The aim of this study was to evaluate the effects of leukocyte- and platelet-rich fibrin (L-PRF) on the pain and soft tissue healing after tooth extractions. Twenty-six patients  were treated with multiple extractions (2 to 8), with a total of 108 extractions. This was an exploratory single blinded randomized clinical trial with a split-mouth design. The pain after the surgery was assessed in each patient by the VAS scale (1 to 10) at intervals of 24-48-72-96 hours. The soft tissue healing was clinically evaluated at 3, 7, 14, and 21 days after surgery by the same examiner surgeon, using the modified Healing Index (4 to 12). The mean value of postextraction pain was 3.2 ± 0.3 in the experimental sides and 4.1 ± 0.1 in the control sides. After 7 days from the extractions, the values of modified Healing Index in the experimental and control groups were, respectively, 4.8 ± 0.6 and 5.1 ± 0.9. The use of L-PRF in postextraction sockets filling can be proposed as a useful procedure in order to manage the postoperative pain and to promote the soft tissue healing process, reducing the early adverse effects of the inflammation. The gogenesis . The cliogenesis –10. Platogenesis . Each faogenesis .The PRPs were already tested in many oral surgery applications, with mixed results depending on the kind of preparations –16. Numeβ, and VEGF) [β1 [On the other hand, L-PRF represents a more recent generation of platelet concentrates. The development of L-PRF is very significant in oral and maxillofacial surgery, with many validated applications in periodontal surgery , 21 and nd VEGF) , cytokinnd VEGF) , while ond VEGF) . In anotEGF) [β1 . AccordiEGF) [β1  and in pEGF) [β1 .The aim of this study is to evaluate the effectiveness of L-PRF to improve the soft tissues healing and to reduce pain after tooth extractions.From January 2012 to July 2013 at the Unit of Oral Surgery and Implantology of the University of Naples “Federico II,” 26 healthy patients were selected, including 9 males and 17 females with a mean age of 53 ± 4 years. The selected patients were nonsmokers or light smokers (<5/day); they did not have systemic diseases that could interfere with the healing process  or diseases of the oral mucosa. The study was designed as a prospective split-mouth trial on patients who needed bilateral paired dental extractions; on the side chosen to be the study side, the sockets were filled with L-PRF, whereas on the other side (control), they were allowed to undergo natural healing. Test and control sites were chosen with coin toss randomization. This cross-sectional split-mouth research study was conducted in accordance with the requirements of Helsinki Declaration of 1975 as revised in 2008. Patients were verbally informed about the sample to be taken and gave their written consent. The patients who did not sign the agreement and also the patients with poor oral hygiene, patients with local infections of the soft tissues, patients undergoing bisphosphonates therapy, patients irradiated to the jaws in the past, and patients with psychiatric illness or pregnant patients were excluded from the study.An alveolar nerve block infiltration was administrated with local or regional anesthesia, depending on the dental arch, using 2% mepivacaine. Mepivacaine does not contain epinephrine, so it was used to prevent restriction of the blood supply. To prevent interference with the healing process, no intraligamentous or intrapapillary infiltration was made. The teeth were extracted in a nontraumatic manner without elevation of full-thickness flaps and preserving the buccal and lingual walls of the alveolar sockets in order to minimize the possible trauma and to give adequate support to the L-PRF filling Figures  and 2. AThe L-PRF was prepared through a single centrifugation of blood according to the protocol of Dohan Ehrenfest et al.  for a period of 12 minutes at 2700 rpm. Blood was taken in 9 mL tubes, 30 minutes before the surgery, immediately centrifuged, and used for the filing of the experimental sites. The total amount of blood collected (from 18 mL to 54 mL) was related to the number of tooth extractions, in order to obtain the complete filling of the sockets with the L-PRF. After centrifugation, each L-PRF clot was separated from the portion of red blood cells (red thrombus), obtaining a fibrin clot with a red small portion in order to include the “buffy” coat richer in large leucocytes . The L-PL-PRF was used within 60 minutes after the preparation. It was accurately positioned in the extraction sites and stabilized with a resorbable suture. In the control sites, the same suture was used . All patThe predictor variable was the treatment group status: L-PRF versus control socket. The outcome variables of interest were as follows: pain, postsurgical complications to soft and hard tissues, and the Healing Index modified.A 10-point visual analog scale (VAS) with a score of 0 that equals “no pain” and a score of 10 that equals “very severe pain” was used by the same patient to assess the postoperative pain at 24, 48, and 72 hours. Between groups comparisons for VAS outcomes were carried out by means of univariate analysis of variance, considering the group  and the recording time point as factors and VAS score as dependent variable.The quality of the socket soft tissue healing was clinically evaluated at 3, 7, 14, and 21 days after surgery by an examiner surgeon, using the Healing Index modified  which inAll patients completed the study. No cases of bleeding, infection, alveolar osteitis, or other surgical complications were reported.P < 0.0001) than the mean value of the control sites (4.5 ± 0.7), with a statistical difference average of 0.9 ± 0.3. The VAS score was nearly equal for the 2 sides after 4 days (decreasing to 0).Regarding the postextraction pain, patients enrolled in the study reported a mean value of the study sites of 3.2 ± 0.3, which is lower , reducing the inflammatory process and the risk of infection. The reported results of the experimental sites showed, in the first 7 days after the tooth extractions, a fast evolution of the healing and a positive effect on pain. After a week, minor differences between the two groups are reported (Figures illaries . In relaillaries . The immillaries .The main limitation of this exploratory study was that the extraction sites were voluntarily very simple, with all alveolar walls preserved. It allowed standardizing the study easily to reach a very clean result, but it does not reflect the real strength and advantages of L-PRF. This material is particularly useful and efficient in complex situations, when some walls are destroyed and the bone regeneration is difficult, but an accurate split-mouth study with this kind of cases is virtually impossible to standardize. It is however the needed next step of evaluation and validation of the use of L-PRF during tooth extractions.Even if the selected samples are limited, the reported results suggested that the use of L-PRF in postextraction sockets filling is an efficient and useful procedure in order to manage the postoperative pain and to enhance the alveolar soft tissue healing process, especially in the first days after the extractions, reducing the early adverse effects of the inflammation. This study represents a preliminary clinical trial, which could be used as baseline for further histologic studies.


These findings demonstrate that XAT can effectively reduce bone cancer pain probably mediated by the cytokine mechanisms, facilitate analgesic effect of morphine, and prevent or reduce the associated adverse reactions, supporting a use of XAT, alone or with morphine, in treating bone cancer pain in clinic.Treating cancer pain continues to possess a major challenge. Here, we report that a traditional Chinese medicine Xiao-Ai-Tong (XAT) can effectively suppress pain and adverse reactions following morphine treatment in patients with bone cancer pain. Visual Analogue Scale (VAS) and Quality of Life Questionnaire (EORTC QLQ-C30) were used for patient's self-evaluation of pain intensity and evaluating changes of adverse reactions including constipation, nausea, fatigue, and anorexia, respectively, before and after treatment prescriptions. The clinical trials showed that repetitive oral administration of XAT  alone greatly reduced cancer pain. Repetitive treatment with a combination of XAT and morphine  produced significant synergistic analgesic effects. Meanwhile, XAT greatly reduced the adverse reactions associated with cancer and/or morphine treatment. In addition, XAT treatment significantly reduced the proinflammatory cytokines interleukin-1 Pain is a common symptom in patients with advanced malignant cancer and greatly increases physical and mental suffering. There are approximately ten million new cancer patients annually worldwide. Cancer pain is observed in 30%–50% of all these new-onset patients. Most of the patients (60%–90%) with advanced cancer present different degrees of pain, of which 30% are with unbearable pain symptoms , 2. The  Corydalis turtschaninovii, yanhusuo), wild ginger (Asarum), Arisaema consanguineum, Venenum Bufonis, and Arisaema Tuber  and has been used in clinic for years for reducing chronic pain. However, there is no evidence-based research demonstrating analgesic effect of XAT on cancer pain patients. This clinical study aimed to evaluate the analgesic effect of XAT and its impact on morphine treatment-induced adverse reactions including abstraction, nausea/vomiting, fatigue, and anorexia and quality of life in patients with moderate-to-severe cancer pain. Our results indicate that XAT decoction can effectively alleviate bone cancer pain, suppress morphine-induced adverse actions, reduce the proinflammatory cytokines IL-1β and TNF-α, and increase the endogenous anti-inflammatory cytokine IL-10. This study supports a clinical use of XAT, alone or with morphine, in treating bone cancer pain.Traditional Chinese medicine is an alternative, effective therapeutic measure for treating cancer pain and has potential to overcome the shortcomings of the “Three-Step Therapy” by enhancing treatment effect and reducing toxicity of morphine, the core drug used in the WHO “Three-Step Therapy” . A tradiPatients with painful bone metastasis received treatment at Lianyungang City Oriental Hospital. The clinical trials were conducted according to Declaration of Helsinki principles, approved by the ethics committee of Lianyungang Oriental Hospital (number 20130910088) (2013). A total of 60 patients with painful bone metastasis were included in this study including 32 males (53.33%) and 28 females (46.67%), aged from 44 to 70 years . These patients were randomly divided into four groups: (1) firstly, based on the time sequence, the 1st, 2nd, 3rd, and 4th patient recruited were included in groups 1, 2, 3, and 4, respectively. Subsequently, the 5th to 8th patients recruited were included in groups 1, 2, 3, and 4 again, respectively. Then this method of grouping was repeated for all the patients that were recruited later for this study. However, considering balance and similar proportion of male and female patients in each of the groups, the male and female patients were grouped in a separate time sequence in the same way as in the different groups. Four groups received four different treatments (see treatment procedures in Inclusion criteria for these patients were as follows: (1) pathologically diagnosed as cancer accompanied by painful osseous metastasis, requiring drug treatment; (2) with normal pain sensation and judgment ; (3) the patient's pain self-evaluation Visual Analogue Scales (VAS) , 6 test Exclusion criteria for these patients were as follows: (1) with dysfunctions of heart, liver, kidney, and other severe physical disorders; (2) with histories of psychiatric or analgesic drug abuse; (3) with history of significant respiratory depression, airway obstruction, hypoxia, or bronchial asthma; or (4) received radiotherapy and/or chemotherapy, and so forth. Arisaema consanguineum, Venenum Bufonis, and Arisaema Tuber, 200 mL, q12h, by oral administration for 7 consecutive days. Two groups of patients received treatment of XAT (200 mL) + morphine . The seven treatments in each group were applied daily during days 0–6.Patients that received morphine treatment were taking morphine sulfate controlled-release tablets , 20 or 30 mg, q12h, by oral administration for 7 consecutive days. Patients who received XAT treatment were taking XAT decoction containing Corydalis Tuber, wild ginger,Changes in pain intensity were evaluated by calculating changes of VAS scores , 6, whicThe in-patients sometimes showed adverse reactions such as expiratory dyspnea, changes in blood pressure, pale complexion, cold sweat, palpitation, headache, dizziness, lethargy, delirium, blurred vision, instability of gait, dryness, nausea, vomiting, constipation, bellyache, diarrhea, pruritus of skin, skin rashes, and dysuria. Morphine treatment resulted in or facilitated some of these adverse reactions. These signs were honestly recorded in each of the in-patient's profiles, but most of them were not included in the data show in this study. The data we monitored and showed here included four symptoms, nausea with or without vomiting, constipation, anorexia, and fatigue, which are expressed based on the analysis using the Quality of Life Questionnaire (EORTC QLQ-C30) . This EOP < 0.05.SPSS Rel 17 was used to conduct all the statistical analyses. Alterations of pain intensity following treatment over time among groups were tested with two-way ANOVA with repeated measures followed by Bonferroni post hoc tests, respectively. Differences in changes of the aversive reactions among groups were tested with one-way ANOVA. Data are presented as mean ± SEM with VAS tests or EORTC QLQ-C30 scores, except when indicated separately. Statistical results are considered significant if The total of 60 patients with painful bone metastasis were included in this study including 32 males (53.33%) and 28 females (46.67%), aged from 44 to 70 years . These patients were randomly divided into four groups . Each of the groups received different treatments and included 15 patients with 8 males and 7 females. Patients who received morphine treatment (morphine group) included 15 patients with 8 males aged 58.10 ± 7.14 and 7 females aged 58.04 ± 8.26. Patients who received XAT treatment (XAT group) included 15 patients with 8 males aged 57.60 ± 8.14 and 7 females aged 59.40 ± 7.09. Two groups of patients who received treatment of combination of XAT and morphine (in two different doses) included, in each group, 15 patients with 8 males aged 58.22 ± 8.45 and 57.15 ± 7.62 and 7 females aged 59.33 ± 6.53 and 58.87 ± 6.76, respectively. The data included here were from these 60 patients.Patients in this study received treatment of morphine, XAT, and morphine + XAT, respectively. As expected, morphine treatment alone  greatly reduced cancer pain evidenced by the significantly decreased VAS scores. The analgesic effect quickly reached the peak level after the second dose and was maintained at this level for up to 14 days without obvious tolerance. Interestingly, repetitive oral administration of the Chinese medicine XAT  produced significant, time-dependent, gradually increased analgesic effect on the cancer pain. The significant analgesic effect was starting from the second day (XAT) and reached peak 5-6 days after the daily treatment. The peak analgesic effect was maintained for up to at least 14 days, that is, 8 days after termination of the last treatment. Analgesic effect of XAT was significantly less than that of morphine during the period of 1–5 days. However, during 6–14 days, the analgesic effect of XAT alone was much closer to that of morphine alone. Furthermore, administration of a combination of XAT with morphine at 20 mg produced significant analgesic effect, which was at the similar level of analgesia produced by morphine alone at 30 mg. Administration of a combination of XAT with morphine at 30 mg produced significantly greater analgesic effect than that produced by morphine alone at 30 mg, XAT with morphine at 20 mg, and XAT alone. These analgesic effects were maintained as the best level of analgesia for at least one week after termination of the last treatment. Data are summarized in We also analyzed the possible sexual difference of analgesic effects of XAT and morphine on these patients Figures . The datGiven that repetitive oral administration of XAT reduced cancer pain and facilitated analgesic effect of morphine, we continued to analyze the possible effects of the Chinese medicine XAT on the adverse reactions accompanied with cancer pain and/or with morphine treatment. We used the Quality of Life Questionnaire (EORTC QLQ-C30) to score the adverse reactions in these patients. The higher the score, the worse the adverse reaction. The data showed that the scores of the gastrointestinal adverse reactions constipation and nausea were greatly increased after repetitive morphine treatment . These morphine treatment-related adverse reactions were significantly prevented or reduced by the treatment of a combination of XAT with morphine Figures . Anotherβ and TNF-α, which are important in the development of inflammation and cancer pain, as well as the anti-inflammatory cytokine IL-10, which may inhibit inflammation and pain. Levels of these three cytokines in blood in these patients before application of our treatment prescriptions were 174 ± 25 pg/mL  repetitive oral administration of XAT for 7 consecutive days greatly reduces bone cancer pain; (2) treatment with combination of XAT and morphine produces synergistic analgesic effects; (3) XAT can prevent or alleviate the gastrointestinal adverse reactions constipation, nausea, fatigue, and anorexia accompanied with cancer pain and/or caused by morphine treatment; and (4) XAT treatment significantly reduces the proinflammatory cytokines IL-1Our clinical trials indicate that the Chinese medicine XAT decoction can be used as an effective analgesic for treating bone cancer pain and the associated adverse reactions such as fatigue and anorexia in cancer patients. Further, if used together with morphine, XAT can facilitate the analgesic effect and reduce the side effects including constipation and nausea caused by morphine treatment. This study supports that XAT may be a good candidate for being used alone or with morphine in treating cancer pain in clinic and suggests a general idea that an integrated treatment measure combining certain Chinese herbs or other therapeutic measures such as acupuncture with opioids such as morphine may be a great strategy for treating cancer pain and thus improve the treatment effect of WHO “Three-Step Therapy” for cancer pain. It is an ideal strategy to have effective pain relief with minimal side effects, which greatly enhances quality of life of the patients, particularly for the severe terminal cancer patients.Cancer pain is a severe, lifelong, intractable chronic pain –3. Patho The Medicine of The Yellow Emperor as “bones becoming dry and brittle, muscles becoming emaciated, thoracic fullness, asthmatic inconvenience, inner pain inducing shoulder and neck pain.” Based on the idea of the traditional Chinese medicine, we believe that the cancer pain may be caused by accumulation of toxicity, blood stasis and vital energy retardation, and accumulation of phlegm-dampness in the meridians, and thus resulting in pneuma and blood stasis, which contribute to development of cancer pain. The therapeutic effects of traditional Chinese medicines, in a concept, have been confirmed, as persistent, nonadditive and nonresistant drugs. Some analgesic herbs can be used alone to treat cancer pain in the first and second steps of the WHO “Three-Step Therapy” and considered as a preferred combination in the third step of the “Three-Step Therapy” to reduce the dose of opioid analgesics and the toxicity. In this study, we recommend that XAT decoction, which contains Corydalis Tuber, wild ginger, Arisaema consanguineum, Venenum Bufonis, and Arisaema Tuber, may be used in clinic in treating cancer pain. Actually, recent studies have shown that certain Chinese herbs such as the Corydalis Rhizoma, named Yuanhu in Chinese, have been proved to have analgesic effect on patients and on small animals with neuropathic pain as well as other treatment effects [When we are pursuing better strategy to treat cancer pain, some of the Chinese medicines may provide us with a different view. According to traditional Chinese medicine, the primary pathogenesis of cancer pain involves “stagnation of pneuma and blood” or “malnutrition.” “Malnutrition” is primarily attributed to renal deficiency unlikely to promote bone marrow generation. “Stagnation of pneuma and blood” is mainly associated with the Qi stagnation due to severe cold and blood stasis . Cancer  effects –19. Our β and TNF-α, which could evoke hyperalgesia and allodynia [β and TNF-α associated with the cancer pain. Meanwhile, XAT therapy significantly increases the anti-inflammatory cytokines IL-10. These findings may provide an explanation for the analgesic effect of XAT. Further large-scale clinical studies as well as studies in small animals for underlying the possible mechanisms of analgesia of XAT are urgently needed.Studies have demonstrated that astrocytes and microglial cells, which act as parts of the innate immune system, become active in the status of bone cancer and release various substances, including the proinflammatory cytokines IL-1llodynia –25. In tThis clinical trial indicates that the Chinese medicine XAT decoction is an effective analgesic for treating chronic pain and can alleviate certain adverse reactions such as fatigue and anorexia associated with bone cancer pain and, if used with morphine, can prevent or reduce repetitive morphine treatment-induced constipation and nausea. This study supports a clinical use of XAT decoction in patients with bone cancer pain and proposes a general idea that a combination of certain Chinese herbs with opioids may be a better strategy for treating cancer pain and the morphine-treatment associated adverse reactions, thus improving the treatment effect by the WHO “Three-Step Therapy” for cancer pain. It is an ideal strategy to have effective pain relief with minimal side effects that greatly enhances quality of life of the patients, particularly for the terminal cancer patients with severe pain.


Childhood abuse is a risk factor for depression and anxiety and is reported by 58% of patients with episodic migraine (EM) or chronic migraine (CM). Maximum headache severity >10/10 on a 10-point visual analog scale (VAS) is not uncommon among CM patients. The relationship between inflated pain scores and abuse has never been investigated.To evaluate the relationship between pain severity >10/10 on a ten-point VAS and a history of abuse in women with CM.A retrospective review was conducted on new headache consults in female patients with ICHD-IIIβ-defined CM over a 34-month period. Age, maximum headache severity on a 10-point VAS, and history of physical, sexual, and emotional abuse were collected.80 patients were included. Average age was 43 years in the pain >10 group and 40 years in the pain ≤10/10 group . 28.8% (n=23) reported maximal pain >10/10 and 71.2% (n=57) reported maximum pain ≤10/10. Of those reporting pain >10/10, 87% (n=20) reported an abuse history compared to 35% (n=20) in the pain ≤10/10 group .Among female CM patients, pain >10/10 correlates with a markedly higher likelihood of abuse compared to those reporting pain ≤10/10. As history of abuse is a risk factor for depression and anxiety, and treatment of psychopathology can influence CM treatment outcomes, all CM patients should be screened for a history of abuse, with special attention to those reporting pain >10/10.No conflict of interest.


Cervicogenic headache (CGH) is defined as referred pain from various cervical structures innervated by the upper three cervical spinal nerves. Such structures are potential pain generators, and include the atlanto-occipital joint, atlantoaxial joint, C2-3 zygapophysial joint, C2-3 intervertebral disc, cervical myofascial trigger points, as well as the cervical spinal nerves. Various interventional techniques, including cervical epidural steroid injection (CESI), have been proposed to treat this disorder. And while steroids administered by cervical epidural injection have been used in clinical practice to provide anti-inflammatory and analgesic effects that may alleviate pain in patients with CGH, the use of CESI in the diagnosis and treatment of CGH remains controversial. This article describes the neuroanatomy, neurophysiology, and classification of CGH as well as a review of the available literature describing CESI as treatment for this debilitating condition. A.Pain, referred from a source in the neck and perceived in one or more regions of the head and/or face, fulfilling criteria C and D;B.Clinical, laboratory, and/or imaging evidence of a disorder or lesion within the cervical spine or soft tissues of the neck known to be, or generally accepted as, a valid cause of headache;C.Demonstration of clinical signs that implicate a source of pain in the neck;Abolition of headache following diagnostic blockade of a cervical structure or its nerve supply using placebo- or other adequate controls;Evidence that the pain can be attributed to the neck disorder or lesion based on at least one of the following:D.Pain resolves within three months after successful treatment of the causative disorder or lesion.Cervicogenic headache (CGH) is a clinical syndrome characterized by primarily unilateral pain that originates in the neck, typically provoked by neck movement or pressure over tender points in the neck, with reduced range of movement of the cervical spine. Features of CGH headache can be similar to other primary headache disorders such as migraine, tension-type headache, and related cranial neuralgias such as occipital neuralgia. The diagnostic criteria for CGH headache put forth by the International Headache Society (IHS) are as follows :A.Pain, CGH is thought to be referred pain arising from cervical structures innervated by the upper three cervical spinal nerves, and therefore any structure innervated by the C1–C3 spinal nerves could be the source for cervicogenic headache . These nDifferent subtypes of CGH can be diagnosed and treated with various injections. For example, lateral atlantoaxial joint intra-articular injection can be effective for diagnosis and short-term pain relief for lateral atlantoaxial joint pain. This clinical entity is typically caused by osteoarthritis or post-traumatic event, and may account for up to 16 % of patients with CGH . SymptomC2 nerve root irritation or neuralgia is a subtype of occipital neuralgia that is caused by lesions affecting the C2 nerve root or dorsal ganglion such as neuroma, meningioma, or anomalous vessels. The C2 root lies posterior to the lateral atlantoaxial joint, and thus disorders or inflammation of this joint may lead to irritation or entrapment of the nerve root as well . C2 neurAccess to the cervical epidural space is available by both interlaminar and transforaminal approaches, and fluoroscopy is recommended for either approach –17. In lThe dimensions of the epidural space are smaller in the thoracic and cervical space compared with the lumbar region. The ligamentum flavum may not fuse in the midline, as this can be problematic when using the loss-of-resistance (LOR) technique. The epidural space is narrowed between C3 and C6 vertebral levels, about 2 mm on average . The cerThere is strong evidence that cervical/thoracic/lumbar interlaminar epidural steroid injection as a class of anesthetic treatment is effective in selected patients with radicular pain or radiculopathy. The duration of pain relief is variable. The recent retrospective controlled trials revealed evidence of short-term relief of radicular pain for up to six weeks . FerrantThe literature referenced was obtained via a computer search of PubMed and MEDLINE from 1966 through March of 2014. The search terms included “cervicogenic headache,” “cervical epidural steroid injections,” “post-traumatic headache,” “treatment,” and “therapeutics.”There have been no randomized controlled trials for treatment of CGH with CESI. Six articles were found according to the above search criteria. Two of these were review articles; three were small prospective case-control studies, of which one was a short letter to the editor to report longitudinal follow-up on a retrospective study. One was a retrospective observational study. Upon further inspection, we found that two of the prospective studies were by the same author and were virtually identical; therefore we were able to review only two studies on this topic.Martelletti et al. conducted a prospective case-control study comparing Numerical Intensity Scale (NIS) and Drug Consumption Index (DCI) in nine patients with CGH  and a control group of six sex- and age-matched patients  with chronic tension-type headache (CTH) ••. All CA sharp decrease in NIS and DCI was observed in the CGH group treated with CESI compared with the CTH group. The short-term (12 hours) and medium-term (four weeks) clinical improvement in the CGH patients was statistically significant. The study results suggested that CESI could be beneficial in the treatment of CGH, as the authors hypothesized that this pain syndrome continued its course by “sensitizing the cervical nerve roots” and “initiating a pain-producing loop” involving nerve root and microvascular inflammation as well as mechanically-induced micro-injury. The authors also presented follow-up data on the longer-term effects of CESI on CGH. At the six-month endpoint comparing NIS and DCI values, the responses by CGH and CTH patients were not statistically different.He et al. retrospectively analyzed 37 patients who underwent continuous CESI for CGH ••. The iAccurate diagnosis of CGH is difficult due to the heterogeneity of its presentation and the multiple pain generators within the trigeminocervical nucleus-upper cervical nerve convergence. In addition, it is currently not possible to determine whether the pain generator is somatic referred or radicular-type pain, other than to attempt blockade of cervical nerve root, facet joint, atlantoaxial, myofascial trigger point, or occipital nerve steroid injection. Each cervical procedure carries potential risks. CESI with an interlaminar needle approach at C7-T1 or C6-7 epidural space is relatively safe compared to other cervical procedures. In the study by Martelletti et al., CESI was not proven to be of benefit in the long-term (six months) relief of CGH, but was helpful in the short term (up to four weeks). Based on prior studies of cervical epidural injections, it appears that radicular pain may respond to this treatment. One of the reasons that the Martelletti study failed to show a significant prolonged effect of CESI may be that the inclusion criteria of the study failed to selectively recruit patients with radicular pain from degenerative disc or spondylotic disease. Another consideration is that the authors used methylprednisolone alone, without a local anesthetic. The addition of a local anesthetic medication to the epidural steroid injection may prolong the effects of CESI. Finally, it is unclear whether fluoroscopic guidance, which has been shown to improve patient safety and injection accuracy, was utilized in the study , 25.He et al.’s study of continuous epidural blockade for treatment of cervicogenic headache, although limited by lack of a control group, did show a decrease in the mean number of days patients experienced mild or moderate pain, the occurrence of severe pain, and daily NSAID usage at both three and six months. It is important to note that the inclusion criteria in this study comprised radiographic evidence of C2-C6 disk herniation, bulge, or degeneration, with positive response to blocking of C2 and C3 nerves for at least a one-week duration. This study revealed supporting evidence of CESI as an effective treatment for CGH when upper cervical disc pathologies are present. Cervical disc pathology is one of the etiologies for local nerve root irritation and injury. The injection of steroids in this location can inhibit aseptic inflammation and neurotransmission within the C-fibers. The continuous irritation of the most commonly involved nerve roots  may produce inflammation and secondary swelling, which can perpetuate pain. Conceivably, injections specifically targeting these upper cervical nerve roots may be more effective. Interestingly, in He’s study, the epidural space was accessed at around the C7-T1 level. A steerable epidural catheter was placed through the needle and advanced 10 cm in the cephalad direction, which potentially targeted the upper cervical nerves responsible for persistent CGH. This method of injection to target the potential pain generators, along with the continuous infusion of corticosteroid/lidocaine over three to four weeks, may have contributed to the success of the study.In both the He and Martelletti studies, no serious side effects were reported from epidural steroid injections. In the Martelletti study, one CGH patient and two CTH patients experienced a flushing sensation in the face, which lasted between 45 minutes and four hours post-injection. No long-term sequela of this symptom was seen. In the He study, none of the patients reported any symptoms associated with corticosteroid-related adverse events, such as hypothalamic-pituitary axis suppression, immunosuppression, or gastroduodenal ulceration. Based on the minimal adverse effects reported in these studies, it appears that CESI is a relatively safe injection therapy for CGH.CGH is a complex medical condition that can be debilitating for patients and challenging for the treating physicians. The exact pathophysiology of this condition is not clear. Because of the heterogeneity of the presentation and the numerous pain generators that can cause CGH, it is often difficult to identify the source of this chronic pain condition. As a result, there are several different interventional techniques available for the diagnosis and treatment of CGH. CESI is considered by many interventional pain management specialists to be a reasonable option for patients who have failed conservative treatments. The two studies reviewed above provided preliminary evidence of both short- and long-term pain relief, particularly for patients with clinical and radiographic evidence of upper cervical spinal nerve root irritation. Further studies designed to include such patients with treatment protocols to target upper cervical nerve roots may provide additional evidence that CESI is an effective treatment for cervicogenic headache.


Manual spinal joint mobilisations and manipulations are widely used treatments in patients with neck and low-back pain. Inter-examiner reliability of passive intervertebral motion assessment of the cervical and lumbar spine, perceived as important for indicating these interventions, is poor within a univariable approach. The diagnostic process as a whole in daily practice in manual therapy has a multivariable character, however, in which the use and interpretation of passive intervertebral motion assessment depend on earlier results from the diagnostic process. To date, the inter-examiner reliability among manual therapists of a multivariable diagnostic decision-making process in patients with neck or low-back pain is unknown.This study will be conducted as a repeated-measures design in which 14 pairs of manual therapists independently examine a consecutive series of a planned total of 165 patients with neck or low-back pain presenting in primary care physiotherapy. Primary outcome measure is therapists’ decision about whether or not manual spinal joint mobilisations or manipulations, or both, are indicated in each patient, alone or as part of a multimodal treatment. Therapists will largely be free to conduct the full diagnostic process based on their formulated examination objectives. For each pair of therapists, 2×2 tables will be constructed and reliability for the dichotomous decision will be expressed using Cohen’s kappa. In addition, observed agreement, prevalence of positive decisions, prevalence index, bias index, and specific agreement in positive and negative decisions will be calculated. Univariable logistic regression analysis of concordant decisions will be performed to explore which demographic, professional, or clinical factors contributed to reliability.This study will provide an estimate of the inter-examiner reliability among manual therapists of indicating spinal joint mobilisations or manipulations in patients with neck or low-back pain based on a multivariable diagnostic reasoning and decision-making process, as opposed to reliability of individual tests. As such, it is proposed as an initial step toward the development of an alternative approach to current classification systems and prediction rules for identifying those patients with spinal disorders that may show a better response to manual therapy which can be incorporated in randomised clinical trials. Potential methodological limitations of this study are discussed. Neck and low-back pain are common and costly disorders in adult general populations-6. ManuaTraditionally, manual therapy has a strong focus on the diagnostics, treatment, and evaluation of spinal joint function by emphasising the use of passive physiological and accessory movements-17. PassIn order to yield accurate and uniform decisions about treatment options for patients, test results need to be reliable. ReliabiPhysiotherapists conduct a diagnostic process by collecting data through interview and physical examination and by generating hypotheses as to why a problem exists in order to reach a decision about appropriate patient management,33. DuriOver the last three decades, many systems have been developed for classifying patients with spinal disorders, in particular for those with low-back pain. A systeThis is the protocol of a study that aims to determine the inter-examiner reliability among Dutch manual therapists of indicating spinal joint mobilisations or manipulations in patients with neck or low-back pain based on a multivariable, hypothesis-based diagnostic reasoning and decision-making process. Secondly, using univariable logistic regression analysis of concordant decisions about indications, we will explore which demographic, professional, and clinical factors can explain variation in reliability of therapists’ decisions with specific attention to the contribution of PIVM assessment.This study will be conducted as a repeated-measures design in which pairs of manual therapists independently examine a consecutive series of patients with neck or low-back pain presenting in primary care physiotherapy in the Netherlands. Primary outcome measure is therapists’ decision about whether or not spinal manual therapy (SMT) is indicated in each patient, alone or as part of a multimodal treatment. SMT is defined here as either spinal joint mobilisations or manipulations, or both. Therapists will largely be free to conduct the full diagnostic process as they are routinely used to.Consecutive patients aged 18 years or older presenting with a primary complaint of neck or low-back pain, either referred to primary care physiotherapy by their general practitioner or medical specialist, or by self-referral, will be eligible for participation in the study. Neck pain is defined as pain in the region between the superior nuchal line, the external occipital protuberance, the spines of the scapula, the superior border of the clavicula, and the suprasternal notch, with or without radiation to the head, trunk, or upper limbs. PatientExaminers will be manual therapists working at least 20 hours a week in their private practices in the Netherlands and registered by the Dutch Association for Manual Therapy or the Royal Dutch Society for Physical Therapy. From a database of those graduated from the Institute for Master Education in Musculoskeletal Therapy , 14 pairs of manual therapists will be invited to participate. Each pair works together in the same practice and practices will be selected based on their ability to logistically organise the study. We aim to include therapists who vary in years of clinical experience in manual therapy. Therapists will attend an information session followed by a two-hour training session in which procedures for digitally registering data are explained and practised. They will not receive additional training in history-taking, physical examination procedures, or using questionnaires. Pairs of therapists will be strictly requested not to discuss their experiences during the study with each other until their last patient has been included. Gender, age, years of clinical experience in manual therapy, highest diploma, practice setting, weekly amount of work related to spinal disorders (hours), teaching experience (yes/no), and participation in research (yes/no) will be recorded as professional characteristics from the participating therapists.In each practice, a third colleague will function as a research assistant to coordinate the inclusion and flow of patients. Research assistants will be instructed with respect to applying the inclusion criteria, the order of assigning patients to therapists, and assuring blinding procedures.From eligible patients, demographic  and clinical (type of complaints (neck or low-back pain), duration of complaints (days), radiation (yes/no), traumatic origin (yes/no), comorbidity (yes/no)) data will be recorded as baseline data by the local research assistant. In addition, baseline pain and disability will be determined using the Numeric Pain Rating Scale , and the Quebec Back Pain Disability Scale  for low-back pain patients and the Neck Disability Index Dutch Language Version  for neck pain patients, respectively. The NPRS is a reliable and valid scale to measure pain intensity in adults. The DutAll baseline data will be available to each therapist before he or she starts the diagnostic process. The first therapist of each pair will be the treating therapist to whom the patient was assigned to, so the order in which both therapists act as the first examiner will vary according to the practice’s planning. The first therapist will screen all consecutive patients with neck or low-back pain for the presence of red flags. In accoThe therapist will then be asked to record whether he or she has made any changes to the original examination objectives as well as to specify these changes, and a diagnostic conclusion in terms of specific or non-specific neck or low-back pain is given. Finally, the therapist will make the decision about whether or not SMT is indicated in the patient and, when indicated, it will also be stated whether mobilisations or manipulations, or both, are indicated, and to which spinal motion segments these techniques would be targeted. In addition, the therapist will rate his or her level of certainty of the primary decision about the indication on a bipolar seven-point scale ranging from -3 (completely uncertain) to 3 (completely certain). It will also be recorded which other interventions he or she believes would further be indicated in the patient. However, at this point, no actual treatment will be provided.After the first therapist has performed the full examination, he or she will leave the examination room and the patient will be given a 10 minute break. After checking whether all data have been registered, the research assistant then guides the second therapist into the room and makes sure that there is no visual or verbal contact between the two therapists. The second therapist will then conduct the full diagnostic process, excluding the screening for red flags, whilst being unaware of the outcomes of the first examination. Patients will be requested not to mention any outcomes or conclusions from the first examination. Both therapists will record all their findings and data into a fit-for-purpose software program. The research assistant will check whether all data have been entered by both therapists.International Classification of Functioning, Disability and Health (ICF)[Demographic and clinical baseline characteristics of patients will be summarised using descriptive statistics. Absolute and relative frequencies are used to describe categorical data. Ordinal data relating to patients’ pain and disability will be described with their median and interquartile range. Normally distributed numerical data will be summarised by their mean and standard deviation. In case of non-normality, median and interquartile range are presented. Examination objectives as formulated by therapists will be classified by one researcher (EvT) according to the framework of the World Health Organization’s th (ICF) to descrpos) and negative (pneg) decisions will be calculated in order to evaluate whether kappa was influenced by high prevalence of positive or negative decisions, or by systematic bias between examiners. PI reflects the difference between the proportion of agreement on positive indications as compared to that of negative indications. PI ranges between 0 and 1, and is high when the prevalence of concordant positive (or negative) indications is high, chance agreement is consequently also high, and kappa is reduced accordingly [pos and Pneg are the proportions of agreement on positive and negative indications, respectively, relative to the total number of positive and negative indications, respectively, from both therapists. Overall kappa (95% CI) will be calculated as a generalized chance-corrected reliability across all pairs of therapists. See Additional fileFor each pair of therapists, 2×2 tables will be constructed and reliability for the dichotomous positive or negative decisions about whether or not SMT is indicated will be calculated as chance-corrected reliability using Cohen’s kappa. As reco effect). BI prov effect). Ppos anpos, pneg, and overall kappa (95% CI) will also be calculated. Analyses will be conducted using DAG_Stat[In addition, for each pair of therapists, separate 2×2 tables will be presented for judgements about the indication for PIVM assessment and for judgements about mobility, end-feel, and pain provocation obtained from PIVM assessment . Observed agreement, prevalence of positive decisions, PI, BI, pDAG_Stat.Kappa (95% CI) is interpreted in accordance with value labels as assigned by Landis & Koch: <0.00: Univariable logistic regression analysis will be performed to explore which demographic, professional, and clinical factors contributed to the reliability of therapists’ decision-making. Firstly, patients’ demographic and clinical factors at baseline will concern their gender, age, type of complaints, duration of complaints (less or more than three months), radiation, traumatic origin, comorbidity, pain intensity, and disability. Such factors are associated with variation in diagnostic accuracy, but eviWith a sample size of 165, a two-sided 95% CI around kappa would extend ±0.109 from the observed value of kappa, assuming a true value of kappa of 0.70, and a prevalence of positive decisions of 50%. Consequently, each pair of examiners will be asked to include 12 patients. Multiple imputation will be used to handle records with data points missing at random. If, for any reason, data on the primary outcome measure are not available or obtainable from one or both therapists, all data from this patient will be excluded from the analysis and the pair of therapists will be asked to include a new patient. Analyses will be conducted using IBM SPSS Statistics for Windows version 22.The results of this study will provide 1) an estimate of the inter-examiner reliability among manual therapists of indicating SMT in patients with neck or low-back pain based on a multivariable diagnostic reasoning and decision-making process, as opposed to reliability of individual clinical tests, and 2) a first exploration of which demographic, professional, or clinical factors can explain variation in the reliability of therapists’ decision-making with specific attention to the contribution of PIVM assessment. We do not aim or hypothesise that reliability from a multivariable approach to clinical diagnostics will be higher than that from individual test diagnostics. Rather, we believe that such an estimate will be a more real resemblance of the reliability among therapists of making decisions in daily practice concerning the distinction between patients who are indicated for SMT and those who are not. In addition, this approach will add to the ongoing discussion of the identification of specific subgroups of patients that may be more likely to respond to SMT and we propose alternative research strategies for establishing treatment effects.It has been recognised that treatment effects of SMT, or any other physiotherapy modality for that matter, especially in patients with low-back pain, are, on average, small which may be due to heterogeneity of patients obscuring a wide range of individual treatment responses and variation of treatment effects. Ever siWhen determining treatment effects of SMT, randomised clinical trials currently do not make use of patients’ full clinical health profile according to the domains of the ICF for targeting treatment. For instance, Cochrane Reviews consider primary studies including participants only based on their age and the presence of pain with or without radiation,13,14. Tpos (or pneg), arbitrarily, >60%, this strategy can still be used by randomising only those patients of which the indication was agreed upon by two manual therapists  exceeds 0.60 and with BI, arbitrarily, <0.10, patients with neck or low-back pain with a positive indication can be randomised to receive, for instance, either manual mobilisations or manipulations, or both, within a multimodal treatment on the one hand or multimodal treatment without mobilisations or manipulations on the other  as absolute measures to quantify observer variation regarding a certain diagnosis or decision on an individual patient level[In our sample of manual therapists and patients, we cannot rule out the possibility of a substantially higher (or lower) prevalence of positive indications for SMT. Because of such a skewed distribution of decisions, a distorted interpretation of kappa could then occur. Recently, kappa, as a relative measure of reliability, has been criticised because it can only provide information about the ability to distinguish between patients on a sample level. The autnt level. No singnt level,70. Thernt level,118.We will select pairs of manual therapists as examiners that share a common educational background. With this background from the largest institute for manual therapy education in the Netherlands, they likely form a representative sample from the Dutch population of manual therapists registered with the Dutch Association for Manual Therapy or the Royal Dutch Society for Physical Therapy. Manual therapy education in the Netherlands is strongly embedded within international concepts. In these traditional concepts, especially passive joint motion assessment takes a prominent place. TherefoFinally, when analysing the reliability of indicating SMT, we will not distinguish specifically between mobilisations or manipulations. Despite the disparate mechanisms of these interventions,119, no ICF: International Classification of Functioning, Disability and Health; PIVM: Passive intervertebral motion; SMT: Spinal manual therapy.The authors declare that they have no competing interests.EvT is the principal investigator of the study, developed the research questions and methods, obtained ethical approval, and drafted the article. RL, MS, CL, BK, RO assisted in the development of the methods and wrote the study protocol. RL, EvT, PB developed the statistical plan for this protocol. PB, RO supervised the project. All authors assisted with revisions to the study protocol and methods, and approved the final version of the article.Formulas for kappa and associated measures.Click here for file


In this article, we review the deadliest causes of abdominal pain in this population, including mesenteric ischemia, abdominal aortic aneurysm, and appendicitis and potentially lethal non-abdominal causes. We also highlight the pitfalls in diagnosing, or rather  The world's population is increasing, and the elderly represent its fastest growing segment. The number of emergency department (ED) visits for the geriatric population is also increasing. Providing care to elderly patients presents its own unique set of challenges. This is especially true for elderly patients presenting with acute abdominal pain. This subset of patients is at extremely high risk, with a mortality rate approaching 10% . Th. Th32]. Despite the advances in modern medicine, appendicitis is still misdiagnosed 54% of the time in the elderly patient population . Half ofPeptic ulcer disease (PUD) is a common and often undiagnosed disease among elderly patients. Approximately half of patients over the age of 60 with PUD initially present with a complication, most often perforation ,40]. Ot. Ot40]. Elderly patients with PUD have a higher mortality rate than the general population ,44]. Th. Th44]. Lack of abdominal pain is not the only atypical presentation seen in the elderly. The most common presenting sign is melena . Due to Helicobacter pylori ranges from 53% to 73% in this population, contributing to an increased risk of duodenal ulcers ..HelicobaBiliary disease, specifically acute cholecystitis (AC), is the leading surgical emergency among the elderly . The reaThe typical presentation of AC is a female patient in her forties with fever, right upper quadrant pain, nausea, and vomiting. Elderly patients often do not have these symptoms. Although they might have the classic right upper quadrant pain, nearly 40% do not have nausea and vomiting, and many are afebrile. In addition, laboratory tests that yield abnormalities indicative of AC, such as leukocytosis and abnormal liver function tests, could be normal . UltrasoComplications of cholecystitis such as choledocholithiasis, cholangitis, and emphysematous cholecystitis are also much more common in the elderly . Due to The incidence of pancreatitis increases 200-fold after age 65 . PancreaFailing to consider extra-abdominal causes in the patient presenting with abdominal pain is a frequent pitfall. Several life-threatening illnesses can present with abdominal pain only.Myocardial infarction is the most important diagnosis to consider. One-third of women above the age of 65 who have an acute myocardial infarction present with only abdominal pain. This is most common in diabetics and in patients with inferior infarctions . In a stPulmonary processes, especially those involving the lower lobes, are another cause of abdominal pain. These include pneumonia, pulmonary embolism, pleural effusion, and pneumothorax. Metabolic causes such as diabetic ketoacidosis (DKA), hypercalcemia, Addisonian crisis, and porphyria should be considered as well in the appropriate clinical circumstances. Herpes zoster should be considered in patients with well-localized abdominal pain. It can be very difficult to diagnose in the pre-vesicular phase.Genitourinary issues are a significant source of abdominal pain. Cystitis and pyelonephritis often are associated with abdominal pain. Pyelonephritis can present with only abdominal pain or vomiting without any urinary symptoms . A partiAsymptomatic bacteriuria affects a significant number of elderly patients - women more than men and institutionalized patients more than community dwellers . HoweverElderly patients with acute abdominal pain present a significant challenge to even the most seasoned clinician Table . The atyThe authors declare that they have no competing interests.RS wrote several sections of this manuscript as well as organized, edited, and prepared the final submission. TP contributed several sections of the manuscript, edited, and primarily organized the literature sources used in the paper as well as approved the final submission. DK contributed several sections of the manuscript and edited and approved the final submission. JM wrote the introduction and conclusion, provided experience and insight regarding the content, provided editorial revisions and images, and approved the final submission. All authors read and approved the final manuscript.


We investigated this pathway in the synovium of individuals with RA-specific autoantibodies and in early arthritis patients.Arthralgia may precede the development of synovial inflammation in autoantibody-positive individuals at risk of developing rheumatoid arthritis (RA). A major pathway involved in pain is the prostaglandin (PG) E2 pathway enzymes expression levels .Nineteen autoantibody-positive individuals (IgM-rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) with arthralgia (n=15) and/or a positive family history of RA (n=8), who had been prospectively followed for at least 2 years, were included. In addition, we included early arthritis patients (disease-modifying antirheumatic drug naïve) who after 2 years follow up fulfilled classification criteria for RA (n=63), spondyloarthritis , or had unclassified arthritis . In all subjects we assessed pain and performed synovial biopsy sampling by mini-arthroscopy at baseline. Tissue sections were examined by immunohistochemistry to detect and quantify PGE2 enzymes was not clearly related to pain sensation. Expression levels at baseline were not associated with the development of arthritis after follow up . However, in early SpA patients the expression levels of mPGES-1 and COX-1 were significantly increased compared to RA and UA patients.In both study groups synovial expression of PGE2 pathway or originate at sites other than the synovium. In contrast, in SpA, the PGE2 pathway may be inherently linked to the pathophysiology/etiology of the disease.Pain in autoantibody-positive individuals without synovial inflammation who are at risk of developing RA and in early arthritis patients may be regulated by pathways other than the PGE Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by synovial inflammation with clinically apparent arthritis, which may lead to joint destruction. Joint pain is a major burden for RA patients and it is important to characterize the underlying molecular mechanisms.2 (PGE2) may play an important role, as the prostaglandin pathway has a major involvement in arthritic pain, which is illustrated by the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors (COXibs). PGE2 is a powerful inflammatory mediator that can act both locally and centrally to mediate hyperalgesia. Locally, in the synovial tissue, unmyelinated nerve fibers may be sensitised by PGE2 upon inflammatory stimuli [2, arachidonic acid is metabolized into prostaglandin H2 (PGH2) by the enzymes cyclooxygenase-1 (COX-1) or COX-2. COX-1 is constitutively expressed by a variety of cells and tissues and contributes to homeostasis. COX-2 expression, on the other hand, is almost absent under normal conditions but increases following pro-inflammatory stimuli. The PGH2 yield is subsequently transformed into PGE2 by one of three prostaglandin E synthases (PGES) of which microsomal PGES-1 (mPGES-1) plays a predominant role under inflammatory conditions [2 levels are further regulated at the catabolic end by the enzyme 15-hydroxy prostaglandin dehydrogenase (15-PGDH). With regard to the relationship between the levels of PGE2 enzymes, NSAIDs and the PGE2 biosynthesis it is known that glucocorticoids can downregulate the enzymes of the induced PGE2 pathway, while NSAIDs and COXibs rather inhibit the enzymatic catalysis of PGE2 [The RA-specific autoantibodies rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) can be present years before onset of clinical disease –3. Their stimuli . To prodnditions ,11. PGE2 of PGE2 .2 pathway enzymes are expressed both at the mRNA and protein level in the inflamed synovium of RA, spondyloarthritis (SpA) and osteoarthritis (OA) patients and they are especially high in ankylosing spondylitis patients [Genetic deletion studies have highlighted the importance of COX and mPGES-1 in different mouse models of arthritis, reducing incidence, severity and pain in knock-out mice under the relevant experimental settings –15. Morepatients –18. This2 pathway was positively related to arthralgia and contributed to the development of arthritis in autoantibody-positive arthralgia patients at risk of developing RA. These analyses will give insight into the involvement of the prostaglandin pathway in arthralgia and the development of RA and thereby shed light on the relevance of targeting this pathway in the preclinical phase of the disease. In addition, we studied the expression of these enzymes in the synovial tissue of early arthritis patients with different diseases as well as in prognostic subgroups to get insight into the contribution of the prostaglandin pathway in specific diseases or to the persistence of the disease. These analyses may help to identify subgroups of early arthritis patients in which the use of NSAIDs and COXibs may be more effective. We focused on expression of these enzymes in the synovial tissue, as the synovium is the main target tissue in arthritis. Overall, our study may help to develop NSAIDs/COXibs with higher efficacy, possibly by developing drugs that target more than one arm of the eicosanoid pathway.We hypothesized that synovial expression of enzymes of the PGETwo groups were included. First, individuals with arthralgia and/or a positive family history of RA, but without any evidence of arthritis after thorough physical examination, have been recruited since June 2005 ,8 and fo2 pathway enzymes expression exclusively in patients having a definite diagnostic classification, we selected all patients from this cohort who, after 2 years of follow-up, fulfilled either the 2010 ACR/EULAR criteria for RA (n = 63), or the European Spondyloarthritis Study Group criteria [The second group consisted of early arthritis patients  naïve) with an inflamed wrist, knee or ankle joint who were included in the early arthritis cohort of the Academic Medical Center (AMC) in Amsterdam , since AThe study was performed according to the principles of the Declaration of Helsinki, approved by the institutional review board of the Academic Medical Center, Amsterdam, the Netherlands, and all study subjects gave written informed consent.At baseline and yearly study visits, the following clinical and laboratory parameters were obtained: patient’s visual analogue scale (VAS) for global disease activity ; patient’s VAS for pain in general; patient’s VAS for pain in the biopsied joint; 68 tender joint count (68TJC) and 66 swollen joint count (66SJC); morning stiffness in minutes; IgM-RF levels using IgM-RF ELISA  12.5 IU/mL until December 2009 and thereafter using IgM-RF ELISA ); ACPA using anti-citrullinated cyclic peptide (CCP)2 ELISA CCPlus ); erythrocyte sedimentation rate (ESR); serum levels of C-reactive protein (CRP); x-rays of hands and feet.In the group of autoantibody-positive individuals an additional study visit was performed for individuals who developed arthritis at which the presence of arthritis was independently assessed by two investigators (MS and DG or MH and DG).Early arthritis patients were followed for 2 years, after which they were classified for arthritis outcome: self-limiting disease, defined as no arthritis on examination and no use of DMARDs or steroids in the preceding three months, persistent non-erosive disease, defined as presence of arthritis in at least 1 joint and/or of DMARDs or steroids in the preceding three months, or persistent erosive disease, defined as presence of joint erosions on radiographs of the hands and/or feet .en bloc in Tissue-Tek OCT  immediately after collection. Sections (5 μm each) were cut and mounted on Star Frost adhesive glass slides . Sealed slides were stored at -80°C until further use.At baseline, all study subjects underwent arthroscopic synovial biopsy sampling as previously described ,23. In t2, an arbitrary unit representing the intensity of staining per mm2 [Synovial tissue sections were fixed in 2% formaldehyde and immunohistochemical staining was performed using rabbit polyclonal antiserum raised towards mPGES-1 , rabbit  per mm2 . These e per mm2 . Previou per mm2 .Continuous, normally distributed data were presented as mean  and differences between study groups were analyzed using ANOVA. Not normally distributed data were depicted as median  and differences between study groups were analyzed using Kruskal-Wallis and Mann Whitney tests where appropriate. Categorical data were depicted as number (%) and differences between study groups analyzed using chi2 test. Synovial markers in early arthritis patients, analysed by digital image analysis, were log transformed after which these data were normally distributed. Differences between patients who did or did not use NSAIDs were analysed using the Student’s t-test. Differences between diagnostic groups were analysed using analysis of variance (ANOVA) and Tukey’s post-hoc test. Bivariate correlations between synovial tissue markers and clinical disease parameters were analyzed using either Pearson or Spearman rank correlation test. Statistical analysis was performed using PASW Statistics 18 .Nineteen autoantibody-positive individuals were included in this study. Baseline characteristics of autoantibody-positive individuals are depicted in 2 pathway enzymes was not lower in the group of individuals who used NSAIDs  compared to those who did not . In addition, the VAS pain was not lower in individuals who used NSAIDs  compared to those who did not .Synovial expression of PGE2 pathway enzymes did not correlate with pain scores  as well as COX-2 (p = 0.470) and 15-PGDH (p = 0.352) , panel An scores .2 pathway enzymes was not higher in the individuals having arthralgia in the biopsied joint compared to the individuals having arthralgia in other joints only  with those who did not (n = 13), irrespective of their arthralgia status . We did not observe any differences in the expression levels of mPGES-1, COX-1, COX-2, or 15-PGDH between individuals who developed arthritis and those who did not . Collectively, these results suggest that synovial expression of the PGE2 pathway has no major role in either arthralgia or the onset of arthritis in autoantibody-positive individuals at risk of developing RA.Next, we compared synovial expression of PGEHundred and four early arthritis patients were included in the study. Baseline characteristics of early arthritis patients are depicted in Fifty-five percent of the early arthritis patients in this study used NSAIDs at the moment of synovial biopsy sampling. Expression of mPGES-1, COX-1 and COX-2 was comparable between individuals who did or did not use NSAIDs . This suggests that NSAID treatment will not bias the results of our analyzes. In addition the VAS pain was comparable between individuals who did or did not use NSAIDs (p = 0.977).2 pathway enzymes and pain sensation in early arthritis patients .2 is a mediator of vasodilation and oedema, we observed a positive correlation between expression of COX-1 and CD3 (T cells) and between expression of mPGES-1 and COX-1 and expression of CD68 (macrophages) both in the synovial sublining and lining layer  in the synovium.However, as expected since PGEng layer . None ofBaseline characteristics of the subgroups of early arthritis patients with a definite diagnostic classification of RA (n = 63), SpA (n = 14) or UA (n = 27) after 2 years of follow-up are depicted in Expression of mPGES-1,COX-1 and COX-2 was significantly different between the three diagnostic groups  . Tukey’s2 pathway enzymes between UA patients who later fulfill classification criteria for RA and those who remain UA, we compared patients with UA at baseline who were classified as RA after 2 years of follow-up  with UA patients at baseline who were still classified as UA after 2 years of follow-up  and compared those with patients classified as RA already at baseline . No significant difference could be detected in baseline synovial expression of mPGES-1, COX-1 or COX-2 between the three diagnostic outcome groups  or erosive (n = 11) disease had higher baseline expression levels than patients with self-liming disease (n = 13). Prognostic outcome data were missing for 9 patients. No statistically significant differences between the prognostic outcome groups were observed  receptors on sensory nerve endings to lower their threshold of activation for other stimuli. Sensitization can occur both peripherally, in primary afferent nociceptors of the joint, and centrally, in spinal cord neurons and dorsal root ganglia. Inflammatory mediators other than PGE2, such as bradykinin, histamine, adenosine triphosphate (ATP), and acetylcholine [2 pathway, since other inflammatory markers trigger and/or sensitize nerves to pain as well and pain experience might be a resultant of pain induced by several pathways. Another explanation for our findings may be that PGE2 would be involved in regulating arthralgia centrally  or via release by circulating monocytes that mediate the acute response, but not locally in the synovium. A third explanation could perhaps be that the quantification of enzymes by immunohistochemistry is not accurate enough for correlation with pain scores. An alternative method would have been to analyze the actual concentration of PGE2 in the synovial tissues. This was, however not possible due to limitation of biopsy material, and a clear disadvantage of analysis of whole biopsy samples without morphology is that it does not allow for selection of the specific synovial tissue rather than sublining connective or adipose tissue which would have been as a source of bias, in particular in subjects with a very thin synovial layer as observed in individuals without arthritis. Previous work showing a highly significant relationship between cytokine levels evaluated by immunohistochemistry on the one hand and a score for pain on the other indicate that quantification of sections stained by immunohistochemistry can be used to detect correlations with pain [2 metabolite could have provided information about the systemic involvement of the PGE2 pathway [2 (prostacyclin) in arthritic pain [This is the first study examining the expression of enzymes of the PGEadykinin , resultilcholine , and thelcholine . Therefoith pain . Measuri pathway , but uritic pain .2 pathway was not related to development of arthritis in subjects at risk of developing RA and within RA patients we did not observe a relation with the systemic inflammatory parameters ESR and CRP or with disease persistence. However, expression of these enzymes was positively correlated to the number of macrophages present in the synovium, which has been shown to be one of the main cell types expressing these enzymes [The synovial expression of enzymes of the PGE enzymes .2 pathway in the pathogenesis of SpA, supporting previous studies [Interestingly, in early arthritis patients, synovial expression of mPGES-1 and COX-1 was increased in SpA patients compared to RA and UA patients and a similar trend was observed for COX-2, suggesting involvement of the PGE studies ,36. The  studies . In that2 produced in the synovial tissue. Moreover, a role for the PGE2 pathway in the pathogenesis of SpA has been shown by the positive effects of the use of NSAIDs, the first-line drug treatment for complaints of pain and stiffness in AS patients [The fact that we found increased synovial expression of mPGES-1 and COX-1 in early SpA patients compared to early RA and UA patients may partly explain the difference in radiographic characteristics between RA and UA on the one hand (joint space narrowing and bone erosions) compared to SpA on the other (new bone formation). PGE2 can stimulate new bone formation by stimulating the differentiation of osteoblasts . The benpatients  and in S2 pathway, which are known to be involved in pain sensation. Pain in these patients may therefore be regulated by other pathways or originate at sites other than the synovium, which needs to be addressed in future studies. Synovial expression of mPGES-1 and COX-1 is increased in SpA patients compared to RA and UA patients, supporting involvement of the PGE2 pathway in the pathogenesis of SpA.In conclusion, we did not find clear evidence that arthralgia in subjects at risk of developing RA or in early arthritis patients can be explained by altered synovial expression of enzymes of the PGE


Dear Editor,Farzanegan et al. described quality of life evaluations of patients undergoing lumbar discectomy using the short-form 36 (SF-36) . They prQuality of life and functional status improvement is evaluated by many available tests; one of them SF-36 as utilized in this study. While all these instruments are considered as objective evaluations, they all depend on subjective information. SF-36 is a generic measure, as opposed to one that targets a specific age, disease, or treatment group. Thus, for low back pain, either the Oswestry Disability Index (ODI)  or RolanHowever, there has not been any significant description of a clinically significant change in any condition for SF-36. In contrast, clinically significant change has been described as a 15-point change in patients who undergo spinal fusion before surgery and at follow-up for ODI . Others Consequently, when these issues are taken into consideration, do the changes described in Farzanegan et al.’s manuscript , which lThe clinical implications of the study include not only its usefulness in evaluating lumbar discectomy, but also the questions about meaningful change, which is clinically significant. In the future, studies such as this one should be compared with other disease specific tests such as RDQ. In this case, most patients had subacute pain, whereas ODI is for patients with chronic pain.


The goal of the study was to assess the state of coronary arteries in perimenopausal women undergoing examination before prescription of hormonal replacement therapy.One hundred ninety-three patients were screened, and 43 of them were selected for inclusion to the study. Pretest probability of coronary heart disease (CHD) was 47% for patients with typical angina pain and 20.5% with atypical pain. Patients with typical and atypical pain syndromes had no essential differences in terms of age, but had different hormonal status assessed by follicle stimulating hormone level and different menopause durations.Atherosclerotic lesion causing luminal occlusion by more than 50% was detected in 13 (61.9%) patients with typical pain syndrome and in eight (36.4%) patients with atypical pain syndrome manifestations. Numbers of patients with intact coronary arteries were six (28.6%) and 10 (45.5%) in groups with typical and atypical pain syndrome, respectively. Myocardial bridges were found in five (23.8%) patients with typical pain syndrome and seven (31.8%) patients with atypical manifestations.In spite of modest pretest CHD probability in the group with typical pain syndrome and low pretest CHD probability in the group with atypical manifestations, patients with major atherosclerotic lesions were detected in both groups. Use of this approach to assessment of the state of coronary arteries allows detecting patients at high risk of cardiovascular complications and avoiding the use of hormonal replacement therapy in them. Hormonal replacement therapy is not a recommended method for coronary heart disease (CHD) prevention. Nevertheless, hormonal replacement therapy prescription at early perimenopause and at intact coronary arteries is believed to decelerate formation of atherosclerotic lesions and to result in decreased mortality from cardiovascular diseases , 2. ThusIt should be mentioned that a medical practitioner frequently faces several challenges when diagnosing chronic forms of CHD in women. Thus, evaluation of clinical symptoms (chest pain) in female patients is much more complicated than establishing diagnosis in a man with similar complaints. Classical description of angina pain stated in medical manuals is more typical of male population, while women are more frequently encountered with pain syndrome atypical manifestations. Thus, female patients more frequently experience pain sensations unrelated with physical load, nocturnal pain and pain sensations related with emotional stress, as well as long-term dull pain invoked by physical load .Use of stress testing does not always allow establishing the correct diagnosis as well due to its lower specificity in women compared to men . Stangl In this case, a medical practitioner frequently applies angiography. One of its variants is computed tomography (CT) of coronary arteries, which more and more frequently becomes a part of routine clinical practice due to lack of invasive interventions, and is recommended as a method of choice in patients with low to moderate risk.The goal of the current work was the study of the state of coronary arteries in perimenopausal women with pain sensations in chest.During the period 2011 - 2013, 194 patients referred for examination by a gynecologist before hormonal replacement therapy prescription, were examined. All patients exhibited either menstrual cycle duration changes or the absence of menstruation for not more than 5 years. Pain syndrome was classified as typical/atypical in accordance with criteria of European Society of Cardiologists  [All patients underwent treadmill stress test in accordance with Bruce’s protocol. Electrocardiographic complex with treadmill Cardio-Perfect MD  was used for treadmill test.Patients with acute coronary syndrome, surgically induced menopause, menopause lasting for more than 5 years, moderate to severe diabetes mellitus, cardiac failure of functional class III-IV, valvular heart disease, cancer pathologies, chronic obstructive pulmonary diseases, chronic renal failure of stage II and higher, thyroid gland hormone-producing function disorders, stomach and duodenal ulcers, diseases limiting the life span to 1 year, and patients with acute inflammatory processes were excluded from the study.The study protocol was approved by Local Ethics Commission of NIT of the Academy of Medical Sciences of Ukraine; all patients were informed of the study goal and signed the informed consent for participation in the study.The results were processed by distribution-free statistical methods of medico-biological profile using a statistical software package Excel for Windows and IBM SPSS 19.0. Null-hypothesis testing was carried out using Mann-Whitney U-test. Data were represented as median and 25% and 75% quartiles (Me (25 - 75)).At the baseline, 193 patients were examined. Among them, pain syndrome was classified as non-cardiac pain in 141, and they were excluded from the further study. Besides, nine patients refused to undergo CT of coronary arteries. Forty-three patients were selected for angiographic examination. Patient characteristics depending on pain syndrome type are shown in Patients with typical pain syndrome had longer menopause duration (P = 0.065), and included more individuals with diabetes mellitus type 2 (P = 0.45). Differences in patients’ hormonal status were revealed. Thus, patients of atypical pain syndrome group had higher FSH level (P = 0.04). Pretest CHD probability in groups was 47% for typical pain syndrome and 20.5% for atypical one (P = 0.038).CT-coronary angiography showed the absence of any atherosclerotic lesion of coronary arteries in 20 (45.5%) patients; four (9.1%) had atherosclerotic occlusion of less than 50% of vascular lumen; 20 (45.5%) patients exhibited atherosclerotic occlusion of more than 50% of coronary artery. Among patients with atherosclerotic lesion of coronary arteries, seven (15.9%) had more than one affected vessel. In 10 patients with unaltered coronary arteries, muscular bridges of anterior interventricular branch of the left coronary artery were detected. In two patients, the presence of muscular bridges was combined with 30% atherosclerotic occlusion of the right coronary artery.Patients undergoing CT examination of coronary arteries were distributed into two groups depending on pain syndrome type; coronary angiography results obtained in these two groups are shown in Women with atherosclerotic stenosis of more than 50% of vascular lumen, as well as patients with multivascular lesions, reliably prevailed in the group with typical pain. It is worth mentioning that 30% atherosclerotic lesion of anterior interventricular branch of left coronary artery was combined with hypoplasia of the right coronary artery in one patient from atypical pain syndrome group. Besides, patients with typical pain syndrome had reliably higher Agatston score.Atherosclerotic lesion identification before the beginning of hormonal replacement therapy is an essential step. Patients participating in this study had low scores of CHD pretest probability. Thus, CHD pretest probability is 47% for patients with typical pain in age group 50 - 59 years old, while pretest probability of this disease does not exceed 20% for patients with atypical pain of this age group. At the same time, our study has revealed hemodynamically essential atherosclerotic occlusion of coronary arteries in 61.9% patients of the first group and 36.4% patients of the second group. It should be mentioned that this is the group where hormonal replacement therapy is contraindicated to women, and doctor’s further actions are quite clear in this case.From the examined group, 28.6% women with typical pain syndrome and 45.5% women with atypical pain syndrome had intact coronary arteries. Higher prevalence of intact coronary arteries in women was detected in such studies as CASS (coronary artery surgery study) - 39% of women ; the maxInterpretation of results in patients with muscular bridges is the most complicated. This pathology is inherited; nevertheless, its clinical importance is widely discussed in literature, and there is no unequivocal opinion regarding this issue . We did The last patient group includes women with minimal atherosclerosis manifestations. No literature data regarding the possible use of hormonal replacement therapy in them are available. In accordance with current recommendations , they were not recommended to use therapy with hormonal drugs.Thus, before scheduling hormonal replacement therapy, patients need thorough examination, consideration of risk factors, and comprehensive examination of the state of coronary arteries in order to preclude adverse cardiovascular side effects.This study was conducted in a small patient cohort. This is due to the fact that only women planning hormonal replacement therapy were selected for inclusion. Besides, patients were initially referred by a gynecologist. If the study was conducted with involvement of patients referring to a cardiologist/family doctor (therapist), the level of detected coronary artery lesions could have been higher. Besides, location of atherosclerotic lesions was not performed in the study, as the investigators were first of all interested not in finding out clinical pattern conformity to certain lesion sites, but in detection of an atherosclerotic lesion as such in view of contraindications to hormonal replacement therapy.Perimenopausal patients with typical and atypical pain syndromes represent a heterogenic group in terms of the state of coronary arteries.Among patients with low CHD pretest probability, atherosclerotic lesions were detected in more than half of women (61.9%) with typical pain syndrome, and in 36.4% women with atypical pain.Other coronary angiography findings in this patient group included muscular bridges, right coronary artery hypoplasia and hemodynamically minor atherosclerosis of coronary arteries.


To evaluate the efficacy, safety, pain perception and health-related quality of life (QoL) of percutaneous ethanol injection treatment (PEIT) as an alternative to thyroid surgery in symptomatic thyroid cysts.Thirty consecutive patients  with symptomatic benign thyroid cysts relapsed after drainage were included. In all cases, cytology prior to treatment, maximum cyst diameter and volume were determined. PEIT was conducted using the established procedure, and the volume of fluid removed and pain perceived by the patient were assessed. In each procedure, the volume of alcohol instilled was <2 ml. After follow-up, final cyst diameter and volume were determined and the persistence of symptoms and QoL were assessed by a questionnaire (SF-36).p < 0.05).Mean symptom duration was 10 ± 20 months. A single session of PEIT was required to complete the procedure in 45 % of patients, two in 31 % and three in 13 %. Mean initial maximum cyst diameter was 3.5 ± 1.0 cm and mean extracted liquid volume 61 ± 36 ml. During PEIT, 39 % of patients experienced virtually no pain, 43 % mild pain and 17 % moderate pain. No complications of PEIT were observed. After 12.1 ± 1.4 months of follow-up, cysts were reduced more than 70 % in volume in 86.3 % of patients, more than 80 % in 61.9 % and more than 90 % in 42 %. On the health-related QoL SF-36 questionnaire, patient scores 6 months post-PEIT did not differ significantly from those of the healthy Spanish population. With respect to cosmetic complaints or local symptoms of compression, PEIT-treated patients presented an initial score of 22 ± 8 and 13 ± 5 after treatment (In our experience, percutaneous ethanol injection has prove to be an effective, safe and well-tolerated first-line treatment of symptomatic thyroid cysts. The SF-36 questionnaire is a multipurpose, short-form health survey, commonly used to evaluate patients’ health-related QoL in clinical practice. Eight domains are assessed in this questionnaire, including physical functioning, role limitation due to physical problems, bodily pain, general health, vitality, social functioning, role limitation due to emotional problem, and mental health. The eight health domains were used to provide a physical component summary (PCS) and a mental component summary score (MCS). Interpretation of the SF-36 Health Survey was greatly simplified with the norm-based scoring (NBS) of its health domain scales and component summary measures. In NBS, each scale is scored to have the same average (50) and the same standard deviation  and MCS [49.3 (4.8)] scores of the patients 6 months after PEIT did not significantly differ from those of the healthy Spanish population .p < 0.05) with 47 % of cases reporting a score of ten, i.e. absence of symptoms.With respect to specific questions addressing to cosmetic complaints or local symptoms of compression, PEIT-treated patients presented an initial score of 22 ± 8 and after treatment 13 ± 5  and between baseline calculated volume and volume reduction .In the correlation analysis, a significant relationship observed were between calculated initial cyst volume and evolution time  were resolved with the first or second procedure and whether more than two treatments were required depended on initial cyst volume. In our opinion this feature is important in order to discuss with the patient before the procedure the eventual needing of more than one or two PEITs.The volume of ethanol used in PEIT is a matter of debate. The reported amounts of ethanol administered ranged from 35 to 100 mL depending on the authors , 16, 19,A major concern in all interventional procedures is patient comfort. We specifically tested pain sensation during PEIT using a visual scale, and it is noteworthy that over 80 % of patients reported virtually absent or mild pain and none of the treated group subjects described it as greater than moderate. Previous reports described a transient mild or burning sensation, which was more intense in the largest cysts , 24. BasThere is a lack of information in the literature regarding the quality of life of patients with recurrent thyroid cysts treated with ethanol . We addrPEIT in recurrent thyroid cysts appears to be a highly efficacious and safe technique. The improvement in clinical conditions obtained with very low pain sensation, absence of complications and good QoL perceived after the procedure render PEIT an optimum and more recommendable alternative to thyroid surgery. In our opinion, future guidelines should include PEIT prior to surgical treatment and establish a uniform consensus protocol.