisone was tapered to 10 mg/d over 6 months while she received monthly IV cyclophosphamide induction therapy. The PR3 antibody level was 1.0 and within normal limits. She was eventually started on PO methotrexate 15 mg/week as maintenance therapy for GPA. While she was on methotrexate, 6 months follow-up CT chest showed relapse of the necrotic lung lesions at the same place as before in the right upper lobe. The ANCA (PR-3) antibody level was 2.8 (normal 0.8-1.19 AU/mL). Clinically, she was asymptomatic. Again, she underwent extensive workup with bronchoscopy, and bronchoalveolar lavage was negative for any infection or malignancy. She was diagnosed with GPA relapse and treated with rituximab 375 mg/m2 every week for 4 weeks and was started on azathioprine 50 mg/day for maintenance therapy. Gradually, the azathioprine dose was increased to 150 mg/day over next 2 months. She was followed up as outpatient closely with repeat CT chest every 6 months, which showed regression of the lung lesion. Approximately, 2 years since her initial presentation, she was in complete remission with resolution of the lung lesion. Interestingly, about a year later, routine follow-up labs in the clinic revealed hematuria with 6 RBCs per high-power field (normal 0-4 per high-power field) and urine protein creatine ratio of 0.67 equivalent to 24 hours urinary protein of 670 mg. Follow-up 24-hour urine collection showed proteinuria of 1.3 gm. Physical examination was unremarkable. Her repeat antibody profile showed positive ANA: 206 (normal <100 au/ml), anti-dsDNA Ab:135 (normal <100 au/ml), anti-Smith Ab: 14 (normal < 100 au/ml), anti-RNP Ab: 36 (normal < 100 au/ml), SS-A Ab: 6 (normal < 100 au/ml), SS-B Ab: 7 (normal < 100 au/ml), antihistone Ab: 9 (normal < 100 au/ml), rheumatoid factor: 10 (normal < 14 au/ml), and anti-CCP Ab level: 1 (normal < 5 unit/ml). Follow-up complement levels were normal: C3, 152 (normal: 87-200 mg/dl), and C4, 25 (normal: 19-25 mg/dl). Repeat C-reactive protein levels were 0.6 and 0.7 (normal: < 5 mg/dl). Viral hepatitis screen and cryoglobulin screen were negative. Repeat ANCA and anti-PR3 as well as anti MPO antibodies were negative. Her antibody profile and proteinuria were concerning for new-onset SLE with renal involvement. She was then referred to nephrology and underwent renal biopsy. Renal biopsy showed diffuse thickening of the glomerular basement membrane (GBM) with normal cellularity on light microscopy (Figure 4). Mesangial and endocapillary proliferation were negligible. No cellular crescents, pseudocrescents, or acute necrotizing lesions or vasculitis are seen. Immunofluorescent microscopy showed diffuse, granular immunoglobulin deposition along GBM (Figure 5). Immunostaining was positive for IgG, C3. Electron micrograph (Figure 6) showed subepithelial granular deposits but no subendothelial deposits. Congo red stain for amyloidosis was negative. Staining for anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin (THSD7a) antibodies were negative, which makes primary membranous nephropathy less likely. Considering the + ANA and double-stranded DNA Ab, the renal biopsy diagnosis was consistent with secondary pure membranous (type V) lupus nephritis. Ultimately, she was diagnosed with SLE/AAV overlap syndrome with class V membranous lupus nephropathy. She was started on lisinopril and was titrated to 20 mg/day. Azathioprine was slowly tapered and discontinued because she has finished 3 years of treatment for GPA. She declined high-dose steroid and mycophenolate mofetil for treatment of lupus nephritis. On follow-up CT scan, she had minor relapse of GPA in the form of enlargement of pulmonary nodule even though she was asymptomatic. The ANCA (PR-3) antibody titer was 1.7 (normal 0.8-1.19 AU/mL). She was given another round of rituximab 375 mg/m2 without induction corticosteroid dose. Follow-up 6 months CT chest showed resolution of the mass. Urinalysis and urine protein/creatinine ratio are negative for proteinuria and hematuria. She is completely asymptomatic and back to her normal activities. The patient has been in full remission for lupus nephritis for 1 year and for 9 months after the last relapse of GPA.

PMC4856500_01

Male

A 64 year old male patient, farmer by profession, reported to outpatient department of Oral Medicine, Diagnosis and Radiology with a chief complaint of pain and pus discharge in relation to the left upper back tooth region since 4 months. Past history revealed that patient was asymptomatic 4 months ago, later he developed pain and pus discharge which was slow in onset, localized, dull in nature, intermittent with no aggravating or relieving factors. Further dialog history revealed that patient also experienced numbness on left side of the face since 2 months. Past medical history revealed that patient was hypertensive and diabetic since 5 and 4 years respectively and currently on medication. Past dental history and supportive investigations revealed that patient underwent check up 4 years ago at a ENT doctor where it was provisionally diagnosed as a case of Nasal myiasis, surgical debridement of the lesion was done and maggots were retrieved. Plain and contrast computed tomography of brain revealed a sharply defined, mildly hyperdense space occuping lesion of 24 x 19 mm in left temporal region and effaced sulcal spaces which showed mild enhancement on contrast with mild hyperostosis with widening of diploic spaces of greater wing of sphenoid bones which was suggestive of a meningioma. Following which patient was admitted at a Private dental hospital, treatment protocol was informed to the patient and after obtaining informed consent from the patient, he was posted for surgery under general anesthesia. Maxillectomy on the left side was done, after 2 months of regular debridements and obtaining sterile cultures from the surgical wound, acrylic palatal obturator was fabricated making alginate impressions. Extra oral examination revealed a gross facial asymmetry with sunken appearance with loss of normal nasolabial fold on the left side of the face (Figure 1). TMJ and lymph nodes examination showed no abnormality. Intra oral examination showed a surgical defect in relation to the left maxillary quadrant with well defined borders. The depth of the lesion showed a grayish black necrotic pseudo membranous slough with yellowish areas interspersed all over (Figure 2). Other intra oral findings were multiple missing teeth in left and right maxilla and periodontally compromised mandibular teeth. Based on the past history and intra oral examination, a provisional diagnosis of osteomyelitis of the surgical defect was given. Other lesions such as Tuberculosis, Squamous cell carcinoma, Tertiary syphilis, fungal infections such as Aspergillosis and Mucormycosis were considered. Radiologic investigations of Panaromic radiograph and computed tomography were advised. Panaromic radiograph revealed multiple missing teeth (12 11 21 22 23 24 25 26 27 37) and huge surgical defect in favor of left maxillectomy (Figure 3). Paranasal sinus radiograph view showed radiolucency which is diffuse, with irregular borders involving the left maxillary antrum and deviated nasal spine and changes in favor of left maxillectomy (Figure 4). Computed axial tomography revealed in favor of post operative left maxillectomy, deviated nasal spine to right, left ethmoidal and sphenoidal sinusitis. Changes seen involving left pterygoid plates and posterior wall of maxillary antrum suggestive of residual changes of Osteomyelitis (Figure 5). Biochemical investigations such as complete blood picture, serum creatinine were within normal limits with increased Erythrocyte sedimentation rate and Glycoslyated hemoglobin was 9.2% suggestive of diabetes mellitus. Incisional biopsy was done and the specimen was obtained from the left maxillary antrum through endoscope under local anesthesia and was sent to Culture sensitivity tests which showed positivity for bacterial and fungal growth on KOH culture media. The specimen was further sent for Periodic acid Schiff staining which showed large non septate fungal hyphae branched at right angles (Figure 6). The specimen was sent for histopathological examination (Figure 7) which showed cellular connective tissue stroma composed of mixed inflammatory cell infiltrate predominantly neutrophils and lymphocytes, numerous large non septate fungal hyphae branching at right angle along with few areas of necrosis. There is presence of ciliated columnar epithelium along with few bony trabaculae and extensive areas of hemorrhage along with super added bacterial infection suggestive of "mucormycosis. Correlating clinically, radiologically and histologically a final diagnosis of CHRONIC OSTEOMYEILITIS WITH MUCORMYCOSIS was given. Our patient underwent extensive unilateral endoscopic nasosinusal surgery with debridement of left maxillary sinus, anterior and posterior ethmoidal cells and extensive removal of invaded mucosa under general anesthesia. Extensive fungal masses and necrotic slough were excised from left maxillary and sphenoidal sinus. Necrotic mucosa was removed till the healthy margins were visible which showed initial signs of bleeding. Liposomal Amphotericin B (5 mg/kg) was started immediately after the surgery and dosage was increased to (7.5 mg/kg) after 3 weeks. A week later patient underwent hyperbaric oxygen therapy for 21 dives, each session lasting for 150 min along with systemic delivery of antifungal drugs orally for time period of 4 weeks. Post operative visit of the patient showed negative cultures with no morbidity and patient was delivered an acrylic obturator with soft liners.

diabetes mellitus hyphae, pas stain, myiasis, zygomycosis

PMC10355127_01

Male

A 48-year-old man came to our attention for some relapsing episodes of right hemiparesis. He had also reported many episodes of involuntary movements in the right arm for about 2 weeks before the hospital admission and other episodes of loss of consciousness, without prodromes and with spontaneous recovery. His medical history was unremarkable; in particular, he had no history of headache, hypertension, dyslipidemia, diabetes mellitus, or stroke. He was a current smoker (30 packages/years) and overweight (BMI 33 kg/m2). He did not take any therapy. During his first hospital access, the non-contrast brain CT (NCCT) and the electroencephalogram showed no abnormalities and he refused the hospitalization. A few days later, for the persistence of the recurrent symptoms, he returned to the hospital. The neurological evaluation showed very mild right hemiparesis and myoclonic-like episodes in the right limbs (probably limb-shaking TIA). Atrial fibrillation was also detected, and anticoagulant therapy with low-molecular-weight heparin was started, and the patient was admitted to our ward. Neurological examination was completely negative after a few hours. A transcranial color-coded duplex (TCCD), a CT angiography, and an MR angiography were performed and showed multiple severe intracranial arterial stenosis involving the left carotid terminus, the right carotid terminus, the anterior and the posterior cerebral artery bilaterally, with post-stenotic aneurysmal dilatations (Fig. 1a). Diffusion-weighted images revealed no recent ischemic infarction or signs suggestive of encephalitis. Additional MRI with perfusion sequences showed an area with prolonged mean transit time in the left hemisphere, without evidence of ischemic core. The "black-blood" T1-weighted images showed strong contrast enhancement in the left carotid terminus, particularly in the cavernous and petrous segments. A brain angiography was subsequently performed, confirming the suspicion of cerebral arteritis, with involvement of the large- and medium-sized cerebral vessels. Further exams were performed, including total-body CT-positron emission tomography scanning, and no findings suggestive for an extracranic vessel inflammatory involvement were detected. Other causes of secondary vasculitis were excluded. The biopsy of the temporal artery was not suggestive for GCA. Blood tests showed no signs of systemic inflammation or coagulopathy; toxicological screening was negative. Transthoracic echocardiography did not reveal any pathological findings, except for a mild left ventricular hypertrophy. Duplex sonography of supra-aortic trunks revealed no significant stenosis in the cervical arteries. Lumbar puncture was performed, analysis of cerebrospinal fluid (CSF) was normal, and isoelectric focusing showed a polyclonal pattern. PCR for HSV 1-2, varicella-zoster virus, Epstein-Barr virus, adenovirus, parvovirus B19, Enterovirus, cytomegalovirus, and Borrelia burgdorferi was negative. Serological screening for vasculitis like rheumatic factors, complement C3/C4, antinuclear antibody, antineutrophil cytoplasmic antibody, angiotensin-converting enzyme, lymphocyte typing was negative. No neoplasm was found during neoplastic screening (colonoscopy, testicular ultrasound, blood neoplastic markers, abdomen tomography, peripheral blood film). Chest tomography showed only mild emphysema findings, and gastroscopy showed an erosive gastritis with duodenal ulcer, with negative Helicobacter pylori research. Biopsy of the lesion was not typical for neoplasm, and PPI therapy was started. The quantiFERON test was positive, but no signs of acute TBC pathology were found. Blood exams revealed mild hyperthyroidism, and a thyrostatic therapy with Tapazole was started. Neuropsychological tests showed alterations in visual, spatial, and verbal learning skills, with a deficit in language tests, but a limitation related to the significant language barrier was present. The rheumatological evaluation confirmed the suspicion of probable primary angiitis of CNS, and the patient was treated with a high dose of intravenous corticosteroids (with successive prednisone at daily dose 1 mg/kg) and mycophenolate mofetil (2,000 mg/daily). Because of immunosuppressant therapy, for the patient who was positive for the quantiFERON test, a preventive therapy with isoniazid was started. Despite the immunosuppressant therapy, neurosonological and neuroradiological follow-up exams showed a worsening of the aforementioned stenosis, especially in the left carotid terminus. Brain MRI follow-up showed new small acute ischemic lesions in the left middle cerebral artery (MCA) territory. During the hospitalization, the patient complained of numerous transient episodes of severe weakness in the right limbs and aphasia, many of them evoked by postural changes and arterial hypotension, with spontaneous regression and no paroxysmal activity at the EEGs. This clinical evolution occurred under combined therapy with a high dose of steroids, immunosuppressant, and antithrombotic therapy, and a new brain CT perfusion exam showed a worsening of the left hemispherical hypoperfusion (Fig. 1b). After a multidisciplinary evaluation with an interventional neuroradiologist, a treatment of intracranial stenting of the left carotid siphon was purposed. Dual antiplatelet therapy with Cardioaspirin and clopidogrel was started, and anticoagulant was stopped. The endovascular procedure was performed 30 days after the first DSA angiography and after the initiation of immunosuppressive therapy, in general anesthesia. First angiographic sequences confirmed the complete occlusion of the carotid terminus on the left side and a marked slowing of the flow on the sylvian branches of the ipsilateral MCA. An intracranial stent, Solitaire (Medtronic), was positioned from the distal tract of the carotid siphon to the first tract of the MCA on the left side, without any procedural complication (Fig. 1c). After the procedure, CT perfusion showed a marked improvement, with no more hypoperfusion areas in the left hemisphere, and no more clinical episodes of hemiparesis or aphasia were reported. Moreover, transcranial color Doppler ultrasound revealed a strong improvement in left MCA blood flow. At discharge, neurological evaluation was normal. Anticoagulation therapy with apixaban was started in association with dual antiplatelet therapy.

angioplasty and stenting, endovascular treatment, management of stroke patient, stroke, vasculitis

PMC9518658_01

Male

A 48-year-old man with no relevant medical history was admitted to our hospital for acute abdominal pain and fatigue on September 12, 2016. Palpation of the right quadrant of the patient showed tenderness, but the test of Murphy sign was negative. On the second day after admission, the patient underwent computerized tomography (CT) scan, showing a 5.5 cm x 5.1 cm lesion adjacent to the liver capsule (Figure 1). Combined with the results of pathological biopsy, the patient was diagnosed with ICC. Based on the history, symptoms, signs, and auxiliary examination, the patient was diagnosed with ICC II (AJCC-UICC TNM stage: 8) and cachexia (ECOG score: 2). Meanwhile, after multidisciplinary consultation, the surgical treatment was not recommended due to the poor nutritional status. Hence, the interventional treatment was recommended after improving the nutritional status of the patient. Finally, transcatheter arterial chemoembolization (TACE) was performed on the patient on September 18, 2016. Briefly, the catheter was superselectively intubated into the tumor supplying artery through the skin. And the end of the tumor supplying artery was embolized with iodized oil emulsion (10 mL) containing chemotherapy drugs (epirubicin hydrochloride needle 10 mg). The patient had no apparent discomfort after surgery. The patient's liver function was re-examined after 3 days of treatment, with TB: 11 micromol/L, ALT: 20 U/L, AST: 19 U/L, and ALB: 30 g/L. CT scan of the liver was performed 1 month after TACE treatment. The results showed abnormal right lobe with margin atrophy. The patchy mixed density shadow was observed in the right posterior lobe of liver, and speckled shadow of iodide deposition were observed at the edge (Figure 2). Furthermore, it was assessed as disease stability (SD) by modified Response Evaluation Criteria in Solid Tumor (mRECIST) criteria. These results suggested that ICC is not sensitive to TACE treatment. After a multidisciplinary consultation and discussion, the patient underwent minimally interventional therapy with iodine-125 seed implantation. Briefly, based on preoperative CT scan, treatment planning system (TPS; Beijing Hang Kelin Technology Development Co., LTD) was used to simulate approximate dose distribution of solid tumor at prescribed dose and to determine the particle number and spatial distribution (V100 >= 95% and D90 >= 100%). In order to prevent the particles from entering the blood vessels and migrating, the total radiation dose was 120 Gy, the particle spacing was about 1 cm, and the particles were implanted 1 cm away from the large blood vessels. 3D printing templates were made by TPS before treatment The radioactive particles were placed percutaneously through a 3D-printed template under CT guidance. Complications were observed after operation, including whether there was bleeding under the liver capsule, large blood vessels and whether there was particle displacement or gas embolism in the heart. Moreover, a CT scan was performed after the surgery to make sure the surgery went well. The instruments used in the present operation included pistol type particle implantation device (Figure 3), 18G particle implantation needle, and iodine-125 radioactive particles with an activity of 2.22E + 7 Bq (Beijing Atomic Technology Co., LTD). In order to avoid bleeding, only two injections were used. We adjusted the needle in the liver for multi-point ablation, always avoiding penetrating the liver capsule. The frame heads were adjusted to fan shape, and iodine-125 seeds were planted so that they were distributed in a fan shape with a distance of 1 cm between each two seeds (Figure 4). After 3 months of treatment, CT scan showed that the lesion was atrophic (Figure 5). The mRECIST assessment showed complete remission (CR). The patient's liver function was re-examined on January 1, 2021, and the important clinical indicators of liver function results were as follows: TB: 11.2 mumol/L, ALT: 2018 U/L, AST: 16.9 U/L, and ALB: 47 g/L. Moreover, re-examinations after discharge showed that the lesions were completely necrotic and no signs of recurrence until last CT scan on January 1, 2021 (Figure 6), and mRECIST assessment was CR.

intrahepatic cholangiocarcinoma, iodine-125, transcatheter arterial chemoembolization

PMC8325583_01

Female

A 24-year-old Caucasian female with a past medical history of hypertension, chronic kidney disease stage 3, and type 2 membranoproliferative glomerulonephritis status-post living donor kidney transplant in 2002 managed on an antirejection regimen of cyclosporin, mycophenolate mofetil, and prednisone noticed the onset of paresthesias and pain in her left lower back the evening of April 13, 2020. The morning of April 16, a grouped vesicular rash positioned along the left 3rd lumbar vertebral dermatome erupted, as shown in Figure 1. Worried about a shingles outbreak, she sent a message that evening to her nephrologist inquiring if this was something that needed to be addressed. The next morning (April 17), she received a response from a care coordinator, on behalf of the nephrologist's office, relaying that she should reach out to her primary-care provider for further work up. Unfortunately, the COVID-19 pandemic meant nonemergent visits were to be conducted via telehealth, an overwhelmed system that had yet to adequately adapt. She was unable to secure an appointment in a timely manner and upon showering the evening of April 21 found her isolated dermatomal rash evolved to include multiple pruritic, vesicular eruptions on her chest. Worried about these developments, the patient reached a nurse on the emergency health services line that informed her she needed to go to the nearest emergency room for suspected disseminated shingles. On arrival, she was afebrile (98.4 F), tachycardic (pulse 114 bpm), and hypertensive (160/107 mmHg). The emergency room physician took the photo shown in Figure 1 labeled April 21 and documented that the patient had similar eruptions in the upper chest and was immune compromised. She was diagnosed with disseminated shingles and sent home with the instructions to again follow-up with her primary doctor and to take valacyclovir 1,000 MG by mouth 3 times per day for 7 days. Despite having started the valacyclovir the night of her emergency room visit, the morning of April 22 showed worrisome progression. The vesicular eruptions that had only been on her left lower back and upper chest became diffusely distributed throughout her torso and now included the neck, face, oral mucosa, and tongue, as shown in Figure 2. Fearful of what may happen if she were to wait for a telehealth appointment with her primary-care provider, she again reached out to her nephrologists relaying her emergency-room course, the plan implemented as well as providing the photos shown in Figure 2. In review of this information, the nephrologist refuted the plan for outpatient oral valacyclovir treatment and coordinated for same day hospital admission. On admission 5 : 00 pm April 22, she was afebrile (98.1 F), tachycardic (pulse 123 bpm), and hypertensive (143/90 mmHg). Laboratory studies showed a bump in her baseline creatinine from ~1.40 mg/dL to 2.18 mg/dL indicating an acute kidney injury in the setting of viremia, hypertension, and poor oral intake. In addition, the patient's lesions had progressed to include more of her face and had invaded her proximal arms and legs. Fortunately, an ophthalmic exam did not find any involvement of the eyes. PCR analysis was conducted on lesion swabs that were negative for HSV-1 and HSV-2 but positive for varicella zoster confirming the diagnosis of disseminated shingles. She was promptly started on NaCl fluid supplementation and I.V. acyclovir 10 MG/kg twice per day for 5 days. By April 27, the patient's lesions had scabbed over and her creatinine was back to baseline. She was discharged home and instructed to take valacyclovir 1,000 MG twice per day through May 7 at which time she reported a full recovery apart from lesion scarring.

PMC8326784_02

Female

A 49-year-old female patient was diagnosed with stage III HIV infection 11 years back after presenting with smear negative pulmonary tuberculosis and oropharyngeal candidiasis with a baseline CD4+ count 74 cells/mm3. She was covered with fluconazole as antifungal therapy. She was treated with anti-tuberculosis treatment (ATT) for 6 months and declared treatment completed. ART (AZT-3TC-NVP) and CPT were started two weeks after ATT initiation. She had records of undetected viral load after 2 years of ART initiation. The ART regimen was shifted to TDF-3TC-DTG after 10 years as recommended by the National Comprehensive HIV Care Guideline. She was diagnosed with hypertension and dyslipidemia on follow-ups, and advised on lifestyle modification. She was diagnosed with type 2 diabetes after presenting with polyuria, polydipsia, fatigue and blurred vision, and hyperglycemia (RBS=313 g/dl) which occurred after 1 year of the DTG-based ART regimen (Table 1). No documented preceding infections. No personal or family history of diabetes mellitus. Serum C-peptide level, anti-insulin antibody or anti-GAD antibody were not determined due to limited clinical setup. No documented plasma glucose level prior to changing ART regimen. She was started on NPH insulin 24 IU s/c daily, which later changed to metformin 1 gm po daily. Good glycemic control (FBS=109-135 mg/dl) was achieved with metformin, while the DTG-based ART regimen was continued.

instis, dolutegravir, hyperglycemia

PMC8366463_01

Male

A 38-year-old male presented to the emergency medicine department of our urban academic tertiary care center with painless left eye swelling for the last seven days. He also complained of progressive limitation of left eye movement with drooping of left eyelid, ultimately causing inability to open left eye over last week. He complained of having double vision while looking sideways. While looking himself in mirror two days ago, he also noticed his mouth deviating towards the right side of his body. He had history of high-grade fever, mostly at nighttime, in the last fifteen days, which was responsive to oral antipyretics, as well as few episodes of bloody sputum. His wife also noticed his body excessively sweating at night for the last few weeks and his significant weight loss in the last few months. The patient had suffered from diabetes mellitus for the last seven years, non-compliant to orally administered anti-hyperglycemic agents (OHA) treatment. His past medical history revealed having been diagnosed with pulmonary tuberculosis two years back, for which he took regular treatment only for four months. He has smoked (30 pack years), consumes alcoholic beverages four days a week, and occasionally uses opium. There was no history of trauma, involuntary body movements, pus or watery discharge from ear, epistaxis, alteration in sensorium or behavior, dysphagia, or change in voice. No history of any recent surgery was present. The patient was conscious with Glasgow coma score (GCS) of E3V4M5, afebrile (temp 99.6 F), blood pressure of 100/80 mmHg, pulse rate of 89/min, and respiratory rate of 22/min, cooperative with physician. Neurological examination revealed deviation of angle of mouth to the right side with absent wrinkling of forehead on left side, abnormal grimace with hypoesthesia in distribution of V1, V2 branches of left trigeminal nerve (Figure 1). On blowing of mouth air, leak was present from left side. Left eye ptosis, immobility, fixed mid-dilated non-reactive pupil and complete loss of accommodation, and loss of left corneal sensation were noted. Fundoscopy revealed normal disc and macula. He had bilateral lower and upper limb power of 5/5 with normal reflexes and no other cranial nerve deficit was noted. Nasal discharge from left nostril was seen, which was not blood stained. No infraorbital necrosis, ulcer, or perforation of hard palate were present. Gag reflex was intact. Based on clinical findings, after ruling out possibility of trauma, a differential diagnosis of cerebrovascular accident (CVA), intracranial space occupying lesion, tuberculoma or diabetes mellitus-related neuropathy with tuberculosis reactivation were considered. Initial Non-Contrast computed tomography (CT) scan (NCCT) of the head revealed left maxillary sinusitis. Hematological and biochemical workup done in emergency department revealed anemia, raised total leukocyte count (TLC), and high random blood glucose without ketoacidosis (Table 1). Cerebrospinal fluid examination was unremarkable. Electrocardiogram (ECG) was not suggestive of any abnormality. Urine and blood culture were sterile. Sample for assessing KOH mount of nasal secretion was sent. His sputum was sent for acid fast bacilli (AFB) staining as well as fungal evaluation. Patient was admitted to the emergency medicine ward and started on intravenous (IV) antibiotics empirically, and insulin for glycemic control, as further diagnostic evaluations continued. As per local guideline, his high nasal and oropharyngeal swab were sent for RTPCR for COVID-19, which came negative. His chest radiograph revealed fibrotic bands along with cavitary lesion with surrounding consolidation and air crescent sign present in both hemi thoraces (figure 2). Contrast-enhanced magnetic resonance imaging (CEMRI) of brain, orbit, and paranasal sinuses (PNS) was done to look for intracranial pathology. It demonstrated acute left maxillary sinusitis with posterolateral wall erosion, prominent left optic nerve sheath, and skull base osteomyelitis with cavernous sinus thrombosis (Figure 2). In view of chest X-ray findings, after pulmonary consultation contrast-enhanced CT scan (CECT) of chest was performed to aid in decision regarding initiation of anti-tubercular therapy, which suggested tuberculosis reactivation (Figure 2). Patient's KOH mount of nasal secretion showed non-septate ribbon-like hyphae. Based on cumulative results of initial evaluation, a primary diagnosis of invasive rhino-orbito-cerebral mucormycosis with pulmonary tuberculosis reactivation was made. Anti-tubercular treatment (ATT) was started and ear, nose, throat (ENT) review was sought for assessing need for urgent endoscopic debridement, taking in account intra-orbital and intracranial fungal extension causing multiple cranial nerve palsies threatening vision. Nasal endoscopic debridement and left orbital decompression were performed the next day. Histopathological examination (HPE) of excised tissue revealed broad aseptate hyphae with right angle branching invading both nerves and vessel wall, confirming diagnosis of invasive mucormycosis (Figure 2). Patient was started on amphotericin B, optimal anticoagulation, and insulin therapy for optimization of glycemic control. His biochemistry was regularly monitored for any nephrotoxicity, hematotoxicity, and other infusion-related adverse effects. A repeat endoscopic debridement was performed after a period of seven days. Meanwhile, serial fundoscopy was performed by ophthalmologist to look for possible optic nerve involvement, any optic disc changes, papilledema, or decrease in visual acuity and field. A week after the second debridement and thirteen days of amphotericin B cumulative dose 1425 milligrams, patient complained of severe pain in left side of face, predominant in the orbital region with increased swelling on waking up from sleep. Fundus examination revealed a cherry red spot, optic disc edema with complete retinal opacification, suggesting central retinal artery occlusion in left eye. Patient was started on topical timolol 0.5% and systemic acetazolamide alongside intermittent digital ocular massage with the aim of reducing intraocular pressure. He did not respond to the above measures and decision for left eye exenteration alongside repeat decompression and debridement was made. Post-exenteration monitoring for involvement of right eye and other signs of raised intraocular and intracranial pressures continued alongside antifungal therapy. His condition remained satisfactory and gradual improvement followed. His right eye vision remained unaltered and serial fundoscopy did not reveal any alarming features. Optimal glycemic control was achieved with insulin therapy. He was ultimately discharged home after 48 days of hospital stay in a stable state with residual left facial nerve palsy, written advice to follow up for dressing, ocular prosthesis, and further treatment optimization.

mucormycosis, diabetes mellitus, facial paralysis, retinal artery occlusion

PMC6399132_01

Unknown

Between 2008 and 2018, 209 brain-damaged patients subsequently diagnosed as MCS were admitted into the University Hospital of Liege, including 19 patients who were assessed at two time points using neuroimaging techniques and repeated Coma Recovery Scale-Revised (CRS-R). Inclusion criteria were: >28 days post-injury when first assessed; diagnosis made based on at least 5 CRS-R, diagnosed in MCS- during the first week of assessment and later diagnosed in MCS+ during the second week of assessments. Three patients met our inclusion criteria (age: 23-37 years-old, two TBI, time since onset: 10 months to 5 years). These three patients in MCS- during their first week of assessment, later recovered command following when reassessed during a second week of evaluations (26-31 months later). The study was approved by the Ethics Committee of the Faculty of Medicine of the University of Liege and written informed consents for study participation and data publication have been obtained from the patients' legal representatives as well as from the healthy control subjects.

consciousness, language, minimally conscious state, positron emission tomography, structural magnetic resonance imaging

PMC3079872_01

Female

A 25-year-old woman presented to the hospital with a complaint of amenorrhea for 2 years, increased frequency of fatty stools, and decreased appetite for 6 months, generalized body swelling of 2 months duration, fever of 1 month duration, pain abdomen off and on. Physical examination revealed pallor and pitting edema of bilateral lower limbs. Respiratory and cardiovascular system examination revealed no abnormality. No past history of tuberculosis, diabetes mellitus, or hypertension. Ascitic tap revealed clear fluid (transudate). Laboratory investigations revealed decreased total protein, 4.4 g/dL (normal 6-8 g/dL); reduced albumin, 1.9 g/dL (normal 3.5:5 g/dL); and low serum amylase, 8 somogyi units (normal 20-200 somogyi units). Routine blood tests and liver and renal function tests were normal. Chest X-ray revealed left-sided pleural effusion. Ultrasound abdomen revealed hyperreflective pancreas [Figure 1a], free fluid within the pelvic cavity, and mildly dilated small bowel loops with thickened wall. Computed tomography revealed atrophic pancreas with complete fatty infiltration (attenuation value = -120 HU), and no demonstrable normal pancreatic parenchyma [Figure 1b and c]. Solitary calculus was noted within the pancreatic duct near the ampulla of Vater without pancreatic duct dilatation [Figure 1d]. There was no dilatation of intrahepatic biliary radicals or common bile duct. Small bowel wall thickening with increased intraluminal fluid and dilution of contrast medium was also evident [Figure 1e]. On the basis of the above-mentioned findings, the diagnosis of diffuse pancreatic lipomatosis (secondary to chronic pancreatic duct obstruction by calculus) leading to malabsorption, subsequently fatty steatorrhea, hypoproteinemia, and retention of fluid within the body was made.

computed tomography, malabsorption, pancreatic lipomatosis

PMC9132688_01

Male

The patient was a 67-year-old man who had been on HD for 39 years due to chronic renal failure. About 3 months earlier, he had noticed discomfort in the tongue and was referred by a dialysis doctor for examination. His medical history other than chronic renal failure (at 27 years old) included right nephrectomy for renal cell carcinoma (at 47 years old), left nephrectomy for renal cell carcinoma (at 50 years old), parathyroidectomy (at 51 years old), surgery for lumbar spinal stenosis (at 56 years old), surgery for destructive spondyloarthropathy (at 59 years old), right-side colon resection for ileus due to intestinal tuberculosis (at 63 years old), surgical decompression of carpal tunnel syndrome (at 66 years old), and ileal biopsy suggestive of amyloidosis (at 67 years old). Histopathological examination of the specimen from ileal biopsy showed amorphous eosinophilic deposits on the vessel wall (Figures 1(a) and 1(b)). Immumohistochemically, deposits were positive for beta2m (Figure 1(c)). Current medications included alfacalcidol, ursodeoxycholic acid, sevelamer hydrochloride, and lanthanum carbonate hydrate, and the serum beta2m level was 20.7 mg/L. In addition, the renal cell carcinomas and surgical decompression of carpal tunnel syndrome were not treated at the referring hospital and detailed data were not available. On oral examination, a collection of painless, relatively hard, rugged whitish-yellow papules was found on the ventral surface of the tongue tip (Figure 2). No movement disorder of the tongue was apparent. The patient showed no difficulty in eating or dysphagia. No abnormal findings were found in other sites of the oral cavity or regional lymph nodes. Biopsy was performed under local anesthesia. Histopathologically, the specimen showed amorphous eosinophilic extracellular deposits in the subepithelial region (Figure 3(a)). Extracellular deposits showed positive results from DFS staining, and also from potassium permanganate- (KMnO4-) DFS staining and beta2m staining (Figures 3(b)-3(d)). The pathological diagnosis was amyloidosis, strongly suggestive of DRA. At the 6-month follow-up, no significant change in systemic DRA was seen, including tongue symptoms.

PMC6382085_01

Male

A 74-year-old gentleman complained of a right neck swelling that had been increasing gradually in size for the past 2 years. He had no pain, dysphagia, dyspnea or dysphonia. He also did not complain of any shortness of breath, foul-smelling breath, fever, weight loss or loss of appetite. He had no symptoms of hyperthyroidism or hypothyroidism. Interestingly, he complained of cough whenever the neck mass was touched. The patient was a diabetic with hyperlipidemia and hypertension. He also had a cerebral insult in the previous year with right hemiparesis which had resolved. He had no history of tuberculosis or any contact with such patients. The patient was a chronic smoker. The patient was alert and conscious and oriented to time and place. All cranial nerves were intact. The oral cavity and oropharyngeal examination was unremarkable. The neck examination revealed a fullness on the right Level III measuring 4 cm x 3 cm (Figure 1). There were no skin changes and the fullness was not tender and soft on palpation. However, during the palpation of the mass, the patient developed bouts of coughing. Otoscopy and nasoendoscopy showed normal findings. On examination of the larynx and hypopharynx, all structures were normal, and the bilateral vocal cords were mobile. A computed tomographic (CT) scan demonstrated a well-defined, solitary mass in the right carotid space, posterior to the carotid artery and internal jugular vein (Figure 2). The mass was hypodense to the skeletal muscles and showed mild enhancement post-contrast. There was no calcification or necrosis within it. The mass measured 2.3 cm x 2.4 cm x 7.6 cm and extended from the level of C2/C3 to C6/C7. It compressed the right internal jugular vein, abutted the common carotid artery and stretched the adjacent sternocleidomastoid muscle. However, the vein was still patent and was not separated from the common carotid artery. These features were suggestive of a right vagal schwannoma. Microscopically, the smears of high cellularity were composed of clusters of uniform spindle cells in a bloody background. The spindle cells had oval nuclei, inconspicuous nuclei and a moderate amount of cytoplasm. Blood vessels were also seen intermingled with these clusters. No mitosis or bizarre cells were seen. No lymphoid or squamous elements were noted. Sections from the cell block showed sheets of spindle cells arranged in a hypercellular pattern. Some cells exhibited palisading and formed vague Verrocay bodies. The fine needle aspirate of the mass showed the presence of spindle cells, indicating that it was most probably a schwannoma. An attempt to perform fine needle aspiration for cytology (FNAC) failed due to coughing induced by palpation of the mass. In view of risk to the adjacent vascular structures, an ultrasound-guided FNAC was performed with difficulty due to the patient's paroxysmal cough during the procedure. The ultrasound reported a homogenous hyperechoic solid lesion measuring 2.3 cm x 2.6 cm in the right neck lateral to the right internal jugular vein and internal carotid artery. No calcification or vascular activity was noted within it. Based on the patient's age and co-morbidities, we discussed the treatment plan with the patient and his family. In consideration of the patient's multiple co-morbidities; possible complications, such as hoarseness and injury to the adjacent structures; and the patient's preferences, we agreed to conservative watchful management, as the tumor was benign and slow-growing. As of now, the patient has been under our observation for the past year, tumor growth has been static and no compression symptoms or airway compromise have been exhibited.

cough, neck mass, parapharyngeal, vagal schwannoma

PMC4681891_01

Male

A 48-year-old man was referred with a 2 month history of chest tightness, intermittent non-productive cough and unintended weight loss of 3 kg in the past 2 month. He had no reported fever and had no prior medical history. He smoked around 30 cigarettes per day and had estimated 45 pack years. Physical examination revealed no abnormalities. Routine laboratory investigations, including leukocytes (L) and C-reactive protein (CRP) presented normal values. The lung functions tests showed normal ventilation parameters with forced expiratory volume in 1 s (FEV1) of 3.5 l (94% of the predicted value) and forced vital capacity (FVC) of 4.5 l (97% of the predicted value). The chest X-ray presented an approximately 2 cm nodular infiltrate in the left lung (Fig. 1). Computed tomography (CT) scan of the chest confirmed infiltrate in segment 6 of the left lower lobe (Fig. 2). Under the presumptive diagnosis of malignancy we ordered a whole-body 18 flour-deoxyglucose positron emission tomography (18-FDG-PET) and CT scan. It revealed a high metabolic activity of the lesion (Fig. 3). With this imaging appearance, a provisional diagnosis of lung cancer was made. The patient underwent bronchoscopy with brush biopsies, endobronchial ultrasound transbronchial needle aspiration (EBUS -TBNA) and CT-guided lung biopsy with negative result concerning malignancy and without any diagnostically clarification. We still considered that the patient has lung cancer, so the next step was Video-assisted thoracoscopic surgery (VATS). The pathologic examination revealed no malignancy but instead caseous granulomatous inflammation. PCR for mycobacterium TB complex taken from the resected lung tissue was positive, so the diagnosis of pulmonary TB was confirmed, and the patient received standard anti-TB-therapy composed of pyrazinamide, isoniazid, ethambutol and rifampicin.

lung cancer, lung tuberculosis

CT thorax showing infiltrate in the left upper lobe.

PMC4681891_02

Male

A 56-year-old man with a 12 month history of productive cough, thorax pain related to respiration and around 10 kg unintended weight loss was referred to our department with a presumptive diagnosis of lung cancer. He smoked up to 60 cigarettes per dag and had estimated 100 pack/years. Routine laboratory investigations, including L and CRP revealed no abnormalities. He was diagnosed with COPD and lung function tests showed FEV1 over 2.2 l (59% of predicted value) and FVC over 3.7 l (79% of predicted value). He had a family history of lung cancer and had a history of alcohol overconsumption. Chest X-ray showed consolidation in the upper right lobe (Fig. 4) and the CT scan revealed an infiltrate with cavitations and irregular margins (Fig. 5). The patient underwent 18-FDG-PET and CT scan with the result of high metabolic activity of the lesion (Fig. 6). The next diagnostic step was bronchoscopy with brush and forceps biopsies with negative results concerning malignancy. We also sent bronchial wash samples to microbiological diagnostic with negative results concerning bacteria, fungi, legionella, mycoplasma, chlamidiae, negative direct microscopy and PCR for mycobacterium TB complex. Only cultivation of the bronchial wash provided the diagnosis by documented growth of the mycobacterium TB. The patient was started on standard anti-TB-therapy.

lung cancer, lung tuberculosis

PMC3236477_01

Female

PBC has been considered as the most common liver disorder in patients with systemic sclerosis (SSc). This association was first described to co-occur by Milbradt in 1934, and it has been noted historically in several case reports. One such case from 1964 reports two patients with SSc and possible (but unconfirmed) PBC. Murray-Lyon et al. report two cases of SSc and PBC. The first case was that of a 64-year-old female with Raynauds and scleroderma of the right hand and arm, who was found to have hepatosplenomegaly. She was positive for AMA, and a liver biopsy confirmed the diagnosis of PBC. The second case was similar, with AMA positivity and PBC confirmed on liver biopsy. Despite several similar reports over the years, liver disease has not been considered a significant feature of scleroderma, and a higher prevalence of liver disease was found in the control populations of several large studies. The association of lcSSc and PBC was first described in 1970 with two cases of PBC and limited scleroderma. A further six cases were reported by Reynolds et al., and several other case reports have found an association between lcSSc and PBC. The first case reporting an association of PBC and scleroderma, without features of lcSSc, was described in 1972. The prevalence of clinically evident PBC among patients with SSc was recently reported to be 2.5% in a registry of 1700 SSc patients and 2% in a series of 817 patients with SSc. On the other hand, the prevalence of SSc in patients with PBC is estimated to be around 8%, as demonstrated by two studies comprising large cohorts of patients with PBC. However, case reports and some series reported a wider range of prevalence (3-50%) of SSc, mostly lcSSc, in PBC patients. Large epidemiological studies on PBC note a minority of patients who also have SSc (scleroderma). A large French study found scleroderma in 1% of a cohort of PBC patients, although 1% of their first-degree relatives and 1% of controls were also noted to have scleroderma. One of the most comprehensive epidemiological studies by Gershwin and colleagues found that 2% of PBC patients and 1% of their first-degree relatives had scleroderma, compared to none of the controls. First-degree relatives with scleroderma were more often sisters, followed by daughters of PBC patients. Twin studies in both conditions are scarce. One twin study for SSc found a low concordance of 4.2% among monozygotic (MZ) twins, compared to 5.6% in dizygotic (DZ) twins. Interestingly, there was a 90% concordance for ANA among MZ twins, compared to only 40% among DZ. A higher concordance of 63% among MZ twins was found in the only comprehensive twin study in PBC. Although both twin studies note co-existing autoimmune disease, which was often the same condition in the twin, none have noted SSc in twins with PBC or PBC in twins with SSc. Despite the scarcity of case reports and large-scale studies, the association of PBC and scleroderma seems to be more than coincidental and suggests that these two diseases might have a common autoimmune basis. However, the autoimmune mechanisms behind the PBC-SSc association are still not fully understood. It has been reported that this patient group has clonally expanded CD8(+) T cells expressing one T-cell receptor beta-chain variable region, TCRBV3, which may be involved in the disease pathogenesis. Genetic, epigenetic, environmental, and infectious factors appear to be important for the induction of the underlying autoimmune pathology, but the hierarchy of events and the close interplay of these factors are not well defined. The association between PBC and SSc has been largely based on reports indicating the presence of autoantibodies related to SSc in patients with PBC and vice versa. Autoantibodies which characterize limited cutaneous SSc (lcSSC) include anti-centromere antibodies (ACA), anti-Th/To, anti-U1-RNP, and PM/Scl. Diffuse cutaneous SSc (dcSSc) is characterized by anti-Scl 70 antibody (anti-topoisomerase I antibody, TOPO), anti-RNA polymerase III, and anti-U3-RNP. Severe lung disease is the hallmark of anti-TOPO-positive dcSSC patients. DcSSc patients with anti-RNA polymerase III have the most severe skin disease and the highest frequency of renal crisis. Patients with the nucleolar antibody anti-U3-RNP have dcSSc with multiorgan involvement. The autoimmune basis of association between PBC and SSc was first established by the presence of AMA in approximately 5% of patients with scleroderma and ACA in one-quarter of patients with PBC. A positive ACA is reported in 9-30% of PBC patients and in 22-25% of all SSc patients, almost all of which have lcSSc. Conversely, up to 25% of SSc patients are AMA positive, but the high prevalence rates of AMA are probably secondary to referral bias and overestimate the frequency of AMA in SSc. Another interesting point which needs attention is that of studies reporting a relatively high prevalence of AMA negative PBC in patients with SSc or other autoimmune diseases the autoantibody profile of SSc patients with AMA-negative PBC may require the use of highly sensitive immunoassays for the detection of AMA. It has been shown that such assays are able to detect AMA in serum samples from SSc patients characterized as AMA negative by indirect immunofluorescence, and this may be the case for other PBC-specific autoantibodies, such as ANA specific for sp100. ACA positivity is greater in PBC-SSc than in either disease in isolation, but there is no cross-reactivity between mitochondrial and centromere antigens. Because ACA have been detected not only in SSc but also in other autoimmune diseases including PBC, the clinical significance of ACA in PBC has been the focus of ongoing research. Three major centromere antigens have been recognized: centromere protein A (CENP-A, 18 kD polypeptide), centromere protein B (CENP-B, 80 kD polypeptide), and centromere protein C (CENP-C, 140 kD polypeptide). One study attempted to identify the major epitope of ACA in sera obtained from patients with PBC and to classify the correlation between the presence of ACA epitopes and the clinical features in patients with PBC. The serological results obtained were compared with clinical features of lcSSc in PBC. Forty-one patients with PBC were studied: 10 out of 16 (63%) patients with ACA (all anti-CENP A) had one or more lcSSc feature. The higher incidence of Raynaud's phenomenon seen in ACA-positive patients with PBC than that in ACA-negative patients with PBC suggested a close association of the presence of ACA with clinical features of lcSSc in patients with PBC. From the results of this study, it was proposed that there is a subset of PBC patients with scleroderma who are ACA positive and differ from both ACA-negative PBC-SSc and ACA-negative PBC non-SSc patients, based on their clinical features and ACA epitope reactivity. Over the past two years, a tremendous amount of data has come available as to the genetics underlying PBC and SSc. In regards to SSc, several HLA and non-HLA regions have been identified, with HLA regions showing variability among ethnic groups. Positive HLA associations in whites and Hispanics include HLA-DRB1*1104, DQA1*0501, DQB1*0301. Negative associations in those groups included DRB1*0701, DQA1*0201, DQB1*0202, and DRB1*1501. Positive HLA associations in African Americans included HLA-DRB1*0804, DQA1*0501, and DQB1*0301. That study also noted that ACA positivity was closely associated with HLA-DQB1*0501, and another study found an association between TOPO positivity and HLA-DRB1*1104. A smaller study of a Spanish cohort showed similar HLA findings to those noted above. Several non-HLA regions have also been identified in SSc. These include STAT4, IRF5, BANK1, TNSF4, TBX21, IL-23R, and C8orf13-BLK among others. As with SSc, several HLA and non-HLA regions have been identified in PBC. HLA regions include DRB1, DQA1, DQB1, and DQA2. Non-HLA regions include IRF5, STAT4, SPIB, IKZF3-ORMDL3, IL12A, IL12RB, MMEL1, DENND1B, CD80, IL7, CXCR5, TNFRSF1A, CLEC16A, and NKFB1. Interestingly, PBC and SSc have several genes in common: HLA-DRB1, DQA1, DQB1, IRF5, and STAT4, although it should be noted that DR11, which is positively associated with SSc, is considered protective in PBC. Infectious agents have been implicated in the pathogenesis of both SSc and PBC. A number of organisms, such as E. coli, have been strongly associated with PBC, but not with SSc. Helicobacter pylori and Chlamydia have been implicated in both conditions; however, some studies indicate the Chlamydia is not involved. It is possible that certain infectious organisms contributes to the development of PBC or SSc in isolation and that other organisms induce the disease in both conditions. Given the overlap between PBC with SSc and vice versa, including ACA positivity in PBC patients and AMA positivity in SSc patients, the major challenge remains to clarify which screening method would be best for early diagnosis of the associated conditions. Firstly, routine screening for PBC-specific antibodies in patients with SSc needs to be further refined. Recently, Norman et al. investigated the presence of antibodies against PBC disease-specific mitochondrial antigens and antibodies against the sp100 nuclear body antigen in 52 patients with SSc, by using two commercially available ELISAs. In that study, 13% of cases were positive for AMA and 2% for ANA (anti-sp100), and one patient (2%) was diagnosed with symptomatic PBC. These figures were reproduced by Mytilinaiou et al., who confirmed 13.5% positive results with ELISA testing for antibodies against PBC disease-specific mitochondrial antigens in 37 SSc patients. However, this was not confirmed with the conventional indirect immunofluorescence based on unfixed rodent kidney, liver, stomach tissue sections, or HEp-2 cells as antigenic substrates, and none of the ELISA-positive patients showed features of PBC. It remains to be clarified whether ELISA testing is less specific with false positive results or that it simply represents a more sensitive method with respect to indirect immunofluorescence, which should currently remain the technique of choice. Nevertheless, the presence of AMA can precede clinical symptoms of PBC. Indeed, Mitchison et al. and Metcalf et al. showed that the vast majority of AMA-positive subjects have typical histological features of PBC despite being asymptomatic with normal biochemistry. Furthermore, the study by Prince et al. suggested that 36% of initially asymptomatic PBC patients would become symptomatic within a median time of 5 years. Thus, AMA-positive SSc cases require immediate attention and close, long-term monitoring for early detection of symptoms, signs, and liver biochemistry suggestive of chronic cholestatic liver disease. Routine followup of AMA-positive SSc patients should include liver tests (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, albumin, bilirubin, international normalized ratio), thyroid function, and possibly an annual ultrasound abdominal scan. Transient elastography of the liver has been used to assess biliary fibrosis in patients with PBC. This test is emerging as a useful screening tool to detect undiagnosed chronic liver disease in apparently healthy subjects. Whether patients with SSc, who are tested positive for PBC-specific AMA, need regular checks with transient elastography or more common tests, such as liver ultrasound, needs to be evaluated in large prospective multicentre studies. Currently, there is no evidence that either of these would be of value. Figure 1 illustrates the diagnostic and screening algorithm for PBC in SSc patients. Screening PBC patients for ACA is not mandatory but can be considered, especially in the presence of disease-related symptomatology. Nakamura et al. reported that, in PBC patients, ACA positivity was significantly associated with more severe ductular pathology on liver histology and was a significant risk factor for the development of portal hypertension. In another study, ACA-positive PBC patients without clinical features of SSc were shown to have similar symptoms and signs at diagnosis. Although ACA positivity is not pathognomic of SSc, it is associated with an increased risk of developing connective tissue disease. One review reported a sensitivity of 32% (17-56%) for SSc and 57% (32-96%) for lcSSc and specificity of at least 93%, while ACA positivity was present in 5% of patients with other connective tissue diseases and less than 1% of disease-free controls. Since ACA could be predictive of rheumatic disorders, it has been suggested that an assessment of PBC patients should always include screening for SSc-related symptoms, such as Raynaud's phenomenon and CREST-related symptoms (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia). The use of nailfold videocapillaroscopy in patients suspected of having connective tissue disease may be a useful indicator. Some evidence suggests that this assessment can be useful for the diagnostic and/or clinical management of patients with PBC and suspected SSc. Experimental and clinical observation suggests that patients with PBC have endothelial dysfunction. In an interesting study, nailfold videocapillaroscopy abnormalities were found in 91% of patients with PBC, and capillary alterations characteristic of SSc were found in 54%. Eleven out of the 22 PBC patients (50%) had extrahepatic signs of connective tissue disease with most being related to SSc, while patients with other types of chronic liver disease did not present with rheumatic manifestations. In PBC patients, there was a significant association between SSc capillary pattern and rheumatic manifestations. The high prevalence of nailfold capillary abnormalities characteristic of SSc in patients with PBC, and correlation with sclerodermal manifestations, suggests that this capillaroscopic finding could be a useful indicator to investigate rheumatic manifestations in these patients. Further clinical assessment of organ involvement (especially lung by spirometry) in association with evaluation of pulmonary artery pressure on echocardiography should be considered in PBC patients with a definite diagnosis of SSc. A proposed diagnostic and screening algorithm for SSc in PBC patients is presented in Figure 2. In approximately 60% of the cases, the clinical presentation of SSc precedes that of PBC. The demographics of the disease in patients with overlapping features are not well defined. For example, it is not clear whether in the PBC-SSc group the diagnosis of PBC occurs at a lower age than that in patients with PBC alone. In a study of 43 PBC-SSc patients, the median age at diagnosis of PBC made after SSc diagnosis was lower (46.1 years) than in PBC diagnosed before SSc (51.1 years). This was lower than the diagnosis in PBC alone, with a median age of 53.2 years at diagnosis. The different age at diagnosis in the PBC-SSc patients, compared to patients with PBC alone, was probably due to the effect of lead time bias (i.e., screening for PBC in SSc patients and thus early diagnosis of asymptomatic PBC, since 56% presented with SSc alone). PBC-SSc patients were reported to have a higher incidence of a first episode of spontaneous bacterial peritonitis and septicaemia during followup with respect to patients with PBC alone. This is likely due to an increased risk of infection due to immune abnormalities and organ system manifestations associated with SSc. Both SSc and PBC are associated with increased morbidity and mortality compared with the general population. Among the disease-related causes of mortality in SSc patients, pulmonary fibrosis, pulmonary arterial hypertension, and cardiac causes (mainly heart failure and arrhythmias) are reported to account for the majority of deaths. The most frequent non-SSc-related causes of death are infections, malignancies, and cardiovascular causes. In PBC patients, liver-related causes account for roughly 50% of deaths, whereas cardio- and cerebrovascular causes together with malignancies are responsible for the non-liver-related deaths. Some case reports suggest that PBC in association with SSc is associated with a more favourable prognosis than PBC alone, whereas others reported increased mortality due to SSc. In the study which included 43 PBC-SSc patients, liver disease had a slower progression in PBC-SSc compared to matched patients with PBC alone. A lower rate of liver transplantation and liver-related deaths was demonstrated in PBC-SSc patients compared to patients with PBC alone, and these differences were not due to earlier SSc-related deaths. However, the improvement in liver-related survival in the PBC-SSc cohort was outweighed by an increase in non-liver-related deaths due to SSc, and, thus, overall survival was not different in PBC-SSc patients and those with PBC alone. These data emphasize the importance of comorbidity in PBC. More data on the outcome of patients with PBC and PBC with SSc are needed. If patients with PBC and SSc have a lower rate of liver transplantation and liver-related deaths compared to patients with PBC alone, it would be expected that patients with PBC and SSc-related ACA would also have better prognosis than their seronegative counterparts, but this does not appear to be the case. It may be that the outcome of patients with ACA-positive PBC, who do not have SSc-related symptoms, differs from that of ACA-positive SSc and PBC overlap. Prince and colleagues observed an increase in non-hepatic deaths in asymptomatic PBC, even with a reduced liver-related mortality, in comparison with symptomatic PBC. Since the causes of death in PBC-SSc patients are mainly due to SSc and not to liver disease, these patients may need different prognostic models in order to better predict their liver-related survival. Prognostic models for PBC alone may not be applicable for PBC associated with SSc or for other associated autoimmune diseases to assess the risk of liver-related mortality and the need for liver transplantation. All PBC patients with abnormal liver biochemistry should be considered for specific therapy. UDCA at the dose of 13-15 mg/kg/day on a long-term basis is currently considered the mainstay of therapy for PBC. In the early stages of PBC, UDCA protects injured cholangiocytes against the toxic effects of bile acids. In later stages of the disease, UDCA stimulates impaired hepatocellular secretion, mainly by posttranscriptional mechanisms. In addition, stimulation of ductular alkaline choleresis and inhibition of bile acid-induced hepatocyte and cholangiocyte apoptosis are included among the beneficial effects of UDCA in PBC. UDCA has been demonstrated to markedly decrease serum bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, cholesterol, and immunoglobulin M levels and to ameliorate histological features in patients with PBC in comparison to placebo treatment. However, no significant effects on fatigue or pruritus were observed in these large trials nor were effects on survival. Favorable long-term effects of UDCA are observed in patients with early disease and in those with a good biochemical response, which should be assessed after one year from start of treatment. A good biochemical response after one year of UDCA treatment is currently defined by a serum bilirubin <=1 mg/dL (17 mumol/L), alkaline phosphatase <=3x ULN, and aspartate aminotransferase <=3x ULN, according to the ''Paris criteria". The "Barcelona criteria" indicates a good response with a 40% decrease or normalization of serum alkaline phosphatase. Whether treatment with UDCA has an effect on the symptoms and the outcome of SSc remains poorly understood. Prospective studies of patients with PBC-associated SSc who are followed-up for many years under UDCA treatment are needed to address this issue. The treatment of SSc is complex and may include drugs with hepatotoxic potential. For example, the use of endothelin-1 receptor antagonist bosentan, which is the treatment of choice for SSc-related pulmonary artery hypertension, has been associated with increased risk of elevated aminotransferases. When PBC is present, the management of SSc patients is more challenging, as this autoimmune liver disease may pose further risk factors or unwanted complications. Whichever therapy is to be implemented, it is recommended that collaboration takes place between specialists responsible for the care of these patients.

PMC9582243_01

Male

A 49-year-old male patient was admitted to our department due to increased frequency of urination, urodynia, and hematuria for about 11 months. Ultrasonography identified a solid mass with the size of 3.7 cm x 2.6 cm in the anterior wall of the bladder. Computed tomography of the abdomen further showed that the bladder was irregularly thickened. A tumor with the size of 4.0 cm x 2.7 cm x 4.0 cm and progressive annular enhancement was observed in the anterior wall, which extended superiorly up to just below the umbilicus ( Figure 1 ). Cystoscopy identified a cauliflower-like tumor with the size of 4 cm x 4 cm and a broad base on the top wall of the bladder. Diagnostic resection was then performed, and histological analysis revealed that there was bladder adenocarcinoma (predominantly consisting of signet ring cell type) in the excised mass. Immunohistochemistry showed that villin, CK20, CDX-2, and Ki-67 were positively stained in the tumor, while P40, P63, and CK7 were negatively stained. No gastrointestinal tumor was found by gastroscopy, colonoscopy, or gastrointestinal barium. Radical cystectomy was prepared for this patient according to the above findings. During the surgical exploration, a urachal mass extending from the umbilicus to the dome of the urinary bladder was found. Unfortunately, multiple metastases were seen in the sigmoid colon, terminal ileum, mesentery, and peritoneum, so palliative surgery including partial cystectomy and urachal mass cystectomy was conducted for this patient. Postoperative pathology showed that the tumor consisted of poorly to moderately differentiated adenocarcinoma, including signet ring cell carcinoma and mucinous adenocarcinoma ( Figure 2 ). The carcinoma invaded the subserosal fibrous connective tissue and some area had broken through the serosa. The immunohistochemical results were as follows: CKpan (+), villin (+), CK20 (+), CDX-2 (+), beta-catenin (+), SATB (+), cdh17 (+), CK7 (-), GATA-3 (-), CK5/6 (-), P40 (-), P63 (-), PAP (-), PSA (-), CK7 (-), and Ki-67 (+). In addition, the periodic acid-Schiff stain and mucin carmine staining were both positive in the carcinoma tissue. Postoperative PET-CT identified several metastases in the peritoneum and omentum. The clinical stage for this patient was finally referred to as IVb according to the Sheldon staging system. Chemotherapy was conducted for this patient after surgery. A chemotherapy regimen (repeated every 21 days) involving fluorouracil (100 mg/m2, civ 96 h, days 1-4) combined with cisplatin (75 mg/m2, ivgtt, days 1-3) was made for this patient. In addition, the patient also received oral anlotinib (10 mg/day on days 1-14 of a 21-day cycle) for targeted therapy. So far, this patient has received 4 cycles of pharmaceutical therapy and is now doing well on regular follow-up. The treatment timeline for this patient is summarized in Figure 3 . Tumor biomarkers, including carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigen 72-4 (CA72-4), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125), were detected for this case. CEA was 1.2 ng/ml (normal: 0-5), AFP was 1.9 mug/L (normal: <7), CA72-4 was 11.3 U/ml (normal: 0-6.9), CA19-9 was 9.3 U/ml (normal: 0-39), and CA125 was 145 U/ml (normal: 0-35) in the first month after surgery. In the most recent follow-up, CEA was 1.3 ng/ml, AFP was 2.6 mug/L, CA72-4 was 12.8 U/mL, CA19-9 was 10.3 U/mL, and CA125 decreased to 22.2 U/ml.

case report, diagnosis, signet ring cell carcinoma, treatment, urachal carcinoma

PMC8254146_01

Male

A 63-year-old male, with a past medical history (PMHx) of recurrent abdominal adhesions requiring multiple surgeries, presently with Abcarian stoma and mucus fistula, presented with a history of abdominal pain and fever. The results of his initial physical examination revealed a body temperature of 36.8 C, a blood pressure of 109/54 mmHg, a pulse rate of 109 beats/min, and a respiratory rate of 18 breaths/min. The breathing sound was coarse; his heartbeats were regular without audible murmur; the abdomen was soft with tenderness in the right upper quadrant, with positive murphy signs. There was no palpable mass or hepatosplenomegaly noted. The initial blood investigations revealed mild anemia, hemoglobin level of 10.6g/dl, with marked neutrophilic leuocytosis, white blood cell count of 28,000/ml. The C-reactive protein level was 100 mg/L. His troponin I level was mildly elevated at 48 ng/L. Renal function was deranged with a creatinine level of 176 umol/L and urea of 19 mmol/L. Other laboratory findings, including electrolytes, liver function tests, serology, and urinalysis, were all within normal limits. Chest X-ray findings were unremarkable, as was the initial ECG. Ultrasound of abdomen showed thick gallbladder wall greater than 3mm, with pericholecystic fluid. There was also evidence of sludge and cholelithiasis. He was admitted with the impression of sepsis secondary to acute cholecystitis. He was started on antibiotics along with other supportive measures. On the next day, the patient continued to be highly febrile and became hypotensive requiring intensive care unit (ICU) admission and inotropic support. On the 2nd day of ICU admission, he started complaining of retrosternal chest pain which was associated with profuse sweating. ECG was notable for ST-segment elevation on leads V2-V4 [Figure 1]. The patient's troponin-T level was elevated at 781 ng/L. A diagnosis of anterior wall ST-segment elevation myocardial infarction was considered. An emergent coronary angiography was done which demonstrated nonobstructive CAD. Echocardiographic evaluation revealed dilated left ventricular cavity with extensive apical dyskinesis and relative preservation of the basal to midseptal and basal-lateral wall contraction [Figure 2]. Estimated left ejection fraction was approximately 25%. Sepsis-induced TCM was the final diagnosis in this patient. The patient recovered after antibiotics and other conservative therapies, and finally, he was discharged from the hospital. He had repeated echocardiogram 4 weeks later which showed complete resolution of left ventricular systolic function, estimated ejection fraction was >55%.

st-elevation myocardial infarction, sepsis, takotsubo cardiomyopathy

PMC4720805_01

Male

A 30-year-old male (height: 175 cm, body weight: 105 kg) presented with fever for 6 days, and abdominal pain and diarrhea for 2 days. He was admitted to the gastroenterology department of an outside hospital. He did not have any history of underlying disease and had recently stopped smoking. He worked for 2 weeks at another hospital where a patient diagnosed with MERS. His initial vital signs and results of initial laboratory examination were unavailable to us, because he was admitted to an outside hospital. However, according to information from that hospital, physical examination on admission to that hospital revealed normal vital signs (except for fever) and initial laboratory examination showed mild elevation of liver enzymes. In that hospital, he firstly underwent chest and abdominal radiographs and abdominal CT for further evaluation of abdominal pain. The initial chest radiograph, which was taken 6 days after the onset of fever, showed a patchy increased opacity in the left lower lung zone, retrocardiac area (Fig. 1A). Abdominal CT showed no specific finding in abdominal and pelvic organs; however, a patchy area of consolidation with an air-bronchogram was detected in the left lower lobe of the lung, which was mainly peripherally located (Fig. 1B). Conservative treatment with intravenous fluid was used for abdominal pain. Although he did not initially have any respiratory symptoms, he began coughing 9 days after the onset of fever. Because of this new respiratory symptom, occupational history, and a recent MERS outbreak in Korea, he underwent laboratory examination for MERS. A follow-up chest radiograph, which was taken 10 days after the onset of fever, showed newly developed patchy areas of ill-defined increased opacity in the right upper lung zone and increased extent of the previously detected consolidation in the left lower lung zone (Fig. 1C). A chest CT scan performed on the same day showed multifocal patchy areas of nodular consolidations orgwith ground-glass opacity (GGO) halo and nodular GGO lesions in both upper lobes, which were mainly slightly peripherally located (Fig. 1D). Moreover, this scan also demonstrated increased extent of mixed consolidations and GGOs with air-bronchograms in both lower lobes, mainly in the dependent area (Fig. 1E). There was no pleural effusion or significant lymph node enlargement. Finally, he was diagnosed with MERS by testing the sputum by real-time reverse-transcriptase-polymerase chain reaction (rRT-PCR). For intensive care and management of MERS, he was transferred to a negative pressure room of our hospital on the day of diagnosis. Physical examination in our hospital showed fever (38.4C) and elevated blood pressure (154/106 mm Hg). His vital signs on admission are summarized in Table 1. Laboratory examination on admission of our hospital showed normal white blood cell counts (5640/microL), and elevated serum aspartate aminotransferase (AST, 155 international unit [IU]/L), alanine aminotransferase (ALT, 77 IU/L), lactate dehydrogenase (904 IU/L), and C-reactive protein (CRP, 9.39 mg/dL). He was administered antiviral agents (ribavirin, kaletra [ritonavir + lopinavir], and interferon-alpha) and antibiotics (tabaxin [piperacillin + tazobactam] and cravit [levofloxacin]). Daily follow-up radiographs were taken to evaluate disease progression. Fever disappeared after 2 days of treatment; although radiologic abnormalities remained on early follow-up radiographs, then their extent decreased after 5 days of treatment. After a week of treatment, he showed no symptom. Follow-up laboratory examination showed normalization of CRP (0.14 mg/dL), slightly deceased but remained elevated AST (131 IU/L), whereas increased ALT (142 IU/L). Finally, follow-up sputum tests by rRT-PCR (conducted twice) showed negative results, and he was discharged after 13 days in our hospital. On the day of discharge (23 days after the onset of fever) he underwent chest radiograph and chest CT scan. The chest radiograph depicted markedly decreased extent of previous increased opacities in the right upper and left lower lung zones (Fig. 1F). The chest CT scan showed markedly decreased extent of previously detected lesions with residual nodules or GGOs in both lungs, and developed traction bronchiectasis within retracted consolidation with volume loss in the left lower lobe, which suggested fibrosis (Fig. 1G, H).

ct, clinical course, middle east respiratory syndrome, radiograph, serial imaging finding

PMC4246679_01

Female

The patient was a 32-year-old woman with an irregular menstrual cycle and a previous menstrual period lasting 8 days (from November 29, 2002). Amenorrhea and pain in the lower left abdominal region prompted the patient to consult a neighborhood gynecologist. Although the result of a pregnancy test was positive, transvaginal ultrasonography did not reveal a gestational sac (GS) in the uterus. However, a cystic tumor containing a solid, fetus-like mass was observed in the left uterine appendage. Atypical genital bleeding was absent. Based on these findings, an ectopic pregnancy was suspected and the patient was referred to Iwate University Hospital the following day. The patient had been pregnant three times, two involved spontaneous abortions and one resulted in delivery. The patient's medical and family history did not present cause for concern. Pregnancy test results were positive, and transvaginal ultrasonography did not reveal any symptoms normally associated with pregnancy, such as the occurrence of a GS in the uterus. However, a 28-mm cystic tumor (Fig. 1), containing a 6.5-mm, solid mass (Fig. 2), was observed in the left uterine appendage. Both side ovaries were observed by transvaginal ultrasonography. Urinary and blood human chorionic gonadotropin (hCG) levels were <1000 IU/L and 189 IU/L, respectively. Based on these test results, the patient was diagnosed with an ectopic pregnancy in the left uterine appendage; in response to the persistent pain in the lower left abdominal region, the patient was admitted for emergent laparoscopy. Swelling of the left fallopian tube ampulla was confirmed during surgery (Fig. 3), and with a diagnosis of ampullary tubal pregnancy, linear salpingostomy and evisceration were performed. A 20-mm, fetus-like, solid tumor was observed inside the cystic tumor (Fig. 4). Postoperatively, the patient recovered well and was discharged 5 days after surgery. Since chorionic villi were not seen macroscopically in the resected mass, we carefully checked up the level of hCG value. However, 7 days after surgery, urinary (1800 IU/L) and blood (2289 IU/L) levels of hCG were elevated compared to preoperative values. Furthermore, transvaginal ultrasonography, performed 16 days after surgery revealed a 25-mm GS in the uterus as well as fetal heartbeats. Histopathological observations of the excised tumor confirmed adenofibroma of the left fallopian tube. At the insistence of the patient and her spouse, the pregnancy continued to term and a 3394 g baby girl was vaginally delivered at 39 weeks gestation. The baby was born healthy, with mother and infant discharged 6 days after delivery. The infant's post discharge condition was satisfactory. The tumor was firm, with a cauliflower-like surface. Microscopically, it was papillary in appearance and composed of fibrous tissue containing scattered glands. Chorionic villi were not seen macroscopically in the resected mass. (Fig. 4).

adenofibroma of the fallopian tube, ectopic pregnancy

PMC9483631_01

Male

A 38-year-old man who had been working in an automotive parts manufacturing plant for 5 years developed jaundice in the middle of January 2022. The patient visited a local hospital on January 28, 2022. The patient's aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were very high (AST 1,140 IU/L, ALT 2,650 IU/L), gamma glutamyl transpeptidase was 215 IU/L, and total bilirubin (TB) and direct bilirubin (DB) were 9.41 mg/dL and 6.77 mg/dL, respectively. Abdominal computed tomography revealed acute hepatitis with mild hepatosplenomegaly (Fig. 1). The patient was immediately transferred to the department of gastroenterology for further evaluation and treatment. The patient had not recently taken hepatotoxic medications such as herbal medicines, antifungal drugs, anti-tuberculosis drugs, or anti-inflammatory drugs and did not have a history of drug allergies. He had no specific familial or genetic problems and had never smoked. He drank a bottle of soju twice per week. He was diagnosed with acute hepatitis; however, the exact cause of hepatitis was not identified. The patient's general condition was tolerable; therefore, he was treated on an outpatient basis. Though he was diagnosed with acute hepatitis, he continued to work until hospitalization. One week later, on February 4th, the patient visited the hospital for follow-up treatment. The jaundice improved and there were no other symptoms. In addition, the liver enzyme values showed a tendency to decrease (AST 662 IU/L, ALT 482 IU/L, TB 5.5 mg/dL, DB 2.7 mg/dL). He visited the department of occupational and environmental medicine of the same hospital on February 9th. The patient reported that his condition was tolerable and jaundice and other symptoms continued to improve. On February 15th, during an outpatient examination, the patient reported that abdominal discomfort and jaundice had recurred 4-5 days earlier. He was hospitalized in the gastroenterology department due to poor general condition and increased liver enzymes (AST 937 IU/L, ALT 409 IU/L, TB 18.8 mg/dL, DB 9.9 mg/dL). The complete blood count was normal, and coagulation factors were also normal (prothrombin time 23.3 seconds, prothrombin time/international normalized ratio 2.00, 32.7%, and activated partial thromboplastin time 41.4 seconds). Antibody tests were performed to exclude viral and autoimmune hepatitis, and the results were as follows: anti-HAV IgG (-), anti-HAV IgM (-), HBs Ag (-), anti-HCV (-), HIV Ag/Ab (-), ANA (IF) (1:320 dilution), anti-smooth muscle Ab (-), ANCA (-), AMA (-), anti-LKM Ab (-), and anti-dsDNA IgG (20.6, within normal range). Abdominal ultrasonography findings were compatible with acute hepatopathy and reactive gallbladder wall thickening. For a more accurate differentiation of acute hepatitis, elastography was performed. The mean shear wave velocity was 3.26 +- 0.24 m/s, suggesting stage 4 fibrosis (> 1.86 m/s) (Fig. 2). Although stage 4 fibrosis indicates liver cirrhosis, it was determined to be a change due to acute inflammatory findings based on the clinical correlation with other symptoms and test results. The laboratory findings during the hospitalization period are summarized in Table 1. The patient's general condition and liver function were restored after hydration and conservative treatment. He was discharged on the 8th day of hospitalization. The AST and ALT levels 20 days after discharge were 33 and 13 IU/L, respectively. On February 9th, the patient visited the occupational and environmental medicine department for consultation regarding occupational accidents. The patient's liver function was normal during regular health check-ups conducted in May 2021. The patient worked for an automotive parts manufacturer that produced powertrain mounting products, chassis, hoses, and dampers. He had worked on coating using organic solvents on spot 10 in Fig. 3 since June 2016, and he always wore the provided personal protective equipment including respirator, gloves and apron while working. He worked two shifts. The two groups worked in shifts at weekly intervals and worked five days a week. The day shift was from 8 am to 8 pm, and the night shift was from 8 pm to 8 am the next day. His actual working time during a 12-hour shift was 10 hours 40 minutes and the remaining time was used for meals and rest (50 minutes for lunch and 30 minutes for dinner, including the time for rest). The main process consists of six parts: sanding, shotting, washing, coating, refining, and adhesive application. After washing the manufactured goods, the patient worked on the coating part. Organic solvents are mainly used in washing and coating processes. The patient reported that the residues of the washing agent used in the washing process were almost always present in the coating process. In addition, some solvents were changed a month before the onset of jaundice (December 2021). The patient showed us several material safety data sheets (MSDSs), but none of them showed hepatotoxicity. He said that the material had recently changed, but he did not see the data. He promised to bring it to the next visit, but he was hospitalized five days later. The Ministry of Employment and Labor conducted the workplace inspections. As a result of analyzing the sample for the washing agent, it was found that it contained chloroform, which was not mentioned in the MSDS, and the content was very high (28%-38%). A time-weighted average (TWA) was used to measure the workplace environment, and 8 individual samples and 2 area samples were analyzed. The measurement time was approximately 360 minutes. They reported that the washing agent contained chloroform, and that concentrations in the workplace were up to 4.7 times the TWA when corrected (based on the Korean occupational exposure limit; 10 ppm for 8 hours TWA). However, as workers worked more than 8 hours in this case, it was necessary to calculate the corrected exposure limit according to actual working hours (7.5 ppm for 10 hours 40 minutes TWA). It has been determined to be the main cause of toxic hepatitis. Consent for publication of this case report and any accompanying data was obtained from the study participant on July 1, 2022. This study was approved by the Institutional Review Board of Dong-A University Hospital (DAUHIRB-22-134).

chloroform, toxic hepatitis

PMC3534390_01

Male

A 76-year-old man with liver cirrhosis caused by chronic hepatitis C was admitted to the intensive care unit. He had a history of thoracoplasty for the treatment of pulmonary tuberculosis. Two days before admission, he experienced common cold-like symptoms and consulted a doctor at a nearby medical clinic. However, his symptoms worsened, and on the morning of admission he lost consciousness at home. He was transported immediately to our hospital by ambulance, during which he required cardiopulmonary resuscitation. A return of circulation was observed on arrival at our hospital. His vital signs included a consciousness level of E1V1M1 on the Glasgow Coma Scale, body temperature 34.4 C, blood pressure 63/46 mmHg, and heart rate 66 beats per minute. Loss of light reflex was observed. Laboratory studies on admission revealed signs of inflammation (white blood cell count 13,330 cells/mL, C-reactive protein 2.16 mg/dL), elevated liver enzyme levels (aspartate transaminase 459 U/L, alanine transaminase 171 U/L), and mild renal dysfunction (creatinine 1.38 ng/dL). A chest radiograph revealed right upper and lower lobe consolidation with collapse of the left chest wall caused by his previous thoracoplasty (Figure 1). Gram staining of endotracheal-aspirated sputum revealed a large number of neutrophils, and light microscopy at high magnification (1000x) showed numerous fibrous constituents (Figure 2A-E). The same specimens were analyzed using immunohistochemistry with DAPI (4',6-diamidino-2-phenylindole) staining (Invitrogen, Carlsbad, CA) for DNA detection (Figure 2A), anti-human histone H3 mouse monoclonal antibody (MABI0001, MAB Institute Inc, Sapporo, Japan) for histone (Figure 2B), and anti-human neutrophil elastase rabbit polyclonal antibody (GTX72042, GeneTex Inc, Irvine, CA) for neutrophil elastase (Figure 2C). Figure 2D is a merged photograph of Figure 2A-C. The specimens were visualized using a fluorescence microscope (BZ-9000, Keyence Corporation, Osaka, Japan). The findings suggested that the fibrous structures in sputum were mainly NETs, defined as extracellular string-like structures that are simultaneously immunoreactive for DNA, histone H3, and neutrophil elastase. A number of Gram-negative coccobacilli, some of which had been phagocytosed by neutrophils, were observed at high magnification (1000x, Figure 3). Despite immediate administration of broad-spectrum antibiotics upon admission, the patient died on the day following hospitalization. H. influenzae was later isolated and detected in both sputum and blood from the culture performed on admission. The blood culture results identified nontypable H. influenzae (Denka Seiken Co, Ltd, Tokyo, Japan), and we diagnosed invasive disease caused by nontypable H. influenzae infection with multilobar pneumonia and bacteremia/sepsis in a patient with liver cirrhosis post thoracoplasty.

haemophilus influenzae, neutrophil extracellular traps, nontypable, pneumonia, sepsis, type b

PMC10267296_01

Male

Dear Editor, We describe a case of a 27-year-old male who presented to the hospital with a 3-week history of epistaxis, cough, chest pain, haemoptysis and bilateral lower extremity swelling. His past medical history was significant for post-streptococcal glomerulonephritis diagnosed at age 7 years, for which he received glucocorticoids for 3 years. Despite treatment, he progressed to chronic kidney disease stage 5. Other past medical history was notable for non-crystal-proven gout and three or four episodes of shortness of breath, wheezing, dry cough and sinus congestion over the past 2 years, all glucocorticoid responsive, with a presumed diagnosis of asthma. The patient resided in Ohio, without recent travel or tuberculosis exposure. He had never smoked or used recreational drugs. Physical examination at presentation revealed stable vital signs. The patient appeared pale and had friction rubs and bilateral crackles on cardiac and lung auscultation, respectively. He was noted to have diffuse sinus tenderness and nasal crusting, without nasal deformity or septal perforation. There was no evidence of a purpuric rash. Initial laboratory evaluations were notable for normocytic anaemia, with a haemoglobin of 7.6 g/dl (baseline haemoglobin ~12 g/dl), leucocytosis of 16.39 x 103/mul (79% neutrophils, 10% eosinophils, with absolute eosinophil count 1740/mul), elevated creatinine at 22.44 mg/dl, blood urea nitrogen of 223 mg/dl, high-sensitivity troponin at 264 ng/l and B-type natriuretic peptide at >70 000 pg/ml. ECG showed sinus tachycardia, without ST segment elevation or T wave inversion. Plain chest radiography showed diffuse airspace opacities in both lungs. CT of the chest without i.v. contrast revealed multifocal bilateral ground glass and consolidative opacities involving all lobes, a cavitary lesion in the left lower lobe, and trace pericardial and bilateral pleural effusions. Initial echocardiogram showed normal left ventricular systolic function, with an ejection fraction of 61%, and a small pericardial effusion, without tamponade physiology. The patient was started on haemodialysis immediately for treatment of severe fluid overload and uraemic pericarditis. Uraemic pericarditis was considered owing to the presence of chest pain and prior dyspnoea in the setting of known kidney disease. However, owing to other accompanying clinical features, inconsistent ECG findings and the presence of eosinophils, alternative aetiologies were explored. An extensive respiratory infectious work-up, including a viral panel, Legionella and Streptococcus pneumoniae urine antigens and a tuberculosis test, was negative. He underwent bronchoscopy, which showed no evidence of alveolar haemorrhage or underlying infectious process. However, cell differential on bronchoalveolar lavage fluid showed 6% eosinophils. Autoimmune work-up was notable for an elevated IgE level at 567 kU/l, negative ANCA and anti-GBM antibodies, and normal complement levels (C3 and C4). A CT of the sinuses showed severe diffuse mucosal thickening in most sinuses. The combination of presumed diagnosis of adult-onset asthma, sinonasal symptoms, peripheral and tissue eosinophilia, and pulmonary opacities on CT chest raised the suspicion for eosinophilic granulomatosis with polyangiitis (EGPA). While awaiting cardiac PET to evaluate potential myocardial involvement, the patient became haemodynamically unstable. Repeated chest imaging showed stable diffuse airspace opacities but an enlarged cardiac silhouette (Fig. 1A); an echocardiogram showed worsening pericardial effusion, with tamponade physiology (Fig. 1B-D). Therefore, the patient underwent emergency pericardiocentesis, during which 700 ml of bloody fluid was drained, with analysis showing 11% eosinophils. The patient was administered pulse-dose CSs for 3 days and given rituximab infusions, which led to significant improvement in clinical status. Eventually, cardiac PET revealed no myocardial enhancement. Open lung biopsy was not pursued owing to iatrogenic tension pneumothorax during the emergency pericardiocentesis. Eosinophilic granulomatosis with polyangiitis (previously called Churg-Strauss syndrome) is a rare systemic necrotizing vasculitis that primarily affects small and medium vessels. The disease is classified as ANCA-associated vasculitis; however, only one- to two-thirds of patients have positive ANCA, which often makes the diagnosis challenging. EGPA is characterized by adult-onset asthma, chronic sinusitis, nasal polyposis, peripheral or tissue eosinophilia, pulmonary opacities or nodules, peripheral neuropathy and cardiac and renal involvement. Cardiac involvement, which is noted in 27-43% of cases, is more prevalent in ANCA-negative patients with high eosinophilic counts and is associated with a high mortality rate. Although it may be subclinical in 17% of cases, most cases are symptomatic. Manifestations include cardiomyopathy (51.6%), coronary artery vasculitis (34%), intracardiac thrombus (22.6%) and pericardial effusion (37.1%), as reported in a large meta-analysis that included 62 EGPA patients with cardiac involvement. Although pericarditis and a variable degree of pericardial effusion presenting as mild chest pain and dyspnoea are described in many studies, pericardial tamponade with life-threatening presentation is rarely reported (only 6.5% of cases). In such cases, urgent pericardiocentesis must be performed, which may reveal tissue eosinophilia and help in confirming the diagnosis of EGPA. Recent guidelines by the ACR and Vasculitis Foundation recommended high doses of glucocorticoids in addition to either CYC or rituximab for the treatment of severe EGPA. This case highlights that cardiac involvement in EGPA is considered a severe manifestation with potential life-threatening presentation and consequences, especially when severe cardiomyopathy or pericardial tamponade is present.

PMC3322929_02

Male

Starting from day 6, the patient's fever and chest condition gradually improved. However, over the next 2 weeks, 138 persons (mostly healthcare workers) who had been in contact with him had onset of a similar illness with high fever and pneumonia. The patient was subsequently confirmed to be the index case-patient in this hospital outbreak of SARS. Three family members were also infected. Further history showed that he had visited a hotel in Kowloon, Hong Kong, where a 64-year-old physician from southern China had stayed for 2 days; this physician later died of severe atypical pneumonia 10 days after admission to a regional hospital in Kowloon. The cause of the illness was not known at the time of the physician's death. Our patient was identified as the index case-patient 5 days after the onset of this large outbreak at the Prince of Wales Hospital, as he was the first patient who had the characteristic clinical, radiologic, and laboratory features of SARS and had epidemiologic links with other infected persons. After 8 days, use of the nebulized bronchodilator was stopped because of the possibility of enhancing SARS transmission, and the patient was isolated in a private room with negative-pressure ventilation. Healthcare workers entering the room wore disposable gloves and N95 masks. After the patient completed a 7-day course of cefotaxime and a 10-day course of clarithromycin, his pneumonia recovered gradually, and serial chest radiographs confirmed resolution of his consolidation (Figure, part C). His diarrhea and other systemic symptoms also resolved spontaneously. An immunofluorescence test for antibody against SARS-CoV subsequently confirmed an elevated titer of 1:5,120 in convalescent-phase serum collected on day 21 of illness. Polymerase chain reaction of nasopharyngeal aspirate was negative for coronavirus. Convalescent-phase serum was negative for other atypical pneumonia organisms, including adenovirus, psittacosis, Q fever, influenza A and B, and mycoplasma. Repeat complete blood count showed that lymphocytes and thrombocytes had returned to normal, along with serum creatinine and alanine transaminase levels. The patient was isolated in a private room until day 27 of his hospital stay, when his nasopharyngeal aspirate and urine samples were confirmed to be negative for SARS-CoV. Repeat chest radiograph at follow-up 2 weeks later showed no residual parenchymal opacity, and the patient remained asymptomatic.

PMC6917779_01

Male

We report the case of a 20-year old man who developed a transient febrile episode with chills and debilitating headaches accompanied by severe neutropenia, lymphopenia, and mild thrombocytopenia within 24 h after a tick-borne encephalitis (TBE) booster vaccine. The patient resides in Switzerland, which is an area endemic for TBE. Per the recommendations of local health authorities, he received a series of three TBE vaccinations at the age of ten. Ten years later, his general practitioner (GP) administered a TBE booster vaccination (FSME-Immun CC, Lot. VNR1T04E). Nine hours later he started to feel feverish, experienced chills, joint pain, and severe headaches. Symptoms persisted after self-medication with a combination drug containing acetaminophen, pseudoephedrine, and dextromethorphan. The following day, he presented to his GP because of persistent symptoms. The GP recorded a fever of 39.0 C. Complete blood count (CBC) revealed leukopenia (0.90 x 109/L; range 3.50-10.00) and low platelet counts (99 x 109/L; range 150-450). The patient was referred to our walk-in clinic at the medical outpatient unit. Clinical examination was unremarkable; in particular, there was no injection site reaction, lymphadenopathy, rash, signs of localized infection, or neurological abnormalities. CBC performed 20 h after vaccination revealed mild leukopenia (3.01 x 109/L) as well as thrombocytopenia (115 x 109/L). Forty hours after vaccination, leukocytes were again substantially lower (1.11 x 109/L). In the initial blood draw in our clinic, neutrophils were normal, but with 37% bands (i.e., immature neutrophils; normal range 5.0-15.0) compared to only 52.5% segmented neutrophils (normal range 40.0-70.0). This suggests an increased neutrophil turn-over. The following day, differential blood counts showed severe neutropenia (0.22 x 109/L; range 1.30-6.70) with a left-shift of 6.4%. The patient was lymphopenic on both occasions (0.22 and 0.38 x 109/L, respectively; range 0.90-0.33) (Fig. 1). C-reactive protein (CRP) was only slightly elevated on the first day (11.0 mg/L; range <10), followed by a peak at 55.6 mg/L 48 h post-vaccination. Interleukin-6 (93.4 ng/L; range <7) and ferritin (581 microg/L; range 30-300) levels indicated an acute phase reaction. Tryptase was normal, and the clinical picture was not compatible with a hypersensitivity reaction. Past medical history revealed exogenic allergic asthma and acne vulgaris, in addition to atopic dermatitis and shingles (single dermatome) at the age of 15 years. He was normal weight (71 kg). Until 4-5 weeks before the current event, the patient was taking low-dose isotretinoin (5 mg every other day) for acne treatment. Therapy was stopped due to good clinical response. Blood counts were regularly checked during the therapy and were always normal, including the most recent one taken 41 days earlier (Fig. 1). Our initial differential diagnosis included a viral infection, a systemic reaction to vaccination, or transient bacteremia in the context of severe neutropenia. We found no clinical focus of infection. The TBE IgG level was high, with 844 VIEU/mL (positive; >=127) and TBE IgM negative. However, there was no clear evidence for an immune-complex-mediated type III reaction, as complement C3 and C4 serum levels were normal, and there was no relevant local injection site reaction. We recommended supportive treatment as an outpatient with high fluid intake, acetaminophen as needed, and close clinical follow-up. White blood cell (WBC) counts normalized spontaneously within just two days, followed by platelets by day ten. Because of a persistent headache, we performed a brain MRI that excluded meningoencephalitis. All symptoms resolved spontaneously during the following days. TBE-post-vaccination titers four weeks later showed a very high TBE IgG level (>1000 VIEU/mL) and elevated TBE IgM level (2.1 S/CO). Because of the patient's history of shingles at a young age and the current immune-dysregulated event, we completed the work-up with an immunophenotyping, which revealed normal immunoglobulin levels (IgG1-4, IgA, IgM) (Supplementary Table S1), lymphocyte subset counts (NK, CD4+ T cells, CD8+ T cells, B cells), and B cell subsets four weeks after the vaccination (Supplementary Table S2). The case was reported via the 'Regional Center of Pharmacovigilance' to the 'Swiss Agency for Therapeutic Products' (Swissmedic), the national authority of pharmacovigilance.

adjuvants, fever, haematological diseases, inactivated vaccines, pain

PMC8140758_01

Female

In October 2018, a 27-year-old woman presented with a 2-week history of a pruritic rash on her face and ears. Her past medical history was significant for SLE diagnosed 5 years ago with cutaneous, joint, and renal tropism. She was treated with different treatments; first, she received 6 Cyclophosphamide boluses with relay by Azathioprine for 3 years, stopped for hematological toxicity, then switched to Mycophenolate Mofetil which was stopped by the patient herself for 1 year due to lack of means. She also had a notion of septic arthritis of the knee having recurred despite well-adapted antibiotic treatment and her aunt was being treated for pulmonary tuberculosis. Therefore, she was hospitalized this time to carry out the SLE systematization assessment and to update her treatment. In the initial physical examination, we found a malar rash; erythematous plaques on her face, ears, and upper limbs; and a diffuse non-scarring alopecia. She also had arthralgia especially in her left knee, with swelling in that area. A small left knee effusion was aspirated and the culture was positive for Mycobacterium tuberculosis; therefore, anti-tuberculous therapy (Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol) was initiated. The cutaneous symptomatology worsened after 15 days from the start of tuberculosis treatment with extended rash at the trunk and neckline, erythematous and edematous plaques, and blisters in the photo-exposed areas. Nikolsky's sign was positive, the affected skin surface was estimated to be 30%, and the mucosal involvement was limited to a simple cheilitis (Figure 1, Figure 2). The antituberculosis treatment was initially discontinued because we had thought of the TEN. Laboratory abnormalities showed proteinuria elevated to 2g/24h, bicytopenia (leucopenia at 3500 per cubic milliliter and anemia with hemoglobin at 10 grams per dl), an elevated anti-double stranded deoxyribonucleic acid (DNA) antibody with negative anti-histone antibodies and consumption of the complement C3 and C4. Moreover, skin biopsy showed diffuse epidermal necrosis, sub-epidermal detachment, interface dermatitis and presence of mucinosis. On direct immunofluorescence (DIF), a deposition of IgM and IgG in the basement membrane (lupus band) was present. Given the clinical history, lesion morphology, pathologic finding and laboratory studies, the diagnosis of TEN-like ACLE was established. After the administration of systemic corticosteroids, we have observed a healing of the skin lesions after two weeks. Anti-tuberculous treatment was reintroduced without any particular incident and Cyclophosphamide boluses were subsequently started. Joint swelling resolved within two months after the initiation of anti-tuberculous treatment and full joint range of motion was restored. There has been no recurrence of the bullous eruption to date.

acute cutaneous lupus erythematosus, ten-like acle, case report, toxic epidermal necrolysis

PMC6754851_01

Male

The first patient was a 15-year-old boy with no family history of TB. He suffered chronic snoring since the age of six. He presented with headache, asthenia and weight loss. Examination on admission revealed multiple bilateral cervical lymphadenopathies in jugular areas. Nasal endoscopy (Figure 1) discovered a polypoid mass occupying the nasopharynx. A biopsy was performed. Computed Tomography (CT) showed a polypoid thickening of the posterior wall and the roof of the nasopharynx, measuring 2.5cm (Figure 2) with bilateral cervical lymphadenopathies in jugular areas.

tuberculosis, headache, hearing loss, lymph node, nasal obstruction, nasopharyngeal disease, nasopharyngeal neoplasm, nasopharynx, treatment

PMC6754851_02

Female

The second patient was a 17-year-old girl without family history of TB. She presented with numerous bilateral cervical lymphadenopathies and nasal obstruction. Nasal endoscopy found a polypoid uprising of the superior and posterior nasopharyngeal walls. CT scan showed a nasopharyngeal mass with central hypodensity suggesting tissue necrosis (Figure 3), with multiple cervical lymphadenopathies. A biopsy was performed.

tuberculosis, headache, hearing loss, lymph node, nasal obstruction, nasopharyngeal disease, nasopharyngeal neoplasm, nasopharynx, treatment

PMC6754851_04

Unknown

A 45 years old patient, chronic smoker, presented with unilateral lymphadenopathy gradually increasing in size with weight loss, associated with nasal obstruction and hearing loss of the right ear. Clinical examination found a painless firm lymphadenopathy of the right jugular era measuring 3cm and a secretory otitis media. The endoscopy found a tumor in the right posterolateral wall of the nasopharynx. CT scan showed a mass in the posterior wall of the nasopharynx with retropharyngeal lymphadenopathies. A biopsy was performed. In four cases, histopathological study showed nasopharyngitis and granulomas with histiocytic, epithelioid, and giant multinucleated Langhans cells as well as caseous necrosis (Figure 4). Further examinations searching for other locations were negative confirming the diagnosis of primary nasopharyngeal tuberculosis. All patients received anti bacillary treatment based on rifampicin 10mg/kg/day, isoniazid 5mg/kg/day, pyrazinamide 20mg/kg/day during 2 months followed by rifampicin and isoniazid during 4 months. A clinical, endoscopic and histological surveillance was implemented and the evolution was favorable in all cases.

tuberculosis, headache, hearing loss, lymph node, nasal obstruction, nasopharyngeal disease, nasopharyngeal neoplasm, nasopharynx, treatment

PMC9869259_02

Male

In order to find out the cause of bronchiectasis and treat it, we asked in detail about clinical symptoms and past medical history, and conducted a series of tests. Initially, we asked about the child's previous pathological symptoms. The caregiver clearly stated that the child did not have recurrent cough, expectoration, hemoptysis, chest pain, bloody sputum, fever, night sweats, fatigue, weight loss, nausea, acid reflux, heartburn, postnasal drip, salty skin or sinusitis. His growth and development were similar to those of his peers, but his athletic endurance was not as good as theirs. He had no history of tuberculosis, measles, whooping cough, GERD and hospitalization for respiratory infection, nor had he been exposed to pollution and toxic gases. He had only one history of mild and chronic cough, and the symptoms lasted for about 1 month when he was four years old. After several outpatient visits and taking oral medication, he gradually recovered. A pediatric chest x-ray showed inflammation in the right lower lung, but no signs of bronchiectasis. He did not undergo a HRCT of the chest at that time. What's more, he had a history of Pendred syndrome. He suffered from hearing loss at the age of 2 and received a cochlear implant surgery at the age of 3 and a half. He had a mild enlarged goiter, but no thyroid dysfunction. We performed extensive diagnostic tests on this child. A complete blood count, C-reactive protein, results of kidney- and liver- function tests, serum procalcitonin, tuberculin test and interferon-gamma release assays were normal. A test for antineutrophil cytoplasmic antibody was negative, as were tests for some viruses which could cause secondary immunodeficiency, such as human immunodeficiency virus. Immunoglobulin level and absolute lymphoblastic counts in serum were also normal. The detection of allergen-specific IgE revealed a mild positive reaction to dust mites. Moreover, we performed fiberoptic bronchoscopy, bronchoalveolar lavage (BALF), and bronchial biopsy. Bronchoscopy revealed condensed secretions in the right lower lobe bronchus. The results of next-generation sequencing of BALF revealed Tropheryma whipplei (sequence number 13,200). Electron microscopy of bronchial biopsy showed mild inflammatory changes in cilia, without typical ultrastructural pathological changes of PCD (Figures 2A-C). We also tested for CF and alpha1-antitrypsin deficiency related mutant genes. These results were negative. Because infection was the most common cause of bronchiectasis, and a large number of bacteria called Tropheryma whipplei were shown in BALF, we first considered whether bronchiectasis was caused by Whipple's disease. Common signs and symptoms of Whipple's disease included diarrhea, stomach cramping and pain, inflamed joints, weakness, and anemia. Obviously, the child did not meet the diagnosis criteria. Secondly, we analyzed other common causes of bronchiectasis. The evidence for the diagnosis of the above-mentioned causes of bronchiectasis in this child was also insufficient. So far, a definitive diagnosis of the child has not been determined. Considering the importance of medical history in making an accurate diagnosis, we inquired the child's medical history again and recommended a genetic test for this child. The caregiver supplemented the medical history and stated that the child was found to have hearing loss at the age of 2. Genetic testing for hearing loss showed a heterozygous mutation in the SLC26A4 gene, and the mutation site was IVS7-2A > G (Table 1). We learned that IVS7-2A > G may lead to the deletion of exons surrounding the splice site. Mutations in the SLC26A4 gene alter the structure or function of pendrin, which disrupts ion transport. In the inner ear, pendrin dysfunction affects Cl- transport, leading to vestibular aqueduct enlargement and sensorineural hearing loss. Goiter is mainly related to the reduction of pendrin-mediated transport of I-. Pendrin also plays an important role in airway defense and airway homeostasis in vitro. We questioned the link between SLC26A4 mutation and bronchiectasis. The loss of pendrin function could cause airway acidification, impair airway epithelial defense, and increase of the volume of ASL. In the case of infection (even opportunistic pathogens), patients may not be able to effectively eliminate the infection, but show persistent chronic infection and inflammation. Chronic airway inflammation and airway blockage interact with each other, and finally lead to irreversible tracheal dilatation. Based on the above analysis, we speculated that mutations in the SLC26A4 (pendrin) may cause non-CF bronchiectasis. Unfortunately, our conclusions were speculative. And the proposed mechanism has not been verified by experimental researches. To the best of our knowledge, no similar cases have been reported in other clinical studies. The root causes of this phenomenon is worth further exploration. We explained the analysis and speculative conclusions to the patient's family members and get their recognition. Bronchiectasis possibly caused by pendrin dysfunction, like bronchiectasis caused by other causes, may be currently incurable. However, studies have shown that the expression of pendrin in the endolymphatic sac can be successfully restored in mice by transgenic technology. Perhaps the function of pendrin in the airway could be restored in the future. Therefore, we gave the child a series of treatments, including inhalation of bronchodilators and corticosteroids, taking oral apophlegmatisant and antibiotics, and mechanical vibration expectoration. And he was taught to avoid respiratory tract infection, get the pneumonia vaccine, master the ability of airway clearance and regularly follow up. After 1 month of treatment, the child returned to our outpatient clinic and performed a CT of the chest. The images showed that the inflammation disappeared, but the tracheal dilatation remained. Figure 3 showed timeline of clinical events, diagnostics, and treatments of the patient.

bronchiectasis, slc26a4, cystic fibrosis, gene mutations, pendred syndrome

PMC9755863_01

Male

A 6-year-old boy was admitted to our hospital with a 3-week history of fever and neck mass. He was initially seen in the local infectious diseases hospital after a chest radiography indicated potential acute milia pulmonary tuberculosis; however, the cause of the fever remained unclear after subsequent examinations. After showing minimal response to antibiotic treatment, he was transferred to our hospital. Upon admission, a physical examination revealed scattered bleeding spots on the extremities, swollen eyelids and lips, and thrush in the oral cavity, but no rash, joint swelling, or joint pain. The breathing sounds were slightly coarse in both lungs, and moist rales were evident, but the heart sounds were normal. The patient's abdomen was distended, and a neurological examination showed no significant abnormality. The chest computed tomography (CT) examination revealed enlarged mediastinal lymph nodes, and the abdominal CT showed significant splenomegaly, multiple mesenteric and retroperitoneal lymphadenopathy, and a small amount of pelvic effusion. Gastroenteroscopy revealed multiple ulcers in the rectum and sigmoid colon. The serum high-sensitivity C-reactive protein level was 88.25 mg/L (reference range: <10 mg/L), and the procalcitonin level was 6.65 ng/ml (reference range: <0.05 ng/ml). The routine full blood count results revealed pancytopenia with a white blood cell count of 1.38 x 109/L (reference range: 4.3-11.3 x 109 cells/L), a hemoglobin level of 86 g/L (reference range: 110-160 g/L), and a platelet count of 86 x 109/L (reference range: 100-300 x 109 cells/L). In addition, the serum ferritin level was 87,741.30 ng/ml (reference range: 22-322 ng/ml), the fibrinogen level was 1.82 g/L (reference range: 2-4 g/L), and the triglyceride level was 2.69 mmol/L (reference range: <1.7 mmol/L). The cellular immune function tests indicated that 52.29% of the cells were CD3+, 27.32% were CD3+CD4+, 23.47% were CD3+CD8+, 41.85% were CD19+, and 2.07% were CD16/56+. B lymphocyte subsets were also detected, of which 95.30% were naive B cells, 0.50% were memory B cells, 3.90% were transitional B cells, and 0.20% were plasmablasts. The immunoglobulin profile revealed an IgG level of 3.85 g/L (reference range: 5.28-21.90 g/L), an IgM level of 1.80 g/L (reference range: 0.48-2.26 g/L), and an IgA level of 0.33 g/L (reference range: 0.41-2.97 g/L). Additional results are found in Supplementary Table S1 . The patient's HIV serology was negative. The bone marrow smears revealed the presence of hemophagocytosis and fungal spores. In summary, the child had a fever for >7 days, followed by generalized lymphadenopathy, pancytopenia, decreased fibrinogen levels, significantly elevated triglycerides and serum ferritin levels, and an enlarged spleen. According to the HRH-2004 guidelines, the child could be diagnosed with HLH. The initial blood cell analysis suggested the presence of abnormal cells, which were identified as mature granulocytes engulfing fungal spores ( Figure 1 ). After consulting the medical records, it was suspected that the patient had TM infection. Metagenomic next-generation sequencing (mNGS) and Sanger sequencing were used to identify infectious pathogens for further confirmation ( Figure 2 ). The subsequent mNGS of the bronchoalveolar lavage fluid and blood culture supported TM infection ( Figure 3 ). There was no evidence of autoantibodies, and bone marrow and lymph node biopsies and CD40 expression excluded autoimmunity and a possible hematologic neoplasm. The cellular immune function tests revealed a decrease in the number and activity of NK cells, lower CD107a expression, normal levels of hemophagocytic proteins:such as perforin, granzyme B, SAP, and XIAP:and an sCD25 expression level of 7,630 U/ml (>2,400 U/ml). With the consent of the patient's family, samples from the child and family members were collected to conduct whole-exome sequencing of potential genetic diseases. Due to the child's fungal infection and immune deficiency, whole-exome sequencing results were analyzed and sorted using Exomiser Software, and CARD9 and CD40LG mutations were screened. A hemizygous missense variant, c.346G > A (p.Gly116Ser), was detected on the patient's CD40LG gene ( Figure 4 ) that was not present in either parent's validation samples. The activated T cells from the patient had 52% CD40L expression as compared to 80.7% expression in a healthy control ( Supplementary Figure S1 ). This finding was supported by abnormal immunoglobulin levels. A heterozygous frameshift variant, c.820dup (p.Asp274GlyfsTer61), was also detected in CARD9 and found to be inherited from the patient's mother ( Figure 4 ). The 3D structure of the patient's CARD9 protein differed from the wild-type protein ( Supplementary Figure S2 ). The patient's family history revealed that all immediate family members were healthy except for the child who had a history of poor immune function. Notably, the child and his two brothers were born prematurely at approximately 33 weeks of gestation. His mother reported that she suffered from mild dermatitis, including tinea pedis, and had generally self-medicated for this condition. After TM infection was suggested by peripheral blood smear, voriconazole and amphotericin B treatment was administered, followed by chemotherapy for HLH. On the fourth day of administration, the abnormal cell clusters in the patient's blood routine scatter diagram disappeared ( Supplementary Figure S3 ). During treatment, the child had a series of complications caused by severe sepsis, including multiple organ dysfunction syndrome and fungal enterocolitis complicated with massive bleeding. However, due to the early implementation of antimicrobial and symptomatic treatment, the patient was finally cured and discharged after 2 months.

card9, cd40lg, talaromyces marneffei, hemophagocytic lymphohistiocytosis, immunodeficiency disease

PMC6360061_01

Female

A 2-year-and-8-month-old Swiss girl presented to a pediatric office with fever of 38.8 C, vomiting, and refusal to eat for 3 days. Prior to admission, according to the parents, the patient had drunk ca. 500 ml of fluids. This was a response to a reviewers remark concerning signs of thirst. Blood analysis demonstrated severe hypernatremia (196 mmol/l), prompting urgent hospital admission. The patient was born at term (40 + 1 weeks of gestation) and had a birth weight of 3390 g. She was delivered through a C-Section due to pathological cardiotocography (CTG) and green amniotic fluid. The APGAR score was 6/8/10. On the second day of life, she developed bilateral parenchymal and intraventricular grade III brain hemorrhage diagnosed by ultrasound. Additionally, she had recurring seizures, which were successfully treated with phenobarbital (3 mg/kg/d). cMRI at two weeks of age showed hydrocephalus with intraventricular hemorrhage in the caudothalamic groove displacing, but not including the thalamus, as well as a small intraparenchymal hemorrhage of the right parietal side and subarachnoid hemorrhage of the left occipital side, along the tentorium and the cisterna cerebellomedullaris, with signs for slight hypoxia. Postnatally, the patient also had hypernatremia of 180 mmol/l, which was treated with infusion therapy (glucose 5%). We are not aware of any further urine or serum measurements (e.g. osmolality). Neonatal ultrasound showed, slight hyperplasia and no adrenal hemorrhage and tumor. She was discharged with a sodium level of 160 mmol/l. A "central dysregulation" etiology was hypothesized. Sodium levels in the first year were normal (or slightly elevated) and ranged from 136 to 154 mmol/l. After birth, fT3 and fT4 serum levels were decreased; thus, thyroxine substitution was initiated. The therapy was ended after 1 month because of a hyperthyroid metabolic state (differential diagnosis at that time was euthyroid sick syndrome). Neonatal screening was unremarkable. Two weeks later, at the age of 6 weeks, fT4 was decreased again to 15.6 pmol/l (normal values 17-32), and thyroxine substitution was restarted. At the age of 1 year, growth arrest (<3rd percentile, before 25-50%) as well as reduced oral intake were observed. IGF1 was reduced to 1.8 nmol/l (normal values 3.67-20.4), IGFBP3 was normal (1.07 mg/l), with no adrenal insufficiency (ACTH, cortisol, aldosterone, renin, FSH, LH, and prolactin normal), sodium was 136 mmol/l, no celiac disease, and bone age was normal. After re-evaluation of cMRI at 2 weeks of age, retrospective diagnosis of pituitary hypoplasia was carried out (ca 60 mm3, normal values 148 +- 37). Growth hormone deficiency was postulated followed by substitution with Norditropin. At the age of 12 months, cMRI was performed again, which showed partial pituitary dysgenesis and hydrocephalus malresorptivus. The patient was regularly seen in endocrinological and neurological offices. She showed motor development delay which improved partially until the age of 2 years. At this age, a general development delay of 3-4 months and strabismus divergens/alternans on the left side were observed. She had one seizure at 18 months of age lasting 30-40 minutes with postictal paresis of the right arm and facial nerve paresis on the right side; cMRI at that time was unremarkable. The patient was referred to our hospital in a reduced general condition. On presentation, the skin color was pale and turgor slightly reduced. She had symmetric limb movements with good muscle tonus but appeared tired. The pupils were equal and reacted promptly to light. The percentiles for weight (10.4 kg), length (93 cm), and head circumference (46 cm) were all below the 3rd percentile. Body temperature was 37.6 C, blood pressure was 97/65 mmHg, and heart rate was 102/min. The remainder of the physical examination was normal. The patient was admitted to the pediatric intensive care unit. Blood gas analysis showed excessive hypernatremia (187 mmol/l) and hyperchloremia (148 mmol/l) with normal pH and base excess (Table 1). Osmolality was 362 mmol/kg (normal values 280-300 mmol/kg). Infusion with isotonic glucose-electrolyte solution (sodium 140 mmol/l and glucose 5%) was initiated. Potassium chloride (7.46%) was added due to mild hypokalemia of 3.02 mmol/l. Blood gas analysis was performed hourly, revealing a slow decrease of sodium to a minimum of 143 mmol/l (Figure 1), decreasing by an average of 0.5 mmol/l per hour. Blood glucose on admission was 11.1 mmol/l and normalized with rehydration, suggesting the high blood glucose on admission was due to stress hyperglycemia. Supplementation of thyroid and growth hormones was continued. On the day of admission, urinary excretion was slightly reduced (ca. 2.4 ml/kg/h), and on the second day, the excretion increased (ca. 4 ml/kg/h). There was no fever or edema, vital parameters were stable, and other laboratory tests showed no abnormalities. The following values were measured on admission: Urine osmolality was 876 mosmol/kg (normal values 50-1200 mosmol/kg), urine antidiuretic hormone (ADH) level was 23.70 ng/l (normal values 1.3-42.4 ng/l), plasma aldosterone level was 7.0 ng/dl (normal values < 9.0 ng/dl), and copeptin pro-arginine-vasopressin (AVP) was 4.4 pmol/l (normal values 1.70-11.25 pmol/l) The cortisol level was slightly elevated to 32.72 microg/dl (normal values 5-25 microg/dl). After normalization of serum electrolytes on day 4 of hospitalization, the child developed tremors, particularly while standing, and a general reduction of movement was observed. A slight bilateral rigor of both arms and ataxia were observed. The rest of the neurological evaluation was normal. A 10/20-electroencephalography (EEG) was normal. MRI of the head showed vague, nonischemic diffusion impairment in the basal ganglia, corpus callosum, and subcortical regions on both sides (Figure 2), with only discrete signal modulation in the T2 fluid-attenuated inversion recovery (FLAIR) sequence (Figure 3). No signs for hemorrhage were observed. Slightly dilated lateral ventricles with no active hydrocephalus or indication of increase in pressure were observed. The pons was unremarkable (Figure 4). The findings were interpreted as meningoencephalitis, so lumbar puncture was performed. The results of cell count, protein, and glucose in the cerebrospinal fluid (CSF) were normal. Cefotaxime and aciclovir intravenous were initiated. Multiplex polymerase chain reaction (PCR) of the CSF was negative for cytomegalovirus (CMV), Cryptococcus neoformans, Escherichia coli, Enterovirus, Haemophilus influenzae B, human herpesvirus 6 (HHV-6), human parechovirus, herpes simplex virus (HSV) 1/2, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae (group B streptococcus (GBS)), Streptococcus pneumoniae, and varicella zoster virus (VZV). Additional PCR for Mycoplasma and Rotavirus was negative. The antibody specificity index (ASI) for mumps, measles, rubella, varicella, CMV, Epstein-Barr virus (EBV), herpes simplex and Borrelia, as well as tick-borne encephalitis (TBE) antibodies was normal. CSF examination showed an absence of oligoclonal bands, and only a slight increase of immunoglobulin M (IgM) of 2.4 mg/l (normal up to 1.3 mg/l) and a slight increase in albumin quotient of 8.5 (normal up to 4.2) were noted. Creatine kinase (CK) was extremely elevated (12794 U/l), with normal values for other muscle enzymes (aspartate transaminase (AST), alanine transaminase (ALT)). Although CK-isoenzyme analysis was not performed, the elevated CK levels were assumed to be mostly brain creatine kinase (CK-BB). Rhabdomyolysis due to excessive hypernatremia remains a possible explanation. No seizures, as a possible explanation, were observed throughout the hospitalization. After 5 days, the child was transferred by plane to Switzerland, where the family resides. At the accepting hospital, the neurological symptoms remained. Rehydration was continued and slowly tapered over time. Brain computed tomography (CT) scan was performed to rule out sinus vein thrombosis. Antibacterial and antiviral therapy were stopped. Central dysregulation was discussed again concerning the origin of the hypernatremia. A retrospective review of the MRI was interpreted as extrapontine myelinolysis following extreme hypernatremia. After hospitalization for nearly 2 weeks, the child recovered completely.

PMC8096571_01

Male

A 14-year-old boy presented to the emergency department (ED) after sustaining a twisting injury to his right ankle while playing basketball. Clinical evaluation showed significant swelling and deformity around the ankle. There were no neurovascular deficits. He was unable to bear weight. Radiographs showed a displaced distal tibia SH type II physeal fracture and a transverse fracture of the fibula with valgus angulation (Figure 1). An initial attempt at closed reduction performed in the ED under conscious sedation was unsuccessful; the fracture could not be moved from its displaced position after sustained traction and manipulation (Figure 2). The patient was taken to the operating room, and a second attempt at closed reduction was performed with the patient under general anesthesia and muscle relaxation. Again, the fracture could not be moved from its displaced position. Tendon interposition was suspected and open reduction of the fracture was performed by making an incision on the anteromedial aspect of the distal tibia centered over the metaphyseal spike. The fracture site was exposed, and the posterior tibial tendon was found interposed within the physeal fracture site. The tendon was bowstringing around the metaphyseal fragment from the proximal-posterior to distal-anterior direction between the metaphysis and epiphysis (Figure 3). Traction on the distal fragment increased the tension and worsened the bowstringing of the tendon. Hence, the traction was released and the interposed tendon was retracted out from the fracture site. This allowed the fracture to be reduced without difficulty. The tendon had mild fraying but did not show any laceration or tear (Figure 4). The fracture reduction was confirmed on fluoroscopic evaluation, and two 4 mm partially threaded cannulated screws were used for fracture compression and fixation across the large Thurston-Holland metaphyseal fragment (Figure 5). Postoperatively, the leg was immobilized in a boot and nonweight bearing with crutches was used for 4 weeks, followed by weaning of the boot and gradual transition to full weight bearing. The patient was released to full activities at 4 months. Eighteen months postinjury, he had no pain or deformity, had full ankle range of motion, and had no limitations with sports. The radiographs showed complete healing of the fracture with no deformity and closing physis (Figure 6).

PMC9846957_01

Male

A 21-year-old male with no history of nyctalopia or parental consanguinity presented to the vitreoretinal service at King Khaled Eye Specialist Hospital with a 1-week decrease of vision in the right eye. The patient had no known systemic disorders. On ophthalmic examination, best-corrected visual acuities (BCVAs) were hand motion in the right eye and 20/20 in the left eye. On anterior segment examination, there were 3+ cells in the right eye and the left eye was unremarkable. Fundus examination indicated 3+ vitreous cells in the right eye, obscuring the view of the retina. In the left eye, bone spicules were present and were mostly condensed around attenuated retinal blood vessels. Optic disc or vascular leakage was not clearly evident on fundus fluorescein angiography (FFA) due to the hazy media from the vitreous haze. Systemic workup was negative for complete blood count, renal function test, liver function test, chest computed tomography, fluorescent treponemal antibody absorbed, purified protein derivative, and tuberculosis-quantiferon gold test. Erythrocyte sedimentation rate, C-reactive protein, angiotensin-converting enzyme, antinuclear antibodies, and antineutrophil cytoplasmic antibodies were within the normal limits. The patient was managed with topical steroids four times daily on a weekly taper. Two weeks after initiating therapy, BCVA had improved to 20/30 in the right eye with few vitreous cells and more densely distributed bone spicules than in the left eye [Figure 1a and b]. Fundus autofluorescence indicated hypofluorescent areas corresponding to bone spicules and hyperfluorescent rings in the macular region in both eyes [Figure 1c and d]. Spectral-domain optical coherence tomography indicated photoreceptor loss beyond the macular area bilaterally and a few vitreous cells in the right eye [Figure 1e and f]. Fundus full-field electroretinogram indicated profoundly reduced scotopic and photopic responses in both eyes with a greater reduction in the right eye [Figure 2]. Over 6 months follow-up, the patient maintained 20/20 vision with no recurrence of inflammation. Whole exome sequencing was performed at Bioscientia, Ingelheim, Germany, revealed a novel homozygous c. 3061-6_3061-3del (NM_006445.3) mutation in premessenger RNA (mRNA) processing factor 8 (PRPF8; MIM 600059). This mutation leads to significant alteration of the acceptor 3' splice site based on in silico predictions using in-house prediction programs. The mutation was verified with polymerase chain reaction (PCR) followed by conventional Sanger sequencing. Allele frequency of this variant has not been documented in the normal population (GnomAD v2.1.1 controls; accessed on July 17, 2020). PRPF8 plays an integral role in pre-mRNA splicing and processing of intron-containing transcripts. Pathogenic variants in PRPF8 affect spliceosome assembly and function through interaction with SNRNP200, are present in autosomal dominant retinitis pigmentosa (ADRP).

autosomal dominant retinitis pigmentosa, prpf8, intermediate uveitis, retinitis pigmentosa, splice site mutation

PMC6183653_01

Male

Case 1: Cal/BD aerosol foam in mild-to-moderate psoriasis after previous treatment with a class 3 topical corticosteroid with vitamin D3 analog A 72-year-old male had had plaque psoriasis for 15 years. He had classic psoriasis-related symptoms and was receiving tamsulosin 0.4 mg/day for benign prostatic hyperplasia. He had previously been treated with topical Cal 50 microg/g and betamethasone 0.5 mg/g ointment (2009-2010), methotrexate (2009-2013), and ustekinumab (2015-2017). Physical examination revealed recalcitrant psoriasis, principally on the lower trunk and gluteal regions (Figure 1A). Psoriasis Area Severity Index (PASI) score at presentation was 5.5, and in February 2018, the patient started treatment with daily application of Cal/BD aerosol foam, which was continued for 4 weeks. After 4 weeks' treatment, the psoriatic lesions had markedly improved (Figure 1B) and PASI score had decreased to 1.5. The patient was very satisfied with treatment, and the need for systemic therapy was avoided. Case 2: Cal/BD aerosol foam in mild-to-moderate psoriasis after a long history of systemic therapy, PUVA, and topical drugs A 72-year-old male had a 25-year history of psoriasis. He had classic psoriasis-related symptoms and was receiving atorvastatin for hypercholesterolemia, losartan and bendroflumethiazide for hypertension, and prophylactic clopidogrel for stroke. He had previously received 80 sessions of PUVA, eight courses of UVB, many years of acitretin therapy, and various topical treatments, including Cal/betamethasone and clobetasol. Acitretin therapy was stopped in March 2016, with the hope of controlling the psoriasis without systemic therapy. The patient was keen to try a new treatment. Physical examination at presentation revealed recalcitrant psoriasis on the backs of the hands (Figure 2A), buttocks, and thigh. The patient was particularly troubled by the psoriasis on the back of his hands, which had shown no improvement, even during acitretin treatment. PASI score at presentation was 6.2, and in April 2017, the patient started treatment with daily application of Cal/BD aerosol foam, which was continued for 4 weeks. After 4 weeks' treatment, the psoriatic lesions had markedly improved (Figure 2B) and PASI score had decreased to 2.0. The patient was very satisfied with Cal/BD aerosol foam, with the overall perception of particular efficacy for psoriasis on the back of his hands and no requirement for systemic therapy. Case 3: Cal/BD aerosol foam after previous treatment with class 4 topical corticosteroids A 71-year-old male had a history of psoriasis, which had originally been diagnosed at the age of 30 years; however, throughout his life, the patient had also experienced remissions. Previous treatment had included various topical medications, such as mometasone furoate and clobetasol ointments, and narrowband UVB. The patient was receiving atorvastatin for hypercholesterolemia and omeprazole for dyspepsia. Physical examination at presentation revealed hyper-keratotic psoriatic plaques on the legs and elbows, and the patient was especially troubled by psoriasis on the anterior legs (Figure 3A). PASI score at presentation was 7.2, and the patient started treatment with once-daily application of Cal/BD aerosol foam for 4 weeks. After 4 weeks of treatment, the patient's psoriasis was less distinctive and less keratotic (Figure 3B), PASI score had decreased to 3.2, and the patient was satisfied with the treatment outcome. Case 4: An unsatisfied patient with a long history of using different topical therapies who switched to cal/BD aerosol foam A 35-year-old male had experienced chronic recurrent psoriasis since early adulthood but without attendant joint pain. Previous treatment had included systemic therapy with fumaric acid esters a few years earlier, but this had to be discontinued because of tolerability issues. The patient had used several topical treatments, such as mometasone and betamethasone ointments, and various skin care preparations, but without success. Most recently, the patient had used topical Cal/betamethasone ointment once daily, but no significant skin improvement was attained. The patient was also dissatisfied with the fatty consistency of the ointment. He had reported no significant previous illnesses, other than mild allergic rhinitis and lipomatosis. Physical examination at presentation revealed classic psoriatic plaques, each about 3-4 cm in diameter, on the elbows and knees, and on the posterior thigh (Figure 4A). PASI score at presentation was 4.8, BSA involvement was 5%, and the patient started treatment with once-daily application of Cal/BD aerosol foam. After only 1 week of Cal/BD application, reddening and infiltration of the plaques had significantly decreased (Figure 4B); pruritus had also completely subsided within the first week of treatment. After 4 weeks' application, most of the plaques had completely healed and existing residual lesions showed only minimal erythema without signs of infiltration or desquamation. The PASI score had decreased to 0.8. The patient was satisfied with Cal/BD aerosol foam treatment, particularly the fast retraction of the foam. Case 5: Cal/BD aerosol foam in moderate-to-severe psoriasis after previous treatment with oral systemic therapy A 56-year-old male had had psoriasis for 2 years. A family history was evident, as the patient's father also had psoriasis. The patient's PASI score was 12, DLQI score was 14, and the patient had approximately 13% BSA affected (Figure 5A). Previously, the patient had been treated unsuccessfully with topical corticosteroids, UVB phototherapy, and methotrexate. Because PASI and BSA scores were >10, and previous systemic therapy with methotrexate was unsuccessful, the option of biologic therapy was introduced to, and discussed thoroughly with, the patient. Consequently, biologic drug prescreening (chest X-ray, QuantiFERON-TB [Qiagen NV, Venlo, the Netherlands], and hepatitis and HIV serology) was undertaken. Meanwhile, because of considerable pruritus in the elbow and lower extremity regions, topical therapy was started with Cal/BD aerosol foam. After 2 weeks' application of Cal/BD foam, a significant clinical response (PASI75) and an improvement of itching were attained (Figure 5B). The patient reported that Cal/BD foam was easy and convenient to apply and was very satisfied with the clinical response particularly the fact that his itch had completely disappeared after a few days. Subsequently, after exclusion of tuberculosis, hepatitis, and HIV infection, biologic therapy was started and concurrent Cal/BD aerosol foam was continued for a further 2 weeks.

aerosol, betamethasone dipropionate, calcipotriol, psoriasis

PMC5769203_02

Female

Miss B. 22-year-old female, studied up to 10th std., a semi-skilled worker and unmarried. There was a family history of bipolar illness in the patient's father. Both her parents died when she was 6-year-old, and she was raised by her grandparents. The patient had an early onset of BPAD-mixed affective state precipitated by her transition from school to college. Her symptoms then involved irritability, anger outbursts directed at family members, over-cheerfulness, and increased social interaction with strangers. Along with these symptoms, she also experienced periods of sad mood accompanied by social withdrawal and reduced psychomotor activity. Her behavior would oscillate from being cheerful to very dull, grooming excessively or neglecting self-care, overeating or poor appetite, and sleeping excessively to having insomnia. These symptoms continued for about 8 months after which she was treated with pharmacotherapy and showed significant improvement. However, a year later, she again presented to NIMHANS with the complaints of sad mood, reduced interest in work, easy fatigability, overactivity, over-cheerfulness, and over-talkativeness. The management of her symptoms again consisted of pharmacotherapy, with which her symptoms improved for next almost 4 years. However, she continued complaining of easy fatigability, lack of motivation to go to work, frequent headaches and occasional irritability and anger outbursts. She was referred for psychotherapy for the management of these residual symptoms.

bipolar affective disorder, emotional regulation, interepisodic symptoms, mindfulness-based cognitive therapy, quality of life

PMC9282729_01

Male

A 23-year-old critically-ill male with history of Burkitt's lymphoma, with graft-versus-host disease (GVHD) requiring high-dose corticosteroids, was admitted to the Emergency Department following a 2 days history of somnolence and confusion with evolving respiratory distress requiring endotracheal intubation. On admission neurological examination, he would open eyes to painful stimuli and continued to follow commands. Initial CT head revealed a flame hemorrhage in the left gyrus rectus suspicious for vascular origin and a hypodensity in the left thalamus suspicious for an established infarction. An angiogram performed the next day demonstrated six fusiform aneurysms: three at the frontopolar branch and one at the orbitofrontal branch of the left anterior cerebral artery (ACA); 1 at the frontopolar branch of the right ACA; and one at the anterior temporal artery of the left middle cerebral artery (MCA); [Figure 1]. Body imaging revealed cavitary lung lesions. The patient was started on broad spectrum antibiotics, antifungals, and antiviral medications. The location of hemorrhage pointed to the left ACA branch aneurysms as the source. Surgery was chosen to allow for inspection of all lesions under direct vision for ruptured status as well as obtain tissue for microbiological purposes. A bicoronal craniotomy, parent vessel sacrifice, and excision of the three aneurysms arising from the left ACA were performed on postbleed day 2. Intraoperatively, the aneurysms were friable, thin walled, and prone to bleeding. The right ACA aneurysms were managed conservatively. Microbiology confirmed angioinvasive S. apiospermum infection. Vericonazole, amphotericin B, and caspofunging were started empirically and continued throughout the disease process. CT scan obtained due to neurological deterioration on postbleed day 4 revealed new left frontal intracerebral hemorrhage and intraventricular hemorrhage (IVH). An emergency external ventricular drain was placed and a follow-up angiogram was obtained revealing interval growth of the left orbitofrontal artery aneurysm. Since microbiological diagnosis was available, endovascular parent vessel occlusion was recommended and preceded uneventfully. An interval angiogram on postbleed day 7 demonstrated three new fusiform aneurysms of the right ACA, a new aneurysm of the left anterior choroidal artery (AChA), and the left posterior communicating artery (PCOMA) and confirmed a stable appearing left anterior temporal artery aneurysm. Due to the rapid development of new aneurysms, as well as the hemorrhagic presentation, the treatment was recommended. A3-A3 revascularization was attempted to avoid ACA sacrifice; however, due to the friable nature of the diseased vessels, this was unsuccessful and parent vessel sacrifice had to be performed. An intraoperative angiogram demonstrated a new anterior communicating artery (ACOMA) aneurysm, which was left untreated at the time of surgery. On further follow-up imaging, the ACOMA aneurysm continued to enlarge and, therefore, was treated with endovascular A1 occlusions on postbleed day 9. Finally, continued surveillance imaging demonstrated interval growth of the previously identified left AChA and PCOMA aneurysm, which were ultimately treated with parent vessel sacrifice. Despite multiple parent vessel sacrifice, the patient recovered neurologically, continued to follow commands with upper extremities with expected, severe paraparesis in the lower extremities. His follow-up MRI confirmed a thalamic infarct which was already seen on admission imaging and new, incomplete ACA territory infarctions in keeping with the previous surgeries and parent vessel sacrifice of the bilateral ACAs. Due the severe systemic and pulmonary disease, the patient remained intubated and ventilated and underwent a tracheostomy procedure. His subsequent course was complicated with septic shock from multidrug resistant pseudomonas superinfection of the cavitary lung lesions and the patient died 6 months after the hemorrhagic presentation.

mycotic aneurysm, scedosporium apiospermum, surgery

PMC6159175_01

Female

A 20-year-old asymptomatic female, G1P0, with a history of curettage, is presented to the Department of Gynecology and Obstetrics for termination of pregnancy. Her last menstrual period was 17 weeks and 2 days ago. Abdominal ultrasound revealed a clear gestational sac (GS), fetus with heartbeat and placenta previa. Abdominal ultrasound also showed the GS at a distance from the cavity, with a compressed myometrium between the two of them (Figure 1). The patient received a MRI examination, showing an enlarged uterus of 13.0 cm x11.7 cm x 7.9 cm, because of pieces of evidence. The MRI demonstrated a foetus with clear organs (Figure 2), and compressed the lower uterine segment (Figure 3). The GS was not connected with the uterine cavity and endometrium, but embedded into the myometrium in the right posterior wall of the uterine. A linear hypointensity of the junction zone was observed between the GS and the uterine cavity on T2weighted image (Figure 4). This result is likely to be placenta implantation as the myometrium cannot be separated from the placenta. The patient was at risk of the uterine rupture and life- threatening haemorrhage. Emergent management should be performed. Performing uterine artery embolization (UAE) and interventional therapy is inadvisable because of the obstructing myometrium between the cervix and placenta. Employing a surgical exploration of the abdomen was decided that was undertaken under temporary balloon occlusion of the abdominal aorta to reduce the loss of blood. The balloon was placed in the abdominal aorta between the opening of renal artery and iliac artery just before the operation. If the area of the focal damage was heavy, the subtotal hysterectomy or hysterectomy was needed. Otherwise, clinicians can perform excision by laparotomy and hysteroplasty. Given the age of patient, clinicians did their best to perform hysteroplasty instead of hysterectomy. The intramural ectopic GS in the second trimester was successfully excluded without life-threatening haemorrhage (Figure 5). The patient had an uneventful postoperative course. Her beta-hCG titre decreased to 1727 mIU ml-1 on the second day after operation, and then to 440.1 mIU ml-1 on the sixth day. She was discharged 6 days after surgery.

PMC4356042_01

Female

A sixty-four year old multipar female was admitted to our outpatient clinic with fatigue, abdominal distension, anorexia, hot flushes, and weight loss of 8 kg within eight months. She was hypertensive for a decade but did not report any important disease in her family history. She had no known exposure to TB, never smoked, and never used alcohol. During her physical examination the patient was conscious, cooperative, and showed normal vital signs. The conjunctiva was pale. The examination of the systems was normal except ascites and lymphadenopathies (LAPs). No stigmata of chronic liver disease were found. Multiple painless, mobile, and solid LAPs were found, the biggest being 2 cm in the left cervical and supraclavicular and 3 cm in the bilateral axillary and inguinal regions. The laboratory findings of the patient are summarized in Table 1. Evaluation of the initial laboratory parameters showed mild anemia and leukopenia, a high erythrocyte sedimentation rate (ESR), a high C-reactive protein (CRP) level, increased lactate dehydrogenase (LDH), a albumin globulin rate less than 1, a high CA-125 level, and low vitamin B12. The erythrocytes were normochromic normocytic; mild monocytosis (16%) but no atypical cells were seen in the peripheral blood smear. In the analysis of the ascites fluid, the serum ascitic albumin gradient (SAAG) was <1.1 g/dl, the cell count was 1600 leukocytes/mm3 (70-80% mononuclear), the value of adenozine deaminase (ADA) was 60.4 U/l, and the LDH was high (281 U/L). No malignancy finding was found during the cytological evaluation of the ascites fluid. No bacteriological growth in the ascites fluid culture was observed. She was euthyroid and HIV seronegative. Her hepatitis B and C tests were negative and her coagulation tests were normal. Fecal occult blood revealed a negative result 3 times. No sign of heart failure was detected in both her echocardiography and her physical examination. Chest X-ray revealed bilateral reticulonodullary infiltration (Fig. 1A). On the abdominal USG, there was a LAP of 2 cm in the hepatic hilum and ascites, but no hepatosplenomegaly. The USG scans of the axillary, inguinal, and cervical regions also revealed hypoechoic, lobulated, and heterogenous multiple LAPs. Ground-glass density areas in both lungs, especially in the left one, were seen on thoracic CT (Fig. 1B). On abdominal computed tomography (CT) multiple LAPs were observed in paraaortic region. Ascites, ventral abdominal mesenteric heterogenity and thickness were seen on CT image as well (Fig. 2A). For the exclusion of an occult malignancy, an upper gastrointestinal system endoscopy was performed, and reflux esophagitis was seen. She was consulted to our Gynecology Department to rule out gynecologic malignancies since the serum level of CA-125 was high. A gynecologic examination revealed no pathological finding so a screening PAP smear test and an endometrial curettage were performed. No pathological finding was found in mammographic scan. A supraclavicular lymphadenectomy was performed for a diagnosis. The pathology of the lenfoid tissue and endometrial biopsy showed caseification necrosis in some granulomas. Her PAP smear showed a negative result for malignancy. The intradermally performed purified protein derivative (PPD) test was 15 mm. The direct microscopic examining of induced sputum acid-resistant bacilli (ARB) was negative and sputum cultures for MTB were performed. After all of the diagnostic tests, genital TB became suspicious. A tetrad treatment with isoniasid 300 mg/day, rifampycin 600 mg/day, pyrazinamide 1500 mg/day, etambuthol 1500 mg/day was started. Sputum culture before the treatment was positive for MTB. Four months after the initiation of the treatment, her hemoglobin and CA-125 levels turned to normal. The ascites had disappeared, the diameters of the LAPs had significantly decreased, and the symptoms of the patient had all regressed.

ascites, diagnostic methods, tuberculosis

PMC10129030_01

Male

A 62-year-old man presented with acute dyspnea at rest, requiring high-flow oxygen therapy with a fraction of inspired oxygen of 80% in February 2021. A nasopharyngeal SARS-CoV-2 PCR was negative; however, the patient reported contracting a mild case of COVID-19 in December 2020, which was treated in an outpatient setting. Known comorbidities included hypertension, hyperlipidemia, and diabetes mellitus type II with a negative history of smoking and lung disease. A chest CT scan performed at admission revealed bilateral, diffuse ground-glass opacities, bronchiectasis and subpleural reticular changes consistent with pulmonary fibrosis predominantly in the middle and lower lobes (Fig. 1a, b). Treatment with high-dose glucocorticoids was initiated, starting with 10 mg/day dexamethasone for 21 days with a switch to oral 25 mg/day prednisolone and 1,500 mg/day mycophenolate mofetil. However, therapy remained ineffective, and lung function progressively worsened (forced expiratory volume of 1.23 L [42%], total lung capacity of 3.1 L [51%] 2 weeks after admission). Imaging demonstrated a rapid decline of his condition with an acute respiratory distress syndrome pattern, upon which the patient was intubated (Fig. 1c, d). The indication of lung transplantation was established in line with previously suggested selection criteria. As a bridge to transplantation, a venovenous extracorporeal membrane oxygenation was implanted a month after admission. A week later, bilateral lung transplantation was successfully conducted. No major postoperative complications were reported. After undergoing an intensive rehabilitative program, the patient was discharged 2 months later with steadily improving forced expiratory volume values (2.9 L [92%] in June 2021). The lung explant was examined on grossing and sent for further histological and molecular analysis. The lungs were heavy, firm, with brownish yellowish carnification of the parenchyma, and showed signs of diffuse calcification (Fig. 2), as evidenced by a video demonstration of the macroscopic examination (see online suppl. Materials; see www.karger.com/doi/10.1159/000525457 for all online suppl. material). As a correlate to the calcification, histology revealed extensive, diffuse interstitial dendriform ossification, comprising of lamellar bone with fatty marrow with focal hematopoiesis (Fig. 3a). Diffuse interstitial fibrosis with bronchiolar, mucinous and transitional cell metaplasia of the alveolar epithelium (Fig. 3b); traction bronchiectasis; bronchiolar mucostasis; fibrinous pleuritic; and multifocal alveolar hemorrhages were evident throughout the parenchyma. Hemosiderin-laden macrophages were a frequent finding (online suppl. Fig. 1). A proliferation of interstitial and intra-alveolar bronchiogenic giant cells exhibiting partial positivity for thyroid transcription factor 1 was observed (not shown). There were various signs of pulmonary remodeling, as evidenced by an increase of interstitial collagen and a disarray of elastic fibers, proliferative diffuse alveolar damage (DAD) and an interstitial accumulation of M2-polarized CD163+ and CD206+ macrophages (Fig. 3c) with an increased expression of phospho-ERK (Fig. 3d) and increased neoangiogenesis (CD105+ vessels) (Fig. 3e). Fibrin staining revealed sparse intra-alveolar fibrinous exudates, corresponding to residual exudative DAD without microthrombi. Interstitial lymphocytes were predominantly T cells (ratio of CD3+ T cells to CD20+ B cells is 2:1) with an exhausted phenotype (weak PD1 positivity). Cytotoxic T cells (CD8+) and T-helper 1 subsets (Tbet+ TH1) were more frequent than T-helper 2 subsets (GATA3+ TH2) (Fig. 3f, g). T-regulatory cells (FoxP3+ Treg) and gammadelta T cells (gammadelta+) comprised 2-3% of lymphocytes. Plasma cells were polytypic; there was no plasmablast excess (no MUM1+ cells). Mast cells (as evidenced by mast cell tryptase stain) were increased. Quantitative reverse transcriptase polymerase chain reaction for SARS-CoV-2 revealed low residual viral load in the explanted lung tissue (N-Gene: Ct [cycle threshold] value 36.5) (PCR protocol as previously described). This result was confirmed with the orthogonal method - droplet digital PCR (N1 gene: 0 copies/muL; N2 gene 0.0307 copies/muL). Immunohistochemistry for SARS-CoV-2 nucleocapsid (N)-antigen showed focal endothelial deposition in arterioles (Fig. 3h). Links of the scanned H&E sections as well as all antibody protocols can be found in online supplementary Materials.

covid-19, dendriform pulmonary ossification, lung transplant, post-covid-19, pulmonary fibrosis, sars-cov-2

coronal. chest CT shows ground-glass and reticular opacities in the dependent lung with bronchiectasis (arrow).

PMC10129030_01

Male

A 62-year-old man presented with acute dyspnea at rest, requiring high-flow oxygen therapy with a fraction of inspired oxygen of 80% in February 2021. A nasopharyngeal SARS-CoV-2 PCR was negative; however, the patient reported contracting a mild case of COVID-19 in December 2020, which was treated in an outpatient setting. Known comorbidities included hypertension, hyperlipidemia, and diabetes mellitus type II with a negative history of smoking and lung disease. A chest CT scan performed at admission revealed bilateral, diffuse ground-glass opacities, bronchiectasis and subpleural reticular changes consistent with pulmonary fibrosis predominantly in the middle and lower lobes (Fig. 1a, b). Treatment with high-dose glucocorticoids was initiated, starting with 10 mg/day dexamethasone for 21 days with a switch to oral 25 mg/day prednisolone and 1,500 mg/day mycophenolate mofetil. However, therapy remained ineffective, and lung function progressively worsened (forced expiratory volume of 1.23 L [42%], total lung capacity of 3.1 L [51%] 2 weeks after admission). Imaging demonstrated a rapid decline of his condition with an acute respiratory distress syndrome pattern, upon which the patient was intubated (Fig. 1c, d). The indication of lung transplantation was established in line with previously suggested selection criteria. As a bridge to transplantation, a venovenous extracorporeal membrane oxygenation was implanted a month after admission. A week later, bilateral lung transplantation was successfully conducted. No major postoperative complications were reported. After undergoing an intensive rehabilitative program, the patient was discharged 2 months later with steadily improving forced expiratory volume values (2.9 L [92%] in June 2021). The lung explant was examined on grossing and sent for further histological and molecular analysis. The lungs were heavy, firm, with brownish yellowish carnification of the parenchyma, and showed signs of diffuse calcification (Fig. 2), as evidenced by a video demonstration of the macroscopic examination (see online suppl. Materials; see www.karger.com/doi/10.1159/000525457 for all online suppl. material). As a correlate to the calcification, histology revealed extensive, diffuse interstitial dendriform ossification, comprising of lamellar bone with fatty marrow with focal hematopoiesis (Fig. 3a). Diffuse interstitial fibrosis with bronchiolar, mucinous and transitional cell metaplasia of the alveolar epithelium (Fig. 3b); traction bronchiectasis; bronchiolar mucostasis; fibrinous pleuritic; and multifocal alveolar hemorrhages were evident throughout the parenchyma. Hemosiderin-laden macrophages were a frequent finding (online suppl. Fig. 1). A proliferation of interstitial and intra-alveolar bronchiogenic giant cells exhibiting partial positivity for thyroid transcription factor 1 was observed (not shown). There were various signs of pulmonary remodeling, as evidenced by an increase of interstitial collagen and a disarray of elastic fibers, proliferative diffuse alveolar damage (DAD) and an interstitial accumulation of M2-polarized CD163+ and CD206+ macrophages (Fig. 3c) with an increased expression of phospho-ERK (Fig. 3d) and increased neoangiogenesis (CD105+ vessels) (Fig. 3e). Fibrin staining revealed sparse intra-alveolar fibrinous exudates, corresponding to residual exudative DAD without microthrombi. Interstitial lymphocytes were predominantly T cells (ratio of CD3+ T cells to CD20+ B cells is 2:1) with an exhausted phenotype (weak PD1 positivity). Cytotoxic T cells (CD8+) and T-helper 1 subsets (Tbet+ TH1) were more frequent than T-helper 2 subsets (GATA3+ TH2) (Fig. 3f, g). T-regulatory cells (FoxP3+ Treg) and gammadelta T cells (gammadelta+) comprised 2-3% of lymphocytes. Plasma cells were polytypic; there was no plasmablast excess (no MUM1+ cells). Mast cells (as evidenced by mast cell tryptase stain) were increased. Quantitative reverse transcriptase polymerase chain reaction for SARS-CoV-2 revealed low residual viral load in the explanted lung tissue (N-Gene: Ct [cycle threshold] value 36.5) (PCR protocol as previously described). This result was confirmed with the orthogonal method - droplet digital PCR (N1 gene: 0 copies/muL; N2 gene 0.0307 copies/muL). Immunohistochemistry for SARS-CoV-2 nucleocapsid (N)-antigen showed focal endothelial deposition in arterioles (Fig. 3h). Links of the scanned H&E sections as well as all antibody protocols can be found in online supplementary Materials.

covid-19, dendriform pulmonary ossification, lung transplant, post-covid-19, pulmonary fibrosis, sars-cov-2

coronal. chest CT shows extensive bilateral ground-glass opacities, reticulation, and bronchiectasis consistent with ARDS pattern. ARDS, acute respiratory distress syndrome.

PMC9887264_01

Male

A 78-year-old Japanese man presented with lower back pain of 8 months' duration and bilateral leg pain of 1 month's duration. He had developed tuberculous pleuritis at 11 years of age. The patient had no history of trauma. His mother had a history of tuberculosis when he was 7 years old. He had no occupational or avocational exposure to wet soil or water. He had never traveled abroad. At the presentation, the patient's vital signs were normal. Physical examination revealed an increased patellar tendon reflex on the left side and bilaterally decreased Achilles tendon reflexes. He was capable of bending both knees and moving both ankles as intended. Blood tests showed normal white blood cell counts and elevated C-reactive protein level (6.6 mg/dL) and erythrocyte sedimentation rate (55 mm/hour). Mild renal dysfunction was observed, with a creatinine of 1.35 mg/dL. The soluble interleukin-2 receptor level was elevated to 764 U/mL. T-SPOT.TB (Oxford Immunotec) and anti-human immunodeficiency virus antigens/antibodies tested negative. Computed tomography revealed a fracture with osteolytic changes in Th12-L1 vertebrae and a mass in the right kidney (Figure 1). Magnetic resonance imaging revealed Th12-L1 vertebral fractures and protrusion of the vertebrae into the spinal canal (Figure 2). Three days after presentation, he underwent posterior vertebral decompression and percutaneous thoracolumbar root screw fixation for neurological deficits and vertebral biopsy for a pathological vertebral fracture. No remarkable abscess or necrotic tissue was observed intraoperatively. Vertebral tissue samples were negative for general bacterial culture, concentrated fluorochrome smear microscopy, and nucleic acid amplification testing for Mycobacterium tuberculosis. Pathological examination of the vertebral tissue showed caseous necrosis surrounded by epithelial granulomas and a few multinucleated Langhans giant cells (Figure 3). A few acid-fast bacilli were found on auramine-rhodamine and acid-fast stains; no neoplastic lesions were detected (Figure 4). Based on these findings, the patient was presumed to have tuberculous spondylitis, and oral rifampicin, isoniazid, ethambutol (EMB), and pyrazinamide administration was commenced on the eighth postoperative day. Bacteriological investigation revealed the growth from vertebral tissue cultures on 2% Ogawa medium (Kyokuto Pharmaceuticals) in the second week at 30 C and in the third week at 37 C, respectively. Cultures on a liquid medium (Mycobacteria Growth Indicator Tube, Becton Dickinson) at 37 C were negative for 12 weeks. Bacteria and mycobacteria were not isolated from sputum or urine cultures. Mycobacterium tuberculosis group antigen or mycobacterial protein fraction from bacille Calmette-Guerin of Rm 0.64 in electrophoresis tested negative. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry indicated an NTM suggestive of M arupense infection. Based on these results, pyrazinamide was switched to clarithromycin (CLR) on postoperative day 27. Subsequent identification tests revealed 100% homology with M arupense on 16S ribosomal RNA (rRNA), 99.75% on hsp65, and 98.91% on rpoB gene sequencing. The relationship between 16S rRNA gene sequence of this isolate and that of other species of Mycobacterium terrae complex (MTC) is shown in the Supplementary Figure. Drug susceptibility testing showed that the isolate was susceptible to rifabutin (RFB), EMB, and CLR based on the interpretation for Mycobacterium kansasii of the Clinical and Laboratory Standards Institute document M62 (Table 1). The regimen was then adjusted to 3-drug combination therapy of RFB, CLR, and EMB on postoperative day 126. Subsequently, neutropenia and thrombocytopenia, likely due to the interaction between RFB and CLR, were observed, and RFB was switched to faropenem (FRPM) on a postoperative day 160. Antimicrobial therapy was completed 1 year after the initiation of CLR treatment. His symptoms gradually improved, and his condition has been stable for 2 years after treatment. A partial nephrectomy was performed for renal cancer.

mycobacterium arupense, mycobacterium infections, nontuberculous mycobacteria, osteomyelitis, spondylitis

PMC4643447_03

Male

A 51-year old smoker male without relevant medical history. He was involved in a high-energy motor vehicle accident and suffered from several injuries amongst which a severely dislocated talar fracture type Hawkins IV (Fig. 3), without neurovascular compromise. Treatment consisted of open reduction followed by an external fixator to maintain adequate reposition and to monitor the soft tissues. Sixteen days post injury internal fixation was performed. X-rays six and twelve weeks post injury did not indicate avascular necrosis of the talus. After ten months a subtalar arthrodesis with a cannulated screw and iliac crest bone graft was performed because of pain caused by arthritis due to incongruent articulating surface. Rehabilitation was complicated by a wound infection. Patient did regain limited motion of the ankle joint but pain persisted. CT scans showed a non-union of the talar fracture, the vascularity of the talus could not be determined by the CT scan. After screw removal a MRI was performed. This showed an avascular talus (Fig. 4). The combination of avascular necrosis, low-grade infection and pain warranted a talectomy followed by a tibiocalcanear fusion. Six weeks after surgery patient resumed weightbearing activities. One year after tibiocalcanear fusion patient is in good physical condition and fairly pain free with transcutaneous electro neuro stimulation.

arthritis, avascular necrosis, dislocated talar fracture

PMC3336232_01

Female

A 87-year-old woman with a history of pulmonary fibrosis, chronic heart failure, and hepatitis C infection was admitted at our hospital in April 2010 with right ear otorrhea, otalgia, tinnitus, and peripheral facial nerve paralysis. The patient reported that symptoms gradually appeared over the last two years and for this reason in May 2009 she underwent mastoid curettage with concho-meatoplasty in local anaesthesia due to the high clinical risk of general anaesthesia at another institution. At that stage no serologic, histologic, or microbiologic analysis was performed. On admission the patient was apyretic, even if tachycardic (heart rate 98/min). Blood pressure was 110/75 mmHg and oxygenation saturation 98%. Examination of the right ear showed wide conchomeatoplasty, a large (5 cm) postauricular cutaneous mastoid fistula in the region of the previous retroauricular incision. The mastoid bone was partly uncovered and partly lined by granulation tissue that extended in the middle ear region with no tympanic membrane. Periauricular cutaneous lesions were also evident. Facial nerve function was House Brackmann grade III. Left ear was normal as well as the rest of the otolaryngologic examination. Hearing test showed a right dead ear and severe sensorineural hearing loss on the left side. Laboratory values included a white blood cell count of 9.530/mm3 (86.5% segmented neutrophils, 7.9 lymphocytes, 5% monocytes, 0.5% eosinophils, and 0.1% basophils), haemoglobin 13.0 g/dL, and platelets 185.000/mm3. Blood and urine cultures as well as sputum examination were negative. The chest X-ray was normal while high resolution computed tomographic (CT) scan of the lung showed a reticular pattern on all the pulmonary areas, with associated fibrotic areas. CT scan of temporal bones showed the signs of the previous surgery, as well as inflammatory tissue in the right external auditory canal, the middle ear and mastoid (Figure 1). These findings along with chest X-ray and HRT-CT lung scan, negative for TBC, allowed to exclude a secondary TBC form. The histological examination of the granulation tissue showed caseous necrosis and specific granulation with epithelioid cells and Langhans type giant cells (Figure 2). A swab of the secretion revealed no alcohol-acid-resistant bacilli when Ziehl Neelsen staining method was performed, while the real-time-polymerase chain reaction (rt-PCR) allowed the detection of Mycobacterium tuberculosis. On the basis of the laboratory findings anti-TB treatment including rifampicin and isoniazid was started together with local medications of the mastoid cavity with rifampicin drops. On follow-up facial nerve paralysis resolved after the second month of therapy, and the conditions of the mastoid cavity progressively improved up to the point that the retroauricular fistula was successfully sutured and the granulation tissue disappeared.

PMC9463011_01

Male

A 60-year-old patient was admitted to our hospital because of inflammatory syndrome, polyarthralgia, and weight loss. A physical examination showed only pain in the heels and the first metatarsophalangeal joint as well as hypoesthesia of the left foot. The significant biological results showed nonidentified c-ANCA (non-PR3 and non-MPO) with a titer of 1 : 2560 as well as a C-reactive protein of 99 mg/L, and an erythrocyte sedimentation rate of 67 mm/h. The renal function was in the normal range values. The thoracic computed tomography (CT) scan showed several bilateral nonspecific micronodules (Figure 1(a)), and the positron emission tomography computed tomography (PET-CT) scan showed moderately hypermetabolic retroperitoneal and inguinal lymphadenopathy. A sinus CT scan was performed and showed pansinusitis (Figure 1(b)). A biopsy of inguinal adenopathy was performed in favour of reactive inflammatory nodes with no signs of malignancy. The tuberculosis QuantiFERON ELISA test was positive, but the culture and polymerase chain reaction of the biopsied node were negative. The patient later developed arthritis in the ankle confirmed by IRM, and sinus CT confirmed the presence of pansinusitis. The diagnosis of GPA was made on the basis of high c-ANCA titers (non-PR3 and non-MPO), bilateral pulmonary nodules, and pansinusitis, and treatment with cyclophosphamide and methylprednisolone was administered, followed by azathioprine. This treatment was combined with isoniazid for tuberculosis prophylaxis. The patient presented a good clinical evolution with normalisation of the inflammatory syndrome and a significant decrease in c-ANCA (Figure 2). Five years later, the patient's clinical condition deteriorated with asthenia, weight loss, and abdominal pain. There was an increased inflammatory syndrome as well as increased ANCA titers (variation of titers is shown in Figure 2). The PET-CT scan was not in favour of a vasculitis relapse. The node biopsy performed five years ago was retrospectively reviewed for evaluation of IgG4. The histology of the lymph node was described as an inflammatory node with extensive plasmacytosis as depicted with CD138 immunostaining. The infiltrate showed 50 IgG4 positive plasma cells per high-power field. A serum IgG4 assay was performed and very slightly increased at 1.351 g/L (N < 1.350). The abdominal CT image did not show retroperitoneal fibrosis despite the presence of bilateral uretero-hydronephrosis without objectified obstacle. A possible diagnosis of IgG4-related disease (IgG4-RD) was then carried out, but GPA diagnosis was not completely excluded. The patient was treated by intravenous methylprednisolone and rituximab with a good clinical and biological evolution. Three years later, he developed another relapse with distal digital ischemia of the foot, multiplex mononeuritis, and external popliteal sciatica deficit, rather in favour of GPA with a BVAS score of 6 (Birmingham Vasculitis Activity Score). Afterwards, the patient was treated only with mycophenolate mofetil (2 g/day) without any relapse.

PMC5903130_01

Female

A 66-year-old Japanese woman presented with bilateral blurred vision 4 months prior to visiting our hospital. She had been diagnosed with conjunctivitis and prescribed antibacterial eye drops by a local ophthalmology clinic. While undergoing therapy, she developed general fatigue and lumbar pain. She visited a private clinic, and was diagnosed with bilateral exudative pleural effusions. She was then referred to our hospital for further investigation and treatment. After admission to our hospital, complete physical examinations were done. Her exudative pleural effusion was of unknown origin. The patient had a past history of breast cancer 2 years ago, but no malignant cells were observed in cytology examination, and no malignancy was detected by CT and MRI. In pleural fluid examination, the specific gravity was 1.304, cell count 397/microL (neutrophils 4.0%, lymphocyte 62.0%, macrophage 34.0%), lactate dehydrogenase 105 U/L, adenosine deaminase 8.7 U/L, total protein 4.4 g/dL, rheumatoid factor < 10.0 IU/mL, antinuclear antibodies (+-), and negative cultures. The cause of lumbar pain was also examined by the orthopedic department, and she was diagnosed with multiple spondylitis. Findings of an MRI of the spine and bone scintigraphy are shown in Figure 1. She also had palmoplantar pustulosis beginning several years ago. Based on the findings of spondylitis and palmoplantar pustulosis, she was diagnosed with SAPHO syndrome by both orthopedists and dermatologists, and was prescribed antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs). Seven days after admission, she was referred to ophthalmology for investigation of the cause of her blurred vision. At presentation, her best-corrected visual acuity (BCVA) was 0.6 in both eyes. Intraocular pressure was 18 mm Hg in the right eye and 16 mm Hg in the left eye. Slit-lamp examination demonstrated bilateral shallow anterior chambers. There were no keratic precipitates in both corneas, and no cells in the anterior chambers. Fundus examination revealed bilateral annular choroidal detachment with exudative serous retinal detachment involving the macula. Optical coherence tomography (OCT) showed subretinal fluid with a wavy retinal pigment epithelium (RPE) line and thicker choroid in both eyes. Fluorescein angiography (FA) depicted multiple areas of pinpoint dye leakage from the RPE. Indocyanine green angiography (ICGA) showed multiple areas of choroidal hypoperfusion in both eyes (Fig. 2). B-scan ultrasonography confirmed choroidal detachment with no associated scleral thickening or masses affecting the choroid and sclera. Although the patient did not meet all the diagnostic criteria for VKH disease, differential diagnosis showed no evidence of diseases such as uveal effusion syndrome, posterior scleritis, or choroidal metastasis, and laboratory markers of other types of uveitis including sarcoidosis, syphilis, and tuberculosis were negative. Moreover, autoimmune diseases such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, which are often accompanied by uveitis, were also unlikely because of the absence of antibodies specific to these diseases. Her clinical findings including FA, ICGA, and OCT indicated VKH disease. Treatment was begun with a subtenon injection of triamcinolone acetonide in both eyes, while internists continued investigations to rule out other diseases. After 7 days, when internists finished the diagnostic workup with no additional findings, high-dose intravenous corticosteroids were given for 3 days. Treatment was continued with a slowly tapering course of oral prednisolone to 30 mg per day for 8 days. Because the choroidal and retinal detachments persisted in spite of steroid therapy, the patient was prescribed immunosuppressive medication of cyclosporine 150 mg twice daily. Two weeks after starting cyclosporine, cellulitis occurred in the left leg and C-reactive protein (CRP) increased to 23.5 mg/dL. Cyclosporine was discontinued, and prednisolone was further tapered to 10 mg per day. Because of this episode, ocular findings persisted and worsened. Ten days after discontinuing cyclosporine, her general condition improved and CRP level decreased to within the normal limit. Treatment was resumed with high dose (1 g) of intravenous corticosteroids for 3 days and cyclosporine 150 mg twice daily. Seventy days after the second course of high-dose intravenous corticosteroids, choroidal and retinal detachments were resolved completely, and BCVA was 0.5 in the right eye and 0.7 in the left eye (Fig. 3). Bilateral pleural effusions were also resorbed, and her general condition improved.

choroidal detachment, cyclosporine, sapho syndrome, serous retinal detachment, vogt-koyanagi-harada disease

PMC7243184_01

Male

A 41-year-old male with bronchiectasis, chronic sinusitis, and obstructive lung disease presented to the emergency department in acute on chronic hypoxic respiratory failure. Chart review showed multiple encounters for shortness of breath and cough, with increasing admission frequency over the preceding 2 months. On each occasion he was given a diagnosis of COPD exacerbation and treated with steroids and azithromycin or doxycycline. Symptoms between admissions were poorly controlled despite adherence to albuterol, montelukast, and ranitidine. The patient initially noted dyspnea 12 years prior and had been on 2.5 L/minute home oxygen for the preceding 8 years. The patient reported dyspnea unrelated to exertion and dry cough. Over the last few months, patient denied remission of symptoms and had no history of atopy. Patient admitted night sweats, chills, and a 4.5-kg. unintentional weight loss with suspected exposure to tuberculosis while imprisoned. Patient declared a 5-pack year smoking history with quit date 10 years prior to admission and denied alcohol and illicit drug use. Prior to incarceration the patient worked at a fertilizer factory. Family history and surgical history were non-contributory. On examination, the patient was afebrile with normal vital signs. The patient was a thin white male in respiratory distress with prolonged expiratory phase, diffuse expiratory wheeze and cough. No crackles were heard, and the patient did not exhibit clubbing. A pulmonary function test administered 6 years before presentation demonstrated reduced flow and capacity with mid flow-loop obstruction, which was responsive to bronchodilator, and mildly reduced diffusion capacity. Previous results also included a normal alpha-1 antitrypsin level and a non-diagnostic bronchial alveolar lavage (BAL) that disclosed moderate polymorphonuclear neutrophils with normal respiratory flora. Laboratory testing revealed a white blood cell count of 11.75 K/muL comprised of 93% neutrophils but also an eosinophil count of 0.04 K/muL. The complete metabolic panel was normal. A chest radiograph showed no acute pulmonary radiologic findings (Fig. 1). Due to chronic course and relapses, the pulmonology team performed flexible fiberoptic bronchoscopy with BAL from the right middle lobe of lung. BAL cytology resulted with eosinophilia but microbiology stains, PCRs and cultures were negative. Computed-tomography (CT) showed mild centrilobar emphysema with a few subpleural blebs in the right upper lung and signs of central bronchiectasis. Also, there was minimal apical scarring bilaterally (Fig. 2). The serum specific IgE against A. fumigatus was positive (4.23 kU/L) and serum total IgE (3868 kU/L) was markedly elevated. Serum precipitins (specific IgG) against Aspergillus spp. were negative. A. fumigatus and A. terreus by PCR and fungal blood cultures were negative. Table 1 below summarizes the findings in our case and how the findings differ from the minimum essential diagnostic criteria proposed by Greenberger. A diagnosis of ABPA was made as our case met three of the minimum essential criteria despite not performing a skin prick test and a negative history of asthma. The patient was treated with itraconazole and prednisone. On follow up, the patient reported improvement of cough, sputum, and dyspnea.

CT of the chest showed mild centrilobar emphysema with a few subpleural blebs in the right upper lung and signs of central bronchiectasis.

PMC2826293_01

Male

A 41-year-old Nepalese male of Aryan origin presented with 3 months history of gradually progressive jaundice, intermittent right upper quadrant pain, and weight loss of 5 kg over a 2-month period. There was no history of cough, fever, hemoptysis or shortness of breath. He had received a BCG vaccine at childhood, but there was no prior history of tuberculosis, or family history of contact. On examination, patient was deeply icteric with skin scratch marks all over the body. On abdominal examination, he had mild hepatomegaly and a palpable gall bladder. Initial laboratory values revealed a WBC count of 9200/mm3 (90% neutrophils, 10% lymphocytes), haemoglobin 12.7 g/dL, total bilirubin 24.4 mg/dL, conjugated bilirubin18 mg/dL, ALT 96 U/L (normal 5-45 U/L), AST 161 U/L (normal 5-45 U/L), and ALP 593 U/L (normal 42-128 U/L), albumin 3.5 mg/dL and total protein 5.7 mg/dL. His random blood sugar, serum urea and creatinine will within normal limits. A chest X-ray film was normal. Abdominal ultrasound examination revealed an irregular hypoechoic lesion of 3 cm x 4.4 cm in the head and uncinate process of pancreas, and with dilation of entire bile duct system, distended gall bladder with normal pancreatic duct. Contrast enhanced CT scan showed a heterogeneous mass in the pancreatic head and uncinate process of the pancreas. (Figure 1) The gall bladder was distended along with the dilatation of entire biliary tract. Exploratory laparotomy revealed a mass of size 3x2 cm at the head and uncinate process of pancreas with areas of necrosis on cut section, 50 ml of thick pus at the retroduodenal region, dilated distal common bile duct, distended gall bladder and multiple enlarged perichodochal and peripancreatic lymph nodes. The patient underwent pancreatoduodencetomy with intraoperative diagnosis of pancreatic carcinoma. AFB staining of the pus was negative and culture was sterile. However, the histopathology from the pancreatic mass revealed necrotizing granulomatous lesion which was positive for acid fast bacilli. The histopathological picture of the enlarged nodes was of reactive lymphadenitis. (Figure 2) The patient had uneventful postoperative period. After the diagnosis of tuberculosis, antitubercular drugs were started in accordance to DOTS (Directly observed treatment, short-course), and patient is doing well at the follow up after 6 month.

PMC10197005_01

Female

A 26-year-old Nepalese lady with no previous medical history presented with chief complaints of headache and left-sided monocular blurry vision for one week duration. The headache was located in the occipital region and was intermittent with no aggravating or relieving factors. There was no fever, nausea, vomiting or photophobia. She denied any sick contacts, animal exposure, history of recent infections, night sweats, weight loss, loss of appetite or change in bowel habits. Family history was negative, and her last international travel was to Nepal four months prior to presentation. She was married, had one child, and worked in catering department. Of note, there was no handling of pork meat as part of her job. Vital signs were normal and cranial nerve examination revealed left-sided ptosis and dilated left pupil with sluggish reaction to light. There was mild impairment in adduction, however other extraocular movements were preserved. There were no sensory or motor deficits in any of the extremities and meningeal signs were absent. Rest of the systemic examination was normal. Laboratory workup revealed normal complete blood count, renal and liver function tests. Her inflammatory markers including C-reactive protein and ESR were also normal. Computed tomography (CT) scan of the brain showed a focal hyperdense calcified lesion measuring 6 mm in the midbrain and a calcified focal lesion measuring 5 mm in the left frontal lobe. There was no midline shift or hydrocephalus, and the lesions were interpreted as calcified granulomas (Fig. 1). Magnetic resonance imaging (MRI) of the brain showed a midbrain ring-enhancing lesion with central nodular calcification and significant peri-lesional edema. Another ring-enhancing nodular calcified lesion without edema was reported in the left parasagittal frontal lobe giving an overall impression of granulomatous disease consistent with NCC (Fig. 2). Due to these findings, enzyme-linked immunoelectrotransfer blot (EITB) for anticysticercal antibodies was sent and was reportedly positive. Neurology and infectious disease teams were consulted, and the patient was started on a tapering regimen of dexamethasone for 14 days, in addition to albendazole and praziquantel. The patient was discharged four days later after improvement in ptosis and blurry vision. Unfortunately, post-discharge follow up was not established as the patient travelled back to her home country.

neurocysticercosis, oculomotor nerve, ptosis, qatar, taenia solium

PMC8200608_01

Female

We present the case of a 37-year-old female patient hospitalized in the Gastroenterology Department of the Craiova County Emergency Clinical Hospital in September 2020 for high dysphagia, odynophagia and weight loss (approximately 5kg in the last 2 months before presentation). From the personal medical history, we noted that the patient has been known to have ileo-colonic Crohn's disease since 2007, currently in clinical remission, associating extraintestinal manifestations such as spondylitis and sacroiliitis, for which she underwent biological treatment with Infliximab combined with Azathioprine, discontinued on her own initiative about 5 years ago, subsequently treatment with Mesalazine 3g/day and Azathioprine 100mg/day, and in October 2019 was initiated biological therapy with Adalimumab, discontinued one month before the presentation due to recurrent pharyngitis. The patient's family medical history was insignificant. The patient complained of the onset of symptoms approximately two months before the presentation, by odynophagia, symptoms that did not yield to symptomatic medication, which is why she went to the ENT Department, where, following investigations, the diagnosis of acute erythematous angina was established, for which she subsequently received antibiotic treatment (Amoxicillin+Clavulanic Acid), with no clinical response. Other medical examinations were performed, initially throat cultures were achieved, which highlighted the presence of Enterobacter cloacae, following antibiotic treatment with Ceftriaxone; however, the symptoms did not improve significantly. Subsequently, tonsillar biopsies were performed, which ruled out malignancy. In evolution, the patient's symptoms worsened, from progressive difficulty in swallowing to total high dysphagia, both for solid and liquid foods, accompanied by sialorrhea, marked physical asthenia and weight loss (approximately 5kg). The patient also stated night sweats. At physical examination, the patient was with an affected general condition, temperature 36.9 C, underweight (Weight of 48kg, Height 164cm, body mass index of 17.85), pale and dehydrated skin and mucous membranes, morphologically intact osteo-articular system, with pain when mobilizing the pelvis and lumbar spine, positive Eriksen sign, positive Volkman sign; examination of the superficial lymph nodes system, highlights at the level of the right latero-cervical region, two oval structures, of firm consistency, immobile on deep and superficial planes, without sensitivity to palpation, with a long axis of about 1cm. No significant pathological changes were observed on chest auscultation. ENT examination found congested and hypertrophied palatine tonsils bilaterally and the presence of multiple gray-whitish granules, small in size, diffusely disseminated in the pharynx and larynx. Several differential diagnoses were discussed: viral pharyngotonsillitis, bacterial pharyngotonsillitis, herpetic pharyngotonsillitis, pharyngotonsillitis in acute retro-viral syndrome, oropharyngeal candidiasis, periamygdalian abscess, retropharyngeal abscess, pharyngeal syphilis, acute or chronic laryngitis, tonsillar neoplasm, haematological diseases (agranulocytosis, acute leukemias, lymphomas). Laboratory tests showed mild hypo-albuminemia, moderate microcytic hypochromic anemia, lymphopenia, ESR=120mm/h (N: 2-12mm/h), C-reactive protein=88.24mg/L (N: 0-5mg/L), prothrombin index=61% (N: 79-146%), INR=1.38 (Normal range between 0.8 and 1.16), the rest of the blood tests being within normal limits. Additional biological investigations were performed: microbiological examination of pharyngeal exudate (negative for Candida spp, Staphylococcus aureus, Streptococcus pyogenes), anti-HIV antibodies 1/2 (absent), venereal disease research laboratory (VDRL) (negative); however, we found a positive result for the Koch Bacillus in the patient's sputum. Following the changes encountered in the physical examination and the results of biological tests, it was decided to perform a computed tomography examination of the neck and chest region. At the level of the neck we distinguished a diffuse thickening of the epiglottis, of ariepiglottic folds bilaterally, of vocal cords bilaterally, without obvious asymmetries andhomogeneous, non-specific jugular latero-cervical lymph nodes at the right postero-superior level with dimensions up to 12/7mm and up to 10/6mm at the level of the left postero-inferior triangle with the same characteristics (Figure 1). Computed tomography of the thoracic region showed pulmonary condensation with massive cavitation at the level of the apical segment of the right upper lobe and the segments of the middle lobe; multiple nodular focal condensation areas, disseminated in both lung areas except the basal segments of the left lower lobe, with a tendency to confluence; micronodular lesions with the same arrangement; nonspecific right lower para-tracheal mediastinal adenopathy 14/7mm; without pleuro-pericardial fluid; the described appearance may argue for hematogenous disseminated tuberculous lesion (Figure 2). Based on the information obtained from the anamnesis, physical examination and paraclinical investigations, we established the diagnosis of pulmonary tuberculosis with extrapulmonary, pharyngeal and laryngeal foci, most likely developed in the context of biological therapy with Adalimumab for Crohn's disease. Therefore, therapy with Adalimumab was discontinued, and the patient was referred to a specialized medical unit to initiate the specific treatment. The patient's evolution was favorable with the beginning of the tuberculostatic treatment, being discharged from the Leamna Pneumophthisiology Hospital with good general condition and improved symptoms. Regarding the gastrointestinal pathology, the patient is still in clinical remission (one-two stools of normal consistency per day, without blood in stool), and will return for follow-up control visits, after the completion of tuberculosis-specific treatment. Also, a clinico-biological and imaging re-evaluation of Crohn's disease will be needed in order to establish the new therapeutic approach.

crohn's disease, adalimumab, anti-tnf-α agents, side effects, tuberculosis

CT thoracic region:. pulmonary window, encircled area. right upper lobe condensation area with massive cavitation, arrows. focal pulmonary condensation areas bilaterally.

PMC8200608_01

Female

We present the case of a 37-year-old female patient hospitalized in the Gastroenterology Department of the Craiova County Emergency Clinical Hospital in September 2020 for high dysphagia, odynophagia and weight loss (approximately 5kg in the last 2 months before presentation). From the personal medical history, we noted that the patient has been known to have ileo-colonic Crohn's disease since 2007, currently in clinical remission, associating extraintestinal manifestations such as spondylitis and sacroiliitis, for which she underwent biological treatment with Infliximab combined with Azathioprine, discontinued on her own initiative about 5 years ago, subsequently treatment with Mesalazine 3g/day and Azathioprine 100mg/day, and in October 2019 was initiated biological therapy with Adalimumab, discontinued one month before the presentation due to recurrent pharyngitis. The patient's family medical history was insignificant. The patient complained of the onset of symptoms approximately two months before the presentation, by odynophagia, symptoms that did not yield to symptomatic medication, which is why she went to the ENT Department, where, following investigations, the diagnosis of acute erythematous angina was established, for which she subsequently received antibiotic treatment (Amoxicillin+Clavulanic Acid), with no clinical response. Other medical examinations were performed, initially throat cultures were achieved, which highlighted the presence of Enterobacter cloacae, following antibiotic treatment with Ceftriaxone; however, the symptoms did not improve significantly. Subsequently, tonsillar biopsies were performed, which ruled out malignancy. In evolution, the patient's symptoms worsened, from progressive difficulty in swallowing to total high dysphagia, both for solid and liquid foods, accompanied by sialorrhea, marked physical asthenia and weight loss (approximately 5kg). The patient also stated night sweats. At physical examination, the patient was with an affected general condition, temperature 36.9 C, underweight (Weight of 48kg, Height 164cm, body mass index of 17.85), pale and dehydrated skin and mucous membranes, morphologically intact osteo-articular system, with pain when mobilizing the pelvis and lumbar spine, positive Eriksen sign, positive Volkman sign; examination of the superficial lymph nodes system, highlights at the level of the right latero-cervical region, two oval structures, of firm consistency, immobile on deep and superficial planes, without sensitivity to palpation, with a long axis of about 1cm. No significant pathological changes were observed on chest auscultation. ENT examination found congested and hypertrophied palatine tonsils bilaterally and the presence of multiple gray-whitish granules, small in size, diffusely disseminated in the pharynx and larynx. Several differential diagnoses were discussed: viral pharyngotonsillitis, bacterial pharyngotonsillitis, herpetic pharyngotonsillitis, pharyngotonsillitis in acute retro-viral syndrome, oropharyngeal candidiasis, periamygdalian abscess, retropharyngeal abscess, pharyngeal syphilis, acute or chronic laryngitis, tonsillar neoplasm, haematological diseases (agranulocytosis, acute leukemias, lymphomas). Laboratory tests showed mild hypo-albuminemia, moderate microcytic hypochromic anemia, lymphopenia, ESR=120mm/h (N: 2-12mm/h), C-reactive protein=88.24mg/L (N: 0-5mg/L), prothrombin index=61% (N: 79-146%), INR=1.38 (Normal range between 0.8 and 1.16), the rest of the blood tests being within normal limits. Additional biological investigations were performed: microbiological examination of pharyngeal exudate (negative for Candida spp, Staphylococcus aureus, Streptococcus pyogenes), anti-HIV antibodies 1/2 (absent), venereal disease research laboratory (VDRL) (negative); however, we found a positive result for the Koch Bacillus in the patient's sputum. Following the changes encountered in the physical examination and the results of biological tests, it was decided to perform a computed tomography examination of the neck and chest region. At the level of the neck we distinguished a diffuse thickening of the epiglottis, of ariepiglottic folds bilaterally, of vocal cords bilaterally, without obvious asymmetries andhomogeneous, non-specific jugular latero-cervical lymph nodes at the right postero-superior level with dimensions up to 12/7mm and up to 10/6mm at the level of the left postero-inferior triangle with the same characteristics (Figure 1). Computed tomography of the thoracic region showed pulmonary condensation with massive cavitation at the level of the apical segment of the right upper lobe and the segments of the middle lobe; multiple nodular focal condensation areas, disseminated in both lung areas except the basal segments of the left lower lobe, with a tendency to confluence; micronodular lesions with the same arrangement; nonspecific right lower para-tracheal mediastinal adenopathy 14/7mm; without pleuro-pericardial fluid; the described appearance may argue for hematogenous disseminated tuberculous lesion (Figure 2). Based on the information obtained from the anamnesis, physical examination and paraclinical investigations, we established the diagnosis of pulmonary tuberculosis with extrapulmonary, pharyngeal and laryngeal foci, most likely developed in the context of biological therapy with Adalimumab for Crohn's disease. Therefore, therapy with Adalimumab was discontinued, and the patient was referred to a specialized medical unit to initiate the specific treatment. The patient's evolution was favorable with the beginning of the tuberculostatic treatment, being discharged from the Leamna Pneumophthisiology Hospital with good general condition and improved symptoms. Regarding the gastrointestinal pathology, the patient is still in clinical remission (one-two stools of normal consistency per day, without blood in stool), and will return for follow-up control visits, after the completion of tuberculosis-specific treatment. Also, a clinico-biological and imaging re-evaluation of Crohn's disease will be needed in order to establish the new therapeutic approach.

crohn's disease, adalimumab, anti-tnf-α agents, side effects, tuberculosis

3D reconstruction after CT examination. there is a noticeable damage to the lungs predominantly in the upper two thirds, with minimal damage to the basal regions.

PMC5523231_01

Male

A five-year-old previously healthy bilingual (English and Spanish) boy presented to the ED with his parents due to insomnia for the previous two nights. The family history was negative for neurologic or psychiatric illness. The patient was a typically developing child born after a full term uncomplicated gestation and delivery. He had no prior history of injury, ingestion, psychosocial stressors, change in appetite, involuntary movements, or seizures. One week prior to presentation to the ED, he had been evaluated by his primary care physician after a three-day febrile illness and was diagnosed with a viral infection. Since that time, he had become more irritable and fussy, frequently having outbursts of crying without being able to articulate why he was crying. His father was concerned that he seemed scared during these episodes and was concerned about eye pain. The patients' initial physical examination revealed normal vital signs, cardiovascular, pulmonary, and abdominal findings. He did not have dysmorphic features or a rash. Neuropsychiatric examination revealed an emotionally labile child with periods of calm and seemingly appropriate bilingual language development and behavior for age with episodes of extreme distress during which he would burst into tears and require physical restraint by family members against combativeness. Examination of the cranial nerves, motor tone, strength, coordination, and gait were normal and there was no sign of meningismus on physical examination. Initial differential for this clinical presentation was broad including insomnia secondary to pain from corneal abrasion or other unidentified traumatic or infectious source, traumatic brain injury, thyrotoxicosis, developmental disorder with regression, encephalopathy due to acute intoxication, acute psychosis, postinfectious or parainfectious encephalitis, and autoimmune encephalopathy. Screening in the ED with urine drug screen, serum acetaminophen and salicylate levels, complete blood count, complete metabolic panel, thyroid function tests, inflammatory markers, urinalysis, head CT scan, and EKG all revealed normal results. PCR respiratory panel (nasal swab) was negative for frequently tested viral and bacterial pathogens including negative for mycoplasma pneumoniae. The patient was admitted to the general pediatrics service with support from consulting services for further evaluation and management given his altered mental status and concern for acute encephalopathy.

PMC6739527_01

Male

The patient is a chronically ill 8-year-old boy from Limpopo province in South Africa, living with his adoptive parents. He was born prematurely at 7 months' gestation, weighing 1.9 kg. There was a history of recent travel to the Kruger National Park, and to India 6 months prior to admission. All his vaccinations were up to date on history, but this was never confirmed. He was markedly underweight for his age (with weight-for-age and height-for-age z scores of -2 and -1, respectively, and body mass index of 13) with a 2-year history of abdominal distension, diarrhoea, failure to thrive and drenching night sweats. There was no history of chronic cough. His treatment up to the time of admission included nutritional and iron supplements and repeated courses of antibiotics. No clinical improvement was achieved with this management. The patient was referred to a paediatric gastroenterologist in October 2016. He was acutely ill, severely wasted (17 kg) and pyrexial (39 C). He was clinically pale with a tachycardia and mild oedema of his lower limbs. Hepatosplenomegaly was detected, although there was no peripheral lymphadenopathy. His abdomen was severely distended, and he had recurrent diarrhoea and vomiting with marked intolerance of all foods. Abdominal computed tomography (CT) scan and ultrasound revealed massively enlarged intra-abdominal lymph nodes (see Figure 1) with a moth-eaten appearance of the spleen. Prominent collateral circulation was seen, which was suggestive of portal hypertension. Laboratory investigations confirmed that the patient was HIV-infected with a CD4 count of 59 cells/muL (7%) and HIV viral load of 453 780 copies/mL (log10 5.66). Further testing revealed mildly elevated liver enzymes. Moderate proteinuria was present and the faecal alpha-1 antitrypsin result was in keeping with a protein-losing enteropathy. His blood count showed microcytic hypochromic anaemia, with the iron function studies reflecting a pattern of reticuloendothelial iron blockade (see Table 1). The differential diagnosis included tuberculosis or lymphoma. Over a period of 7 months, endoscopically and surgically obtained biopsy material was submitted for histology (see Table 2). Histological images of the duodenum and a lymph node are shown in Figure 2. The findings were consistent with non-tuberculous mycobacterial infection. Further testing of the biopsy specimens included mycobacterial cultures, all of which showed no growth. Acid-fast bacilli (AFB) were noted during the processing of the tissue samples obtained from the intra-abdominal lymph nodes on 12 October 2016, and again in biopsy material obtained on 08 March 2017. Microscopy performed on a stool sample on 26 March 2017 also showed acid-fast organisms with a coccoid appearance. The polymerase chain reaction (PCR) assay for Mycobacterium avium complex was negative (artus Mycobac. diff. LC PCR from Qiagen, Germany). Numerous PCR assays for Mycobacterium tuberculosis complex were negative, which include Nanogen (Nanogen Inc., San Diego, CA, USA), BD MAX (BD Diagnostics, Sparks, MD) and the Xpert MTB/RIF assay (Cepheid Inc., CA, USA). The urinary lipoarabinomannan test conducted on 22 March 2017 was positive. A cytomegalovirus (CMV) viraemia of 3974 copies/mL (log10 3.60) was measured in March 2017 together with a colon biopsy that was PCR positive for CMV. The Epstein Barr viral load at the time was 9318 copies/mL (log10 3.97). Anti-mycobacterial treatment was started (rifampicin, isoniazid, ethambutol, pyrazinamide and clarithromycin) followed 4 weeks later with antiretroviral therapy (abacavir, lamivudine and efavirenz). The patient's HIV viral load was undetectable at 3 months, and his CD4 count at that stage was 101 cells/muL (6%). Clinically and radiologically, however, there was no improvement in his abdominal signs and symptoms. Malabsorption and refeeding syndrome was considered, and all treatment, including ganciclovir, was given intravenously. His antiretroviral medication was temporarily suspended until oral feeding could be tolerated. Immune reconstitution inflammatory syndrome (IRIS) was considered, and methylprednisone was initiated (1 mg/kg/dose) for 4 weeks, after which the dosage was tapered and stopped. The patient was given a period of bowel rest and free drainage, after which he was placed on an elemental diet. There was no clinical improvement and liver dysfunction worsened (see Table 1), and hence a decision was made to stop rifampicin, isoniazid and pyrazinamide. In May 2017, a diagnosis of Mycobacterium genavense was made, based on sequencing of a mycobacterial 16S rRNA PCR product. This identity was subsequently confirmed using the HAIN Lifescience GenoType (Nehren, Germany) Mycobacterium AS assay that was performed directly on a histology specimen from May 2017. As a result of this finding, and in consultation with an infectious disease specialist and microbiologist, treatment was changed to include moxifloxacin, azithromycin and rifabutin for 2 years, with amikacin for the first 3 months. Methylprednisone was also restarted. Antiretroviral therapy, together with cotrimoxazole prophylaxis, was continued. The patient's response to the new regimen was slow, and initially he was unable to tolerate food. Insertion of a nasogastric tube was required for continuous feeds together with total parenteral nutrition. At the time of writing this article (17 months of treatment completed), his clinical response had improved. He was able to tolerate small regular meals with no nausea, vomiting or diarrhoea. His weight gain had been slow (now up to 20 kg) despite nutritional supplementation. The hepatosplenomegaly and abdominal distension had improved markedly, and his HIV remains virologically suppressed. Dr R. de Gama obtained consent from the patient's parents to publish this case report.

16s rrna sequence analysis, fastidious, line-probe assay, mycobacterium genavense, non-tuberculous mycobacterium, retractile mesenteritis

PMC10361833_01

Female

A 30-year-old female farmer and nonsmoker with chief complaints of hemoptysis from time to time for 3 years with increased amount and frequency for the last 30 days was admitted to Manmohan Cardiothoracic Vascular and Transplant Center, Kathmandu, Nepal. At the time of admission, she complained of cough with associated hemoptysis and chest pain. She was in her usual state of health 3 years back when she developed coughing up blood with a frequency of 1-2 episodes a month. With these symptoms, 7 months later, she visited a nearby medical center where she was diagnosed and treated for pneumonia. The symptoms persisted with occasional episodes of coughing up blood for which no medical intervention was sought. Around a year back from now, she noticed the presence of whitish pieces mixed with blood for 2 episodes while coughing up, which was associated with a sour/bitter taste in her mouth. With the persistence of her symptoms of coughing up blood, a few months later she visited a tuberculosis center near her village where a CT scan demonstrated lesion on her lungs, and she was diagnosed of having a hydatid cyst in her lungs. From there, she was referred to our center for further management. She denied a history of fever, shortness of breath, night sweats, significant weight loss, contact with TB, history of travel, family history of malignancy, the use of immunosuppressive drugs, and similar illnesses in family members. There was no history of pre-existing pulmonary diseases, extrapulmonary symptoms, and known previous medical problems in the patient. Tracing her history, her home was near a jungle, and including hers, nearly all homes had domesticated dogs. She gave a history of prolonged exposure to domesticated dogs. She was a nonsmoker, nonalcoholic, and consumed a mixed diet. In our center, her vital signs showed normality with a blood pressure of 118/70 mm Hg, a pulse rate of 80 beats/minute, a respiratory rate of 18 breaths/minute, an oxygen saturation of 97% in room air, and an axial body temperature of 98 degrees Fahrenheit. Routine laboratory examination showed no abnormality with hemoglobin of 12 g/dl and there was no eosinophilia on peripheral blood examination. Total and differential leukocyte counts were within normal limits. Serum electrolytes, liver function tests, renal function tests, and other systemic examinations were unremarkable. Sputum smears were negative for acid-fast bacilli. She was nonreactive for Hepatitis B and HIV antigens. Physical findings were confined to the chest with decreased breath sound on the right hemithorax. The laboratory parameters of our patient at the time of admission are tabulated in Table 1. Her chest CT upon presentation showed well-defined nonenhancing cystic lesion in the anterior basal segment of the right lower lobe adjacent to a major fissure. Multiple air foci were seen within it. There was a segmental bronchus seen within the cyst with the possibility of communication with the cyst. It was causing segmental collapse with the upward pull of the right hemidiaphragm. No obvious pleural or chest wall communication was seen (Figures 1 (d) and (e)). There was no associated liver lesion on abdominal ultrasonography. The surgery was performed via the right posterolateral thoracotomy from the 5th intercostal space. Intraoperatively, the cyst was approximately of size 7.5 * 5.5 cm in the superior segment of the right lower lobe. Four bronchial communications were identified. A cystectomy was done, and at least 4 cystobronchiole communications were noted which were individually closed with nonabsorbable sutures, and then capitonnage was also performed. The excised cyst was sent for histopathological examination. What was exceptional was the presence of a laminated membrane of the ectocyst along with fungal elements (Aspergillus) in the form of septate hyphae with acute angle branching in hematoxylin and eosin stain (H&E) (Figures 1 (a) and (b)). To further confirm this finding, Periodic acid-Schiff (PAS) staining was done which also showed acute angle branching with thin septa (Figure 1 (c)). This led us to the final diagnosis of coinfection by Echinococcus and Aspergillus. She has been on oral albendazole since the first postoperative day at a dose of 10-15 mg/kg/day in divided doses. Her stay after surgery was uneventful and she was discharged on 3 postoperative days. She had been on routine follow-up.

PMC9886089_01

Female

An 8-day old female is referred to immunology clinic with an abnormal newborn screen reporting undetectable TRECs. Complete blood count (CBC) reported red blood cell macrocytosis for age, thrombocytopenia, and severe lymphopenia (Table 1). Lymphocyte immunophenotyping by flow cytometry showed markedly reduced naive T cells, low/absent B cells and decreased NK cells (Absent bright CD56 cells) consistent with SCID phenotype (Table 2). She was started on Ig replacement therapy (SCIG), antimicrobial prophylaxis with acyclovir, fluconazole, and Trimethoprim-Sulfamethoxazole at 1-month of age. Thrombocytopenia resolved by 2-weeks of age. Her initial work up included molecular testing for SCID and T cell disorders (ADA, CD3, CD45, DCLREIC, FOXN1, IL2RG, IL7R, JAK3, LIG4, NHEJ1, ORA1, RAG1/2, RMRP, STAT5B, STIM1, TBX1, and ZAP70), telomere length measurement, and flow cytometry-based mitogen testing which were all normal. A limited exome that includes >4,800 genes (Trusight, Illumina) was performed and demonstrated a known heterozygous pathogenic variant in GATA2 (p.Thr354Met, c.1061C > T), which was confirmed by Sanger sequencing. Her pattern of lymphopenia of B cells and NK cells, followed by progressive monocytopenia for age, was consistent with GATA2 deficiency. Parental evaluation demonstrated that the mother harbored the same mutation, and even though, mother has not presented with any clinical manifestations of disease, she was noted to have 1.7% CD56 bright cells which is below published normal. Complications during the first 8 months of life included medication induced elevated transaminases requiring discontinuation of fluconazole prophylaxis, chronic diarrhea with a negative infectious work up that self-resolved after 1 month, and an uncomplicated Klebsiella oxytoca urinary tract infection. Bone marrow aspirate and biopsy at 7 months of age revealed a mildly hypocellular marrow for age (80% cellularity) with no dysplasia, no excess blasts, negative FISH panel for MDS and normal cytogenetics. Serial monitoring of lymphocyte immunophenotyping continued to show severe T cell, B cell and NK cell cytopenias that fitted a phenotypic picture of severe combined immunodeficiency (Table 2). Since cytopenias did not recover and worsen over time (specifically T cells), the decision was made to proceed with hematopoietic stem cell transplant (HSCT) before she developed life threatening infections. At 8 months of age, she received a matched unrelated donor bone marrow transplant (male, 34 y old, 10/10 HLA matched, CMV matched) following myeloablative conditioning with busulfan, fludarabine and equine anti-thymocyte globulin (ATG). She engrafted with 100% donor chimerism. She was able to be weaned off SCIG 7 months post-transplant and started vaccinations 2 months after SCIG was discontinued with evidence of seroconversion for vaccine induced antibodies for pneumococcus and Haemophilus influenzae type B. Immunosuppression was discontinued at 10 months post-transplant, and she was off prophylactic antimicrobials after 1 year. Two and a half years after transplant she was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) that was found to be donor derived. She was treated with 4 drug induction chemotherapy per COG protocol AALL1131 and imatinib followed by consolidation with blinatumomab. She achieved complete remission. Two years and 9 months after her initial transplant, she received a second allogeneic HSCT, this time a haploidentical transplant using her father as a donor. The myeloablative conditioning regimen consisted of total body irradiation, thiotepa, cyclophosphamide, and ATG, with alphabeta T-cell and CD19 cell depletion as graft vs. host disease (GVHD) prophylaxis. She engrafted with 100% donor chimerism. She has mild, chronic skin GVHD but is currently 13 months post-second transplant and doing well (Figure 1). The patient's donor derived leukemia case has been reported elsewhere.

gata2, t cell receptor excision circles, hematopoietic stem cell transplant, inborn errors of immunity, severe combined immunodeficiency

PMC8046479_01

Male

A 20-year-old male patient presented with complaints of pain in the left hip since 1 year and difficulty in walking for 6 months. There was no history of trauma, fever, weight loss, and not a known case of diabetes and hypertension. The patient was diagnosed as tuberculosis left hip in the outside hospital without any biopsy, for which he had taken anti-tubercular treatment for 9 months, and still patient was not relieved of pain and stiffness. On examination, the patient had mild tenderness over the left hip with the restriction of joint movements. He had flexion deformity of 30 , adduction and external rotation deformity of 10 and 15 respectively. Wasting of the thigh and leg was present with no true shortening. X-ray of the pelvis with both hips anteroposterior and lateral view revealed calcified nodular mass over superior, inferior part of the femoral head, and anterior part of the neck with decreased joint space (Fig. 1). Computed tomography (CT) pelvis showed multiple intra-articular loose bodies with largest measuring 3*2.2 cm with early changes of secondary osteoarthritis and no evidence of joint effusion and erosion (Fig. 2, 3). Magnetic resonance imaging (MRI) was suggestive of early arthritis with intra-articular loose bodies. There was <10% of articular erosion of postero superior part of acetabulum. As the patient was disabled with pain, stiffness especially restricted flexion and abduction and difficulty in daily routine activities, we planned for surgical excision of the loose bodies and cheilectomy of the overgrown/ossified femoral head on superior part of the femur to improve the stiffness of affected hip joint. The patient was operated in lateral position under spinal anaesthesia using the lateral approach to the hip. Fascia lata was cut along the line of incision and retracted anteriorly to expose the anterior capsule. Arthrotomy was done using 2 cm incision over the anterior capsule and the anterior, inferior loose bodies were removed. Superior loose bodies were approached through gluteus medius and removed (Fig. 4). Capsule was closed using ethibond suture, the wound was closed in layers, and the removed loose bodies were sent for histopathological examination (Fig. 5). Post-operative X-rays revealed the complete removal of the loose bodies (Fig. 6), the patient was started with a hip range of motion from the 2nd post-operative day. Histopathological examination was suggestive of synovial chondromatosis with no evidence of inflammation/granuloma. At present 2-year follow-up, the patient is having full hip range of motion with no difficulty squatting, sitting cross-legged and radiological examination showed no evidence of recurrence, and there is no significant progression of arthritis (Fig. 7, 8, 9). The patient is fully satisfied with the chosen treatment and participating in running and other sports.

hip synovial chondromatosis, hip salvage, loose bodies, mini arthrotomy

PMC6698274_01

Female

A 13-year-old young female presented to the emergency department with abdominal pain, constipation and repeated bouts of vomiting for the last three days. The pain was sudden in onset, colicky in character and intermittent in onset. Her past medical history showed that she was treated with anti-tuberculous therapy for pulmonary tuberculosis. She took anti-tuberculosis treatment for nine months and completed this course two years back. General physical examination showed a heart rate of 110 beats/min and a BP of 90/60 mmHg with obvious clinical signs of dehydration. Abdominal examination revealed mild distension and tenderness with a 5 x 10 cm intra-abdominal mass in the upper abdomen. Bowel sounds were exaggerated. Laboratory results showed a hemoglobin level of 8.7 g/dl and a Serum Creatinine of 1.2 mg/dl. X-ray abdomen showed air-fluid levels in the small bowel. Ultrasonography of the abdomen revealed a 15 x 18 cm hypoechoic mass in the center of the abdomen. These findings were suggestive of small bowel obstruction secondary to abdominal tuberculosis. The patient was resuscitated, and surgical exploration was planned. Exploration revealed a huge cyst with dimensions of 24 cm x 20 cm x 16 cm, arising from the retroperitoneum, projects into transverse mesocolon and displacing loops of the small intestine (Fig. 1, Fig. 2). Cyst contained three liters of serous fluid. Complete excision was possible without resection of the associated organs. The specimen was sent for histopathology. Inspection of the specimen revealed 24 x 12 x 10 cm cyst, with a smooth outer surface and an irregular inner surface. Microscopic examination confirmed the diagnosis of the benign retroperitoneal cyst was made. There was no atypia or malignancy. She was discharged on her 3rd postoperative day. Post-op recovery was uneventful. The patient remains asymptomatic during the two years follow up period.

case series/report, idiopathic benign cysts, retroperitoneal cysts, retroperitoneal mass

PMC9483163_01

Male

A 57-year-old male patient presented to the local hospital in July 2017 for "epigastric pain and discomfort for one month". Gastroscopy showed a large ulcer in the gastric antrum, and biopsy pathology showed poorly differentiated carcinoma, tending to poorly differentiated adenocarcinoma. The patient was admitted to our hospital for surgical treatment. Physical examination showed that there was only mild tenderness in the upper abdomen without rebound pain, no palpable abdominal mass, no obvious jaundice in the skin and sclera, and no obvious enlargement of superficial lymph nodes. Serological examination showed that total bilirubin (TBILI) decreased (1.8umol/L, normal range 7.4-24.1umol/L), hemoglobin (HGB) decreased (93g/L, normal range 120-160g/L), carbohydrate antigen (CA) 724 increased slightly (7.66U/ml, normal range 0-6.9U/ml), carcinoembryonic antigen (CEA), CA19-9, CA125, alpha-fetoprotein (AFP) were all in the normal range. Thorax and abdomen plain scan and contrast-enhanced CT ( Figures 1A -F ) showed gastric cancer thickening in the gastric antrum, considering the tumor, and the tumor was not clearly demarcated from the left lobe of the liver; the size and shape of the liver were normal, the edge was smooth, and no abnormal density and enhancement lesions were found in the parenchyma. Small lymph nodes could be seen in the hepatogastric space, but no obvious enlarged lymph nodes were found in the retroperitoneum. We initially diagnosed it as gastric antrum malignant tumor. After multidisciplinary tumor consultation, we decided to carry out surgical treatment. After excluding surgical taboos, the patient underwent surgery in August 2017. During the operation, the tumor was located in the gastric antrum, about 5 x 4cm in size, infiltrated into the serosa, the anterior wall adhered closely to the left lateral lobe of the liver, and the posterior wall adhered closely to the transverse colon. Enlarged lymph nodes could be seen around the tumor, but there were no obvious metastatic nodules in the liver, peritoneum, and transverse colon. The family members and trustees of the patients were informed of the intraoperative findings, the details of possible adverse prognoses, and the advantages and disadvantages of different surgical methods. After obtaining their consent and signing the informed consent form, we performed radical distal gastrectomy (Billroth II gastrointestinal reconstruction) and partial left lateral lobectomy of the liver ( Figure 1G ). The operation time was about 200min, the blood loss was about 200ml, no blood transfusion was performed. The postoperative pathology showed that the tumor was poorly differentiated adenocarcinoma. The tumor was closely related to the liver tissue, invading the entire layer of the gastric wall to the mucosa from outside to inside and accompanied by ulcer formation. Tumor cells could be seen in the lymphatic vessel, and the nerve was not invaded. 27 lymph nodes were dissected. None of these lymph nodes metastasized. Immunohistochemical staining showed that the tumor tissue expressed broad-spectrum cytokeratin (CKpan), CK-7, and CK-19, but not CK-20, S-100, CD-10, Heppar-1, CD-56, synaptophysin (Syn), chromogranin A (CgA), and Ki67 proliferative index was approximately 70% ( Figures 2 ). After communicating with pathologists and considering the immunohistochemical results, we considered gastric metastasis from intrahepatic biliary adenocarcinoma. The patient recovered smoothly without obvious postoperative complications and was discharged 11 days after the operation. We performed 8 cycles of chemotherapy with the gemcitabine + capecitabine regimen. The first chemotherapy begins one month after the operation, followed by the next cycle of chemotherapy at an interval of 21 days. The patients were reexamined every 3 months after the operation for 2 years and every 6 months after the operation for 3-5 years. No tumor recurrence or metastasis was found 5 years after the operation, and the patient is still alive.

pet/ct, gastric, immunohistochemical staining, intrahepatic cholangiocarcinoma, metastasis