Studies have shown the impact of atrial fibrillation (AF) on the patients'quality of life. Specific questionnaires enable the evaluation of relevantevents. We previously developed a questionnaire to assess the quality oflife of patients with AF (AFQLQ version 1), which was reviewed in thisstudy, and new domains were added.To demonstrate the reproducibility of the AFQLQ version 2 (AFQLQ v.2), whichincluded the domains of fatigue, illness perception and well-being.We applied 160 questionnaires (AFQLQ v.2 and SF-36) to 40 patients, atbaseline and 15 days after, to measure inter- and intraobserverreproducibility. The analysis of quality of life stability was determined bytest-retest, applying the Bartko intraclass correlation coefficient (ICC).Internal consistency was assessed by Cronbach's alpha test.The total score of the test-retest (n = 40) had an ICC of 0.98 in the AFQLQv.2, and of 0.94 in the SF36. In assessing the intra- and interobserverreproducibility of the AFQLQ v.2, the ICC reliability was 0.98 and 0.97,respectively. The internal consistency had a Cronbach's alpha coefficient of0.82, compatible with good agreement of the AFQLQ v.2.The AFQLQ v.2 performed better than its previous version. Similarly, thedomains added contributed to make it more comprehensive and robust to assessthe quality of life of patients with AF. Its prevalence increaseswith age, and 70% of the population with AF belongs to the age group between 65 and85 years. It manifests more commonly in men, but after the age of 75 years, womenconstitute 70% of the population affected.3In Brazil, 1.5 million individuals are estimated to have AF, which accounts for 33%of the hospitalizations. In the United States, persistent and paroxysmal AF ispresent in approximately 2-3 million North-Americans. In Europe, it is detected in4.5 million people, with a projection that by 2050 it reaches 5.6 million people,50% of whom older than 80 years.4Several clinical situations, such as hypertension, heart failure, rheumatic andnon-rheumatic valvular diseases, diabetes mellitus and hyperthyroidism, increase therisk for AF.9The most common clinical manifestations of symptomatic patients with AF arepalpitations, dizziness, dyspnea, chest pain and reduced tolerance to physicalactivity. Less specific symptoms, such as fatigue, anxiety and depression, have alsobeen reported. Therefore, the physical or emotional clinical manifestations ofpatients with AF have a substantial impact on their quality of life.11Although the impact on the quality of life of patients with AF is recognized, fewhealth care services systematically assess that impact to follow those patientsup.12 To introduce that type of approach in the medicalpractice and that of all other health care professionals, simplified questionnairessuitable for the major clinical manifestations, in addition to the patients'emotional responses to the disease process, should be developed. That assessmentimplies the contemplation of the major dimensions of life, comprising physical,social and emotional domains.13From that perspective, the assessment with a specific instrument might even aid withdecision making regarding therapy.9Assessing the quality of life by using specific scientifically validated instrumentscan contribute to objectively characterize the phenomenon.14 After critical review, we proposedan update of that questionnaire by including the new domains of fatigue, illnessperception and well-being.In Brazil, a quality of life questionnaire for AF patients (AFQLQ version 1 - AFQLQv.1) was developed and validated, aiming at assessing the major clinicalmanifestations and treatments in the Brazilian population with AF.This study analyzes the consistency and reproducibility of the AFQLQ v.1 afterincluding those new domains (AFQLQ version 2 - AFQLQ v.2).This is a longitudinal study carried out in the Anticoagulation Outpatient Clinic forAF Patients, in the UNIFESP university-affiliated hospital.This study sample consisted of 40 patients, older than 18 years, with persistent orpermanent AF of any etiology, referred for anticoagulation control .2 and CHA2DS2-vascscores; use of devices; echocardiographic data ; AF classification (permanent or persistent); medications used; and patients'knowledge of the name of the arrhythmia. Quality of life was measured by using thequestionnaires SF-36 , AFQLQ v.1 and AFQLQ v.2. All information was collected at thefirst visit  added by fatigue,well-being and illness perception.To estimate reproducibility or reliability, test-retest and internal consistencymethods were used as follows:-Intraobserver reproducibility: Observer 1 applied 21 AFQLQ v.2 and SF-36 topatients followed up in the Anticoagulation Outpatient Clinic for AFPatients. After 15 days, the same observer reapplied those questionnaires tothe same patients.-Interobserver reproducibility: Observer 1 applied 19 AFQLQ v.2 and SF-36 topatients followed up in the Anticoagulation Outpatient Clinic for AFPatients. After 15 days, observer 2 reapplied those questionnaires to thosesame patients.This study was approved by the UNIFESP Ethics Committee (n.0852/10), and allparticipants provided written informed consent according to the 466/12 NationalBoard of Health Resolution.The scores of the SF-36 and AFQLQ v.2 domains, the AFQLQ v.2 total score and theclinical variables were grouped in a data bank of the SPSS  software, version 19. Initially the descriptive statistics ofthe patients' demographic and clinical conditions was performed, and thedistribution of the absolute and relative frequencies of the categoricalvariables was obtained. The continuous variables were presented as mean ±standard deviation.Test-retest. The stability of the attribute 'quality of life' in the15-day interval was tested by comparing the means obtained in the initialassessment and in the second assessment by using paired t testand Spearman correlation. To assess the reliability of the new version of theAFQLQ, Bartko intraclass correlation coefficient (ICC) was used in the totalsample of patients between the different observers. A measuring instrument isconsidered to have good reliability for ICC values higher than 0.80. The pairedt test assesses the mean scores obtained in twoapplications. A statistically significant difference indicates low reliabilityof the instrument.Internal consistency. Internal consistency was determined by usingCronbach's alpha coefficient. The following were estimated: item-totalcorrelation; total alpha value; and alpha value of each item. Scores greaterthan 0.8 are desirable, and greater than 0.90, excellent.16To reject the null hypothesis, the significance level of p < 0.05 (5%) wasadopted. The 95% confidence intervals were calculated.14Similarly to the previous version, we assumed that the quality of life of thepatients studied has a parametric distribution, thus the normality test was notused.Of the patients assessed, 26 (65%) were of the male sex, and the patients' age variedfrom 43 to 86 years (mean of 61.2 ± 9.6 years).Regarding the characteristics of AF, 47.5% of the patients had persistent AF, and52.5%, permanent AF. Regarding the time elapsed since diagnosis, 35% had the diseasefor up to one year, 40% had it from one to five years, and 25%, for more than fiveyears. Regarding risk classification, most patients were CHADS1 and 2 . The mean left atrial size was 41.4 ± 1.2 mm. Regardingtherapy, 52.5% had already undergone electrical cardioversion, and 10% had undergonecatheter ablation. When asked about knowledge of the disease, 25% reported none.The new version of the AFQLQ maintained the same structure and metric of the original(appendix). Similar to the original, the AFQLQ v.2 remained easy to apply and tounderstand. This information originated from the assessment of the focal groupduring the development of version 2.The AFQLQ v.2 score system remained objective, simple and fast. An individualizedscore for each domain was maintained, as was a total/global value for the additionof the values found in each domain.14 theinternal consistency of the new version also showed highly reliable results ofagreement: Cronbach's alpha > 0.82. The item-by-item assessment showedcorrelation greater than 0.75 between the total result of the test and the domain'well-being' . Similar results were found for the domains'fatigue' and 'illness perception', with Cronbach's alphas of 0.78 and 0.79,respectively  byadding new domains, which are less common to the clinical practice, allows thequestionnaire to meet the objective of quality of life assessment in its manydimensions in the Brazilian population.per se. This does not excludethe possibility of using the questionnaire to analyze the treatments for AF andtheir responses concerning quality of life.The new version of AFQLQ perfected the previous one, confirming its specificity forpatients with AF and more reliably reflecting their reality. Excluding the domain'therapy', which contemplated interventions with drugs, cardioversion and ablation,and including manifestations, such as fatigue, illness perception and well-being,allowed the questionnaire to assess individuals without the potentially confoundingfactors in assessing the impact of AF 28The inclusion of the domain 'fatigue', although a subjective symptom of no metricconfirmation, is crucial, because it appears as the third most frequently foundsymptom in patients with AF, significantly influencing their functional capacity andphysical activity limitation. However, that domain is sometimes assessed as amanifestation related to intolerance to exercise/exertion, which is nottrue.34Similarly, including subjective components, such as well-being and illnessperception, in addition to enabling the assessment with clear questions, providedsupport to assess the individual in other dimensions.30A recent systematic review has shown the concern of health care professionals withthe relationship between the emotional and physical aspects of patients with AF.That review, comprising 34 studies specifically assessing anxiety and depression,has concluded that there is a complex relationship between the symptoms ofdepression and anxiety and the clinical manifestations of AF.35Regarding illness perception, patients and physicians differ about the threat AFrepresents to health, as well as morbidity and mortality. Physicians tend both tounderestimate the understanding of patients about the benefit derived fromtreatment, and to overestimate their knowledge of the complications.36In accordance with the literature, the new version provides quality of lifeassessment, domain-by-domain, both separately and globally: Are there symptoms? Ifthe response is positive, which are they? Can well-being or illness perceptioninfluence quality of life? Which set of domains has the greater influence?A specific and simplified questionnaire, such as AFQLQ v.2, enables assessing whetherphysical symptoms affect well-being and/or emotional health and vice-versa. Notassessing all the quality of life dimensions of individuals with AF can lead us tothe reductionist management of considering only heart rate or rhythm control inthose patients. We believe that hinders a more holistic approach to the disease.The possibility of incorporating the questionnaire into the routine visit to anyhealth care professional, because of its rapid application, makes it a practicaltool in the assessment of patients with AF.It is worth noting that the use of a simple and direct language allows the AFQLQ v.2to be applied to patients of any educational level. The easily applicable scoresystem provides results on the quality of life rapidly and of easyinterpretation.The strict analysis of the psychometric properties of this new version of the AFQLQ,with statistically significant reproducibility as compared to that of thegold-standard, the SF-36, ensures the suitability of the AFQLQ v.2 to be used inassessing the quality of life of patients with AF.The new version of the AFQLQ proposed in the present study (AFQLQ v.2) showed notonly improvement of the original version, but maintained high reproducibility. Thesecharacteristics are essential to the clinical applicability of that instrument.The validation of this new version of the AFQLQ did not classify the participantsinto their socioeconomic levels. This new version of the AFQLQ requires furtherfollow-up studies in the outpatient clinic to confirm its sensitivity to detectoscillations in the patients' quality of life paralleling their clinicalimprovement or worsening.


Pelodiscus sinensis. Samples from the uterine segment of the oviduct were examined by transmission electron microscopy. Tcs were mainly located in the lamina propria beneath the simple columnar epithelium of the uterus and were situated close to nerve endings, capillaries, collagen fibres and secretory glands. The complete morphology of Tcs and Tps was clearly observed and our data confirmed the existence of Tcs in the uterus of the Chinese soft-shelled turtle Pelodiscus sinensis. Our results suggest these cells contribute to the function of the secretory glands and contraction of the uterus.Telocytes (Tcs) are cells with telopodes (Tps), which are very long cellular extensions with alternating thin segments (podomers) and dilated bead-like thick regions known as podoms. Tcs are a distinct category of interstitial cells and have been identified in many mammalian organs including heart, lung and kidney. The present study investigates the existence, ultrastructure, distribution and contacts of Tcs with surrounding cells in the uterus (shell gland) of the oviduct of the Chinese soft-shelled turtle,  Telocytes (TCs) are a novel type of interstitial  cell that have been recently described in humans and other mammals in both cavity and non-cavity organs . TCs areVarious functions of TCs are possible based on their morphological characteristics. In some organs, TCs act as supporting cells for tissue organization ,29. TCs Most studies of TCs have been performed in mammalian species and there are no studies available in the literature examining TCs in reptiles. The reptilian oviduct is an important organ that performs major functions including sperm storage, egg formation, maturation and transportation of unfertilized or fertilized eggs to the exterior of the body. The organ is composed of the following five segments or regions (from anterior to posterior): infundibulum, magnum, isthmus, shell gland (uterus) and vagina. The uterus is an important segment of the oviduct and has several important functions. In addition to salt and water absorption, egg calcification occurs in the uterus to form the calcium carbonate shell. Sperm storage also takes place in the uterus in some reptile species. The egg pigmentation also occurs and finally the uterus (shell gland) contracts to expel eggs. Egg transport is accomplished mainly by contractions of the oviduct, and the oviduct musculature functions as a stretch receptor. The ovum also provides mechanical stimulus by itself ,43. SimiPelodiscus sinensis, by utilizing transmission electron microscopy. The Chinese soft-shelled turtle P. sinensis is an ancient species of reptiles distributed throughout China and many other countries. This species has considerable importance in aquaculture and is an important food source. The aim of this study is to identify TCs and investigate their morphological and ultrastructural characteristics. We have also examined their contact with the surrounding cells in the uterus of the oviduct.The present work was performed with the uterus (shell gland) and oviduct of the Chinese soft-shelled turtle P. sinensis, were purchased from a wild breeding base in Jiangsu province of China. The animals each weighed 660–720 g. The animals were anesthetized by sodium pentobarbital (20 mg/kg) administered intraperitoneally and were killed by cervical dislocation. The uterus samples were collected for transmission electron microscopy. All protocols were approved by Science and Technology Agency of Jiangsu Province (SYXK (SU) 2010-0005).Ten female adult soft-shelled turtles, The samples were cut into small blocks and then fixed in 2.5% glutaraldehyde in PBS  for 24 hrs. The blocks were rinsed in the same PBS and then post-fixed for 60 min. at room temperature in the same way by using buffered 1% osmium tetroxide  and washed in the buffer. The samples were then dehydrated in ascending concentrations of ethyl alcohol, infiltrated with a propylene oxide–Araldite mixture and then embedded in Araldite. The blocks were then sectioned by using an ultramicrotome  and the ultrathin sections (50 nm) were mounted on formvar-coated grids. The sections were stained with 1% uranyl acetate and Reynold's lead citrate for 20 min. The sections were examined and photographed by using a high resolution digital camera (16 mega pixel) connected to the TEM, Hitachi H-7650 (Japan).Telocytes have Tps containing typical podoms that were easy to recognize in our TEM images in the lamina propria Figs  and 2 beThe absence of TC basal lamina was noted. Other organelles, such as the Golgi body and ribosomes, were rarely seen in our images. However, rough endoplasmic reticulum could be clearly seen Fig. .We detected Tps as discontinuous segments with alternating podom and podomer. The Tps were present near the blood vessels and there were network structures or labyrinthine structures between Tps Figs  and 6. WWe found TCs were closely connected with collagen fibres in cross and longitudinal sections Figs  and 10. P. sinensis by TEM. Electron microscopy is currently critical for accurate identification of TCs [versus fibroblasts showed that TCs are different from fibroblasts [This is the first study to identify TCs in animals besides mammals. We have demonstrated the morphological and ultrastructural characteristics of these cells in the uterus (shell gland) of the oviduct of Chinese soft-shelled turtle, n of TCs ,3,11. Horoblasts . We founroblasts . Conversroblasts ,34,38.P. sinensis are similar to those already reported in mammalian species and are consistent with the diagnostic criteria of TCs [The general features of the TCs we identified in the interstitial spaces of the oviduct of soft-shelled turtle a of TCs . The TEMa of TCs ,45. Our a of TCs . The cloa of TCs . Our finCollagen-embedded TCs were found in the dermis , which sPrevious reports indicate that Tps generally form and release vesicles (or exosomes) that help TCs participate in intercellular communication. As in the heart, heterocellular communication among TCs and cardiomyocytes occurs by shedding vesicles and close proximity . Our finin vivo for many cells [P. sinensis. Tps connect with each other and with smooth muscle cells, nerve fibres, blood vessels and collagen fibres. These data demonstrate the existence of TCs in reptiles. Further studies must explore the potential bio-functions of TCs in certain pathological conditions in the uterus and investigate the mechanisms of interaction between TCs and other cells.Intercellular signalling can take place by two mechanisms. These mechanisms include paracrine and/or juxtacrine secretion of small signalling molecules and the shedding of microvesicles. The microvesicles can transport ‘packets’ of macromolecules to the target cells and alter their physiology. These vesicles can transport RNA or DNA among neighbouring cells and induce epigenetic changes ,50. The ny cells . Ectosomny cells . The funny cells ,57,58. I


Auditory dysfunction is a common clinical symptom that can induce profound effects on the quality of life of those affected. Cerebrovascular disease (CVD) is the most prevalent neurological disorder today, but it has generally been considered a rare cause of auditory dysfunction. However, a substantial proportion of patients with stroke might have auditory dysfunction that has been underestimated due to difficulties with evaluation. The present study reviews relationships between auditory dysfunction and types of CVD including cerebral infarction, intracerebral hemorrhage, subarachnoid hemorrhage, cerebrovascular malformation, moyamoya disease, and superficial siderosis. Recent advances in the etiology, anatomy, and strategies to diagnose and treat these conditions are described. The numbers of patients with CVD accompanied by auditory dysfunction will increase as the population ages. Cerebrovascular diseases often include the auditory system, resulting in various types of auditory dysfunctions, such as unilateral or bilateral deafness, cortical deafness, pure word deafness, auditory agnosia, and auditory hallucinations, some of which are subtle and can only be detected by precise psychoacoustic and electrophysiological testing. The contribution of CVD to auditory dysfunction needs to be understood because CVD can be fatal if overlooked. Auditory function is complex, as it anatomically necessitates the transmission of an auditory signal from the ear to the auditory cortex and further processing to facilitate the perception and recognition of sound. Hearing disturbances profoundly affect quality of life and can occasionally be a cause of life-threatening disorders of the central nervous system. Auditory dysfunction is usually masked by other neurological issues and it can be difficult to evaluate in patients with cerebral stroke. Cerebrovascular disease (CVD) is the most prevalent neurological disorder and it can cause various types of auditory dysfunction. This study reviews current understanding of interactions between CVD and auditory dysfunction.The clinical syndrome of cortical deafness with bitemporal infarction has become established since it was first described in 1883 , apperceAn acute ischemic stroke in the distribution of the AICA is associated with facial weakness, hypalgesia, ataxia, vertigo, hearing loss, and nystagmus. Some patients lack or may not be aware of the symptom associated with brainstem or cerebellar signs. Among them,sudden hearing loss is a common sign of an AICA infarct –12. The Huang et al. described seven patients with sudden bilateral hearing loss caused by vertebrobasilar occlusive disease . Toyoda There are several reported cases of CVT affecting the eighth cranial nerve. CVT presenting as multiple lower cranial nerve palsies including eighth nerve was reported . Kim et Cortical deafness is a rare condition that occurs with bilateral temporal lobe lesions  or with Cortical deafness can follow bilateral hypertensive putaminal hemorrhage –31. BilaAuditory agnosia refers to impaired perception restricted to certain classes of sounds. Word deafness, the most striking type of auditory agnosia, is the incapacity to recognize speech sounds . Pure woAcute vestibular syndrome due to cerebellar hemorrhage is similar to those of acute cerebellur infarction. Surgical evacuation of a subpial hematoma partially improved hearing loss and tinnitus that comprised the initial symptoms of a cerebellar hemorrhage . CrossedCentral pontine hemorrhage was associated with auditory dysfunction in four patients . Damage Bilateral ICH, cerebellar, and brain stem hemorrhage are relatively frequent in elderly patients, and the degree and type of auditory dysfunction might considerably vary from a complete bilateral hearing loss to a partial or unilateral hearing disturbance and even auditory hallucinations. Thus, the incidence of auditory dysfunction due to bilateral ICH, cerebellar, and brain stem hemorrhage might be underestimated or misdiagnosed as presbycusis. Symptoms can be subtle and/or transient and thus difficult to diagnose. Thus, auditory function should be carefully assessed in elderly patients during the acute and chronic phases.Distal AICA aneurysms can cause auditory disturbances and cause SAH and complete ipsilateral deafness. The reported incidence of aneurysms of AICA is about 0.1% of all cerebral aneurysms; only 56 patients with such aneurysms have been described in the literature , 39. AmoCentral deafness has been linked historically to bihemispheric involvement of the temporal lobe, with more recent findings suggesting that compromise of other cortical and subcortical structures and brain stem can also result in this disorder . IndividSubarachnoid hemorrhage affecting both inferior colliculi can cause central deafness . The bilA patient with SAH who developed sudden bilateral deafness  also expTabuchi et al. discovered a reversible cortical auditory dysfunction that was caused purely by bilateral cerebral vasospasm after aneurismal SAH . Acute bSurgical excision of an AVM within the internal auditory canal (IAC) that caused sensorineural hearing loss did not affect complete deafness in one patient . A cerebDural arteriovenous fistulae usually between the external carotid artery and dural venous structures are a rare entity accounting for 10%–15% of all cranial AVMs. Spontaneous closure (regression) of a DAVF in the middle ear has been associated with acute hearing loss . IntraosIntrapetrosal cavernous angioma involving the facial nerve is a well-known ontological entity ; howeverA venous angioma arising within the IAC and expanding to the brainstem has caused a unilateral profound sensorineural hearing loss . HearingCapillary telangiectasia is often found incidentally on MRI or at autopsy and may be associated with minor neurologic symptoms, but there has been little evidence about whether such lesions are responsible for these symptoms . SensoriSudden deafness defined as a sudden loss of hearing due to unknown causes is often treated with vasodilators and drugs to improve blood flow. However, cerebrovascular malformations must be ruled out by MRI because their presence would contraindicate the administration of vasodilators and drugs to improve blood flow.Cortical deafness due to bilateral temporal subcortical hemorrhages associated with moyamoya disease (MMD) gradually improved and completely disappeared within two months . Damage Diffuse ischemic damage to the subcortical white matter including areas of the temporal lobes as well as multiple and focal cortical infarctions in both cerebral hemispheres determined by MRI in a 3-year-old boy with MMD and central deafness suggested thalamocortical dysfunction and disconnection between higher brainstem and cortical auditory areas . Sudden Moyamoya disease is principally a bilateral progressive cerebrovascular disorder that can plausibly cause cortical and/or central deafness, either via ischemic or hemorrhagic lesions. The possibility of MMD should be considered especially in children, young adults, and East Asians with sudden hearing loss.Superficial siderosis is associated with sensorineural hearing loss although it is generally considered to be rare and presumably underdiagnosed , 74. SS Cerebellar Bergmann cells, microglia, and superficial astrocytes take up subarachnoid blood and then heme oxygenase intrathecally breaks down heme to free iron, which is cytotoxic as it produces reactive oxygen species. Both iron and heme products cause neurodegenerative injury . Damage The diagnostic modality of choice for SS is MRI , which cTreatment options for SS have not been established. Surgical exclusion of a bleeding source is one therapeutic approach to stop SS progression, assuming that the bleeding source is identified. With respect to hydrocephalus, a CSF shunt is indicated when consciousness is disturbed . ProposeSS has been associated with cerebral amyloid angiopathy (CAA), which is an important cause of intracerebral hemorrhage in elderly patients , 91.Compared to the well-described classical type of SS, which mainly affects brain stem and posterior fossa, SS in CAA showed a preference for the cerebral convexity and only exceptionally occurred in the infratentorial compartment . SS mighRisk of hearing loss is increased among elderly patients with stroke compared with the general population . Stroke Auditory dysfunction is a common clinical symptom that can profoundly affect the quality of life of affected individuals. As the aging population increases, more patients will present with CVD accompanied by auditory disturbances. Henceforth, CVD will probably become an important contributor to the differential diagnosis of auditory dysfunction. General physicians need to understand this likelihood.


Aim of the present study was to evaluate prognostic factors, in particular standard laboratory parameters, for better outcome after idiopathic sudden sensorineural hearing loss (SSNHL).Using a retrospective review, 173 patients were included presenting between 2006 and 2009 with unilateral SSNHL, ≥30 dB bone conduction in three succeeding frequencies between 0.125 to 8 kHz in pure tone audiometry (PTA), and a time interval between first symptoms and diagnostics ≤ 4 weeks. Hearing gain of <10 dB versus ≥10 dB in the affected ear in 6PTA values was the primary outcome criterion. Univariate and multivariate statistical tests were used to analyze predictors for better outcome.p <0.0001); start of inpatient treatment <4 days after onset (p = 0.018); first SSNHL ; initial hearing loss ≥ 60 dB (p < 0.0001); an initial quick value lower than the reference values (p = 0.040); and a pretherapeutic hyperfibrinogenemia (p = 0.007) were significantly correlated to better outcome (≥10 dB absolute hearing gain). Multivariate analysis revealed that first SSNHL (p = 0.004), start of treatment <4 days after onset (p = 0.015), initial hearing loss ≥ 60 dB (p = 0.001), and hyperfibrinogenemia (p = 0.032) were independent prognostic factors for better hearing recovery.The initial hearing loss was 50.6 ± 27.2 dB. The absolute hearing gain was 15.6 ± 20.1 dB. Eighty-one patients (47%) had a final hearing gain of ≥10 dB. Low-frequency hearing loss (Better hearing gain in patients with hyperfibrinogenemia might be explained by the rheological properties of the applied therapy and supports the hypothesis that SSNHL is caused in part by vascular factors. Idiopathic sudden sensorineural hearing loss [SSNHL) is defined as unexplained unilateral sensorineural hearing loss of 30 dB HL or greater over 3 continuous frequencies with onset over a period of less than 72 hours and with no marked vestibular symptoms . SSNHL hAlthough especially vascular factors are constantly discussed to be related to the etiology of SSNHL, it is surprising that so far the prognostic impact of the entire range of routine laboratory values has not been evaluated systematically. Therefore, the present study investigated whether patients with SSNHL and its comorbidity also influence routine pretherapeutic laboratory values and whether these values have prognostic influence on hearing recovery after a standardized combined glucocorticoid and rheological therapeutic regime.A standardized retrospective analysis was performed in the Department of Otorhinolaryngology of the University Hospital Jena in Germany. The study protocol was approved by the institutional ethics committee of the Friedrich-Schiller University, Jena, Germany. All adult patients who were treated for unilateral idiopathic sudden sensorineural hearing loss between 2006 and 2009 were included in the database for this study. Prerequisite was a differential diagnostic evaluation excluding a specific etiology  explaining the sudden hearing loss. All patients received a brainstem electrical response audiometry (BERA). If the BERA was pathologic, a magnetic resonance imaging (MRI) of the head and cerebellopontine angle was performed. Further inclusion criterion was that at least 2 pure-tone audiograms were available: the first at presentation prior to initiation of therapy, and a second after therapy. If more than one follow-up audiogram was available, the last audiogram was taken for analysis. Follow-up audiometry was stopped when no further hearing improvement was seen. Exclusion criteria were: Hearing loss <30 dB bone conduction in three succeeding frequencies between 0.125 to 8 kHz as revealed by pure tone audiometry; time interval between first symptoms and diagnostics > 4 weeks; acute bilateral hearing loss; combination with acute vestibular hypofunction ; history of chronic ear disease . A search of the patients’ electronic charts was performed, and the following variables were obtained: age, sex, smoking behavior (yes/no), Charlson comorbidity index [All patients were hospitalized. Treatment followed the German guideline for sudden idiopathic sensorineural hearing loss as 1-week combination of glucocorticoid and rheological therapy with pentoxifyllin ,7. MainlAudiometric evaluation included air conduction and bone conduction thresholds on the affected and the contralateral side revealed by pure tone audiometry. The pure tone average (PTA) was calculated from the results of bone conduction at 0.25, 0.5, 1, 2, 4, and 6 kHz (6PTA). The severity of the hearing loss was described exactly according to Cvorovic et al. [Hearing gain was expressed as absolute hearing gain  from initial PTA minus dB values from final PTA. If a negative value was calculated, the hearing gain was set to zero. For calculation of the relative hearing gain, the absolute gain ∆PTA was divided by the initial PTA. In order to calculate the relative hearing gain in relation to the contralateral ear, ∆PTA was divided by the initial PTA minus PTA on the contralateral side .The assessment of pretreatment laboratory values included: Hematologic profile with red blood cells, hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cells, and platelets; glucose; electrolytes covered sodium, potassium, calcium, urea and creatinine values; the inflammation parameter C-reactive protein (CRP); lipid metabolism with cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), LDL/HDL index, and finally the coagulation parameters Quick value, activated partial thromboplastin time (aPTT), and fibrinogen. The blood samples were taken before start of treatment to rule out an influence of the treatment on the laboratory values. The normal reference values for all laboratory parameters are given in Table p < 0.05 were included in a binary (<10 dB versus ≥10 dB hearing gain) logistic regression analysis. Nominal p values of two-tailed tests are reported. The significance level was set at p < 0.05.If not indicated otherwise, data are presented with mean values ± standard deviation (SD). All statistical analyses were performed using IBM SPSS, version 20.0. Primary outcome criterion was absolute hearing gain (∆6PTA) dichotomized into two groups of patients (<10 dB versus ≥10 dB). The chi-square test was used to compare subgroups for ordinal parameters . Prognostic factors associated with higher frequency of hearing gain ≥10 dB with a probability value of One hundred and seventy-three (173) patients were included into the study and constituted the database for this study. Patients’ characteristics and details on SSNHL are given in Table Due to the 6PTA, the initial hearing loss was 50.6 ± 27.2 dB. The contralateral ear had a 6PTA of 21.2 ± 15.7 dB. The contralateral ear had a 6PTA of <20 dB, i.e. a normal hearing result, in 56% of the cases. Three patients were deaf on the contralateral ear. The interval between onset of hearing loss and begin of in-patient therapy was 5.7 ± 6.1 days. The average follow-up period, i.e. the time from first to last audiogram without further hearing improvement, was 51.0 ± 44.9 days (range: 10 – 280 days).The absolute hearing gain between the initial audiogram and the final audiogram was 15.6 ± 20.1 dB. The mean relative hearing gain was 27.6 ± 23.7%. The mean relative hearing gain in relation to the contralateral side was 49.4 ± 45.6%. Eighty-one patients (47%) had a final hearing gain of ≥10 dB. Twenty-nine patients (17%) had a relative hearing gain of ≥50%. Seventy-two patients (42%) had a relative hearing gain in relation to the contralateral side of ≥50%.An overview about the serology results at time of diagnosis is presented in Table p <0.0001). Start of inpatient treatment <4 days after onset was better than a delayed treatment ≥4 days after onset (p = 0.018). First SSNHL had a better outcome than recurrent SSNHL (p = 0.001), and initial hearing loss ≥ 60 dB had a better outcome than an initial loss < 60 dB (p < 0.0001). Two laboratory parameters had influence on the outcome: a quick value lower than the reference values (p = 0.040); and a hyperfibrinogenemia (p = 0.007).The univariate analysis on prognostic factors for better outcome is summarized in Table p = 0.004), start of inpatient treatment <4 days after onset (p = 0.015), initial hearing loss ≥ 60 dB (p = 0.001), and hyperfibrinogenemia (p = 0.032) were independent prognostic factors for better hearing gain  and a hyperfibrinogenemia (fibrinogen > 3 g/l), were associated with better outcome.In comparison to other studies, the observed median initial hearing loss was high with 42.5 dB. Absolute median hearing gain after combined prednisolone plus pentoxiphylline therapy was low with 9 dB. The relative hearing was 49%. Including also only SSNHL of ≥30 dB and using carbogen inhalation and prednisone orally, Cvorovic et al. recently reported for 541 patients a 15.1 dB absolute hearing gain and a relative hearing gain of 47%, i.e. in the range of the present study -12. We hThe two clinical factors: start of inpatient treatment <4 days after onset and first SSNHL were associated with better outcome. Furthermore, two audiological factors: low-frequency hearing loss and initial hearing loss ≥60 dB were related to better outcome. These results are partly in accordance to previous studies. It has been shown that hearing recovery is greatest when corticosteroid treatment is started within the first 1-2 weeks after onset of SSNHL ,10. ManyIf at all of interest, laboratory investigations were mainly analyzed on their role as risk factors for SSNHL. For instance, hypercholesterolemia and hyperglycemia were observed more frequently in SSNHL patients than in control populations ,17. ConsUnivariate statistical analysis exposed that a decreased Quick test value (<70%) at time of diagnosis was related to better hearing gain. The Quick prothrombin time test still is the basis for monitoring anticoagulant therapy in many countries worldwide . UnfortuEven more striking was the prognostic effect of fibrinogen at time of diagnosis on the hearing gain as this parameter remained also significantly relevant in the multivariate analysis. A quarter of patients had elevated fibrinogen values at time of SSNHL diagnosis. It has been widely accepted that hyperfibrinogenemia is an independent risk factor for cardiovascular diseases . FibrinoIf fibrinogen is qualified to be a biomarker for treatment selection has to be proven by further prospective trials. In deployment of the assumption that SSNHL is an umbrella term for a disease with several causative factors, such biomarkers are needed at least to select patients with vascular origin of SSNHL as only these patients can profit optimally from vascular therapy regimes.The presented cohort study on 173 patients with SSNHL revealed that beside clinical and audiological factors also the laboratory markers: decreased Quick test value and a hyperfibrinogenemia were positive prognostic markers for better outcome using a treatment regime mainly intending to improve the cochlear microcirculation. Therefore, hyperfibrinogenemia is not only a risk factor for SSNHL but also a positive prognostic marker of outcome when using a rheological regime to treat SSNHL. Especially fibrinogen seems to be an interesting candidate as biomarker for better patient selection for treatment regimens of SSNHL focusing on the refinement of cochlear microcirculation.3 cells per liter; Gpt/l: 109 cells per liter; BERA: Brainstem electrical response audiometry; MRI: Magnetic resonance imaging.SSNHL: Sudden sensorineural hearing loss; PTA: Pure tone audiometry; MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; CRP: C-reactive protein; LDL: Low density lipoprotein; HDL: High density lipoprotein; aPTT: Activated partial thromboplastin time; SD: Standard deviation; Min: Minimum; Max: Maximum; PPT: Partial thromboplastin time; Tpt/l: 10There is no competing interest. The authors confirm that they do not have any financial relationship concerning this research.The authors indicate that they have no a financial relationship with any organization or company mentioned in the manuscript. The research was not sponsored by a third party.OGL and CW had the idea for the study. OGL and MK drafted the manuscript. JW performed the data collection. OGL and JW performed the statistical analysis. OGL designed tables and figures. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6815/14/6/prepub


This novel test was developed in a population of 30 normal hearing young adults and 101 adults with varying degrees of hearing impairment and handicap, including normal hearing. The test had 84% sensitivity and 76% specificity compared to conventional pure-tone screening and 83% sensitivity and 86% specificity to detect disabling hearing impairment. The test outcomes were in line with the degree of self-perceived hearing handicap. The results found here paralleled those reported in the literature for the SUN test and for conventional speech-in-noise measures. This study showed that the proposed test might be a viable method to identify individuals with hearing problems to be referred to further audiological assessment and intervention.This paper describes the development of a speech-in-noise test for hearing screening and surveillance in Brazilian Portuguese based on the evaluation of suprathreshold acuity performances. The SUN test (Speech Understanding in Noise) consists of a list of intervocalic consonants in noise presented in a multiple-choice paradigm by means of a touch screen. The test provides one out of three possible results: “a hearing check is recommended” ( Age-related hearing loss and noise-induced hearing loss are common health problems in adults and older adults. The World Health Organization , 2 recenRecently, some initiatives and a number of studies have promoted the definition and implementation of effective programs of hearing screening, prevention, surveillance, and care for adults and older adults, particularly in Europe and in the United States , 14–16,  afa, aja,…) that are presented in a three-alternative forced choice (3AFC) paradigm by means of a touch sensitive screen. Stimuli are delivered monaurally with unmodulated background speech-shaped noise, which is adequately adapted in level for each stimulus. The test score is computed as the number of VCVs correctly identified and, based on this score, the test outcome is given in a self-explanatory way: either “no hearing difficulties” (green light), “a hearing check would be advisable” (yellow light), or “a hearing check is recommended” (red light). Previous studies have shown that this test is a fast, reliable, easy to use tool that proved to be viable to identify early hearing difficulties in clinical as well as nonclinical settings, including unchecked ambient noise (up to 65 dBA) [Unfortunately, there is still lack of large scale hearing screening and surveillance programs in many developed and developing countries, including Brazil, even though some recent studies have demonstrated that the implementation of adult hearing screening might be a cost-effective way to reduce unmet need for hearing aids and improve quality of life among older adults , 27. The 65 dBA) , 33.The aim of this study was to develop a test of suprathreshold acuity in noise, the SUN test, in the Brazilian Portuguese language. This was done through three main steps, that is, (1) the development of the “building blocks” of the test ; (2) the definition of the test sequence ; and (3) the optimization of the test outcomes so that the agreement between the test outcomes and hearing impairment was the highest. The development procedure and the most relevant results, as well as the overall findings in a population of 101 subjects, will be described in the following sections.aba, aca, aça, acha, ada, afa, aga, aja, ala, alha, apa, ara, arra, ata, ava, and aza). Of the 19 consonants in the Brazilian alphabet, three  were not used because the phonemes ama, ana, andηa a have a nasal sound which is reflected in the nasalization of the first vowel [ ata, alha, and ava) [Sixteen VCVs were recorded for the Brazilian Portuguese language  .The definition of the test sequence entailed the optimization of the list of stimuli and the associated levels of background noise. The rationale was to set the level of noise for each VCV so that the intelligibility of stimuli was approximately the same across the test list . To equTo estimate the RTs, the psychometric curves of the 16 VCVs were measured for a wide range of SNRs, from chance performance to 100% recognition, that is, from −10 dB to +6 dB SNR, in 2 dB steps. In this experiment, the output level of VCVs was fixed at 60 dB HL  and theParticipants were 30 young adults , otologically normal as in the ISO 7029:2000 Standard .  Table T1 and T2) between the three categories of test results  so that the agreement with the reference pure-tone benchmarks for pure-tone screening was the highest , that is, ears that would pass a pure-tone screening at a level of 40 dB HL , that is, ears that might either fail or pass a pure-tone screening at 40 dB HL, depending on whether the frequency 4 kHz is included or not in the pass/refer criterion, respectively , 44. Class III (pure-tone hearing thresholds > 40 dB HL at 1 or 2 kHz), that is, ears that would fail a pure-tone screening, irrespective of the criterion for high-frequency hearing thresholds –45.On a binaural basis, the World Health Organization (WHO) [red light) in at least one ear, as defined in [The optimization of the test outcomes was performed by setting two cut-off scores . On a mon (WHO)  criteriofined in . The senMoreover, to evaluate the agreement between the test outcomes and self-perceived hearing handicap, subjects were also asked to fill in the HHIE-S (hearing handicap for the elderly screening) questionnaire , in the Participants were 101 native-Brazilian adults and older adults  recruited in order to have a wide range of pure-tone thresholds represented across the study sample, from normal hearing to severe hearing loss. The maxima, mean values, and standard deviation (s.d.) of pure-tone thresholds measured in this group of subjects are reported in A PC connected to the RCA analogue input of a clinical audiometer (Auditec PAC-200 with TDH-39 headphones) was used to deliver the stimuli. The speech output was calibrated by using a 1 kHz tone as in the “equal speech level” requirement in the ISO 8253-1:1996 Standard for speech audiometry . A touch RTs was observed across the set, from values lower than 10 dB  to about +2 dB , further supporting the need to equalize the intelligibility of test stimuli. Following the analysis of psychometric curves as well as the statistical distribution of results in this group, the presentation SNR was set at +4 dB for the stimulus aba, at 0 dB for stimuli alha, apa, ata, and ava, at −2 dB for ada, aga, ala, and arra, at −4 dB for aca, afa, aja, and ara, and at −6 dB for aça, acha, and aza. The average psychometric curves of the five subsets of VCVs are shown in As a result, the SUN test sequence was obtained. It consisted in the set of 16 VCVs, presented in five different subsets at the five presentation SNRs listed above, from the highest (+4 dB) to the lowest SNR (−6 dB). In addition, to help subject familiarize with the test procedure, a short list of VCVs is also presented (but not scored) before the actual test list at a comfortable presentation SNR of +8 dB .T1 (T2 (T1 (black marks) and the percentage of ears in Class II or Class III  with score < T1 (white marks) for the different values of T1. The highest agreement between test results and pure-tone screening results was observed with T1 = 11, which provided a sensitivity of 84% and specificity of 76% to identify ears that might fail a pure-tone screening (Classes II and III). T2 (white marks) and the percentage of ears in Class II with T2 < score < T1 (black marks) as a function of T2, with T1 set at 11. Accordingly, the cut-off score T2 was set at 7 as this provided about 69.6% and 56% correct subclassification between Class II and Class III and a sensitivity of 62% and specificity of 92% to identify ears in Class III. On a binaural basis, the sensitivity and specificity of the SUN test to identify people with disabling hearing impairment, as defined by the WHO criterion [T1  and T2 T1 . green category and only a minor percentage  were classified as red. Vice versa, of ears in Class III, an overall percentage of 88.5% were classified as yellow (26.9%) or red (61.6%). As to ears in Class II , the distribution of results was as follows: 19.3% green, 45.2% yellow, and 35.5% red. This outcome might be explained by the fact that puretone thresholds at 4 kHz are typically not per se adequate predictors of speech reception threshold, unless they are combined with thresholds at lower frequencies, at 2 kHz or lower [or lower . As a maor lower  had repoor lower –53. Acco red category, which may be explained by possible early hearing difficulties that are not significant yet and are not detected by hearing threshold testing. Vice versa, 11.5% of ears in Class III were in the green category, possibly because of gradual adaptation to speech-in-noise recognition in people with hearing difficulties and, also, because of the 33% guess rate in the 3AFC task which may lead to higher-than-expected scores. Noticeably, the results found here are in line with findings reported in the literature for other speech-in-noise tests  that are typically used for hearing assessment in the clinic [It might be observed that a mismatch between results of tests of speech recognition in noise and tests of pure-tone detection in quiet is largely justified, particularly in adults and older adults , 54, 55.e clinic , 56–59, e clinic , 59.N = 80,  green in their better ear (right-hand bar); of these, 56.3% had green in both ears, whereas 18.7% and 3.8% had yellow or red in the other ear, respectively. In this group, a minor percentage of subjects  obtained red in both ears, whereas about 16% of subjects (center bar) obtained yellow either in one ear (6.3%) or in two ears (10%). These data suggest that, in individuals with no self-perceived hearing handicap, the better ear plays a major role as most subjects (78.8%) had very good outcomes (green light) in at least one ear. As a matter of fact, good hearing functioning, at least in one ear, is likely to help them to cope with daily  listening situations, thus lowering the degree of self-perceived hearing handicap. In the group with mild-to-moderate handicap  and the percentage of those who had green in at least one ear decreased from 78.8% to 52.9% (right-hand bar), with a parallel decrease in the percentage of those who had green in both ears, from 56.3% (45/80) to 5.9% (1/17). The percentage of subjects who obtained yellow in their better ear was 29.5% (17.7% had red in one ear and 11.8% had yellow in the other ear). The distribution of test results in this group indicates that a higher proportion of subjects with mild-to-moderate handicap are likely to have poorer speech recognition in noise, as measured by the SUN test, in both ears (left and center bars: 47.1%). In the small group of subjects who reported significant handicap  obtained yellow in one ear and red in the other ear, and one  had yellow in one ear and green in the other ear. In summary, the percentage of subjects who obtained red outcomes in both ears markedly increased with increasing self-perceived handicap (from 5% to 17.6% and 50%); vice versa, the percentage of subjects who obtained green in at least one ear markedly decreased with increasing handicap (from 78.8% to 52.9% and 25%—this last percentage corresponding to one out of four subjects). Despite the very small sample size, results in  N = 17, , the perp N = 4, , two  test, a user-operated speech-in-noise test for hearing screening and surveillance, already available in the English, Italian, German, and French languages. This was done by (1) developing its building blocks (speech stimuli and noise); (2) defining the list of stimuli and the associated levels of background noise; and (3) optimizing the test outcomes in a population of adults and older adults with varying degrees of hearing impairment and hearing handicap, including normal hearing. The results obtained with the proposed test fully paralleled those obtained in previous studies in the other language versions –35 and wIt is recognized that this is a preliminary investigation on a relatively small study sample and that more studies and research need to be conducted on this topic, on a bigger group of subjects. For example, it would be interesting to investigate the association between the different degrees and types of hearing loss (including conductive hearing loss) and the test results on a large representative sample or, also, to measure the correlation with conventional speech-in-noise tests or other clinical assessment measures, including questionnaires different than the HHIE-S. Moreover, additional research is still needed to further evaluate the performance of the proposed test and to fully assess its feasibility as a screening tool, also taking into account the peculiar characteristics of the different populations and countries (either developed or developing). Future studies need to be performed in larger samples of subjects to fully assess the viability of the test for the general population; particularly, it would be important to promote large screening campaigns in Brazil by using the test developed here, also searching for specific solutions to provide accessible and efficient services to help people in remote or underserved areas. The importance of these studies would cross the borders of this specific country as valuable, practical indications would be set that might be useful to the scientific and clinical community at large for the future definition and implementation of successful early detection and intervention services for adults.


Patients with chronic renal failure may develop sensorineural hearing loss. Cochlear implantation has rarely done after organ transplantation. Herein, we report on a 33-year-old kidney transplantation recipient who underwent cochlear implantation for her progressive sensorineural hearing loss in Khalili Hospital Cochlear Implant Center, affiliated to Shiraz University of Medical Sciences. The implantation was done successfully with no complications. Cochlear implantation may be an appropriate therapeutic option for sensorineural hearing loss caused by chronic renal failure. Cochlear implantation has revolutionized the treatment of profound hearing loss. This procedure is relatively safe and it becomes the treatment of choice for both children and adults. Most of the patients reported improved quality of life, speech recognition and communication. Recently, patients with chronic diseases like chronic renal failure with hearing impairment, have also considered for cochlear implantation. Chronic kidney disease may result in high frequency sensorineural hearing loss (SNHL). The probable causes include uremia , congeniA 15-year-old Iranian girl developed chronic renal failure due to post-streptococal glomerulonephritis. Although she was on maintenance hemodialysis for seven months, she developed end-stage renal disease and underwent living non-related kidney transplant in 1992. One month later, she was treated for pleural effusion and pneumonia and received the ototoxic drug, amikacin for several weeks and developed bilateral progressive SNHL confirmed by pure tone audiometry and auditory brainstem response audiometry. She was then referred to our center and received a powerful hearing aid which was not successful to increase her speech awareness threshold. Therefore, she was considered for cochlear implantation. Before performing the procedure, multidetector high resolution computed tomography of temporal bone revealed normal anatomy of the temporal bone including mastoid, middle ear, inner ear and internal auditory canal with no evidence of mastoiditis or pathologic findings. The cochlear turns in both sides appeared normal with normal semicircular canals. After evaluation, the right ear was selected for the implantation. An advance bionics prosthesis (HiRes 90 K) was used and the active electrode was inserted fully in an appropriate position in the year 2011. After the operation, the patient was hospitalized in the ENT ward for 24 hours and discharged in good condition with antibiotics. She continued her routine immunosuppressant drugs till now without any signs of wound infection or other complications.Hearing aids are the principle means of auditory rehabilitation for patients with SNHL. Hearing aids also have important roles in the management of conductive hearing loss. Implantable hearing aid has several advantages for patients with hearing loss such as increasing gain and dynamic range, reducing feedback, reducing maintenance, improving appearance and being free to occlude one of the ear canals . CochleaHearing loss is one of the most common debilitating conditions in patients who begin renal replacement therapy. The incidence of hearing loss in children is 8.6% . The effFor cochlear implantation, immunosuppressive drugs can be continued preoperatively without dose adjustments , 5, 9. FWe concluded that cochlear implant may help properly selected renal transplant recipients with SNHL.


The MPN+ domain protein BRCC36 associates with pseudo-DUB MPN− proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity. To understand the basis for BRCC36 regulation, we have solved the structure of an active BRCC36-KIAA0157 heterodimer and an inactive BRCC36 homodimer. Structural and functional characterizations show how BRCC36 is switched to an active conformation by contacts with KIAA0157. Higher order association of BRCC36 and KIAA0157 into a dimer of heterodimers (super dimers) was required for DUB activity and interaction with targeting proteins SHMT2 and RAP80. These data provide the first explanation of how an inactive pseudo DUB allosterically activates a cognate DUB partner, and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity, subcellular localization, and biological function.BRCC36 is a Zn Ubiquitin mediated signal transduction depends on a balance between tightly regulated ubiquitin ligase and deubiquitinating enzyme (DUB) activities . Additio− pseudo DUB proteins KIAA0157 or Abraxas , while others show specificity for hydrolysis of the ubiquitin like protein Nedd8 (e.g. CSN5 cleaving Nedd8 from Cullins), and finally, several are highly selective for particular chain linkages (e.g. AMSH and BRCC36). The archetype family member AMSH-LP cleaves K63 linked ubiquitin chains and represents the only member for which a structural basis for chain recognition has been determined  for purposes that are not well understood. MPN− domains are recognizable by the absence of essential Zn2+-coordinating residues that are required for catalytic function. Established MPN+–MPN− domain pairings include CSN5 and CSN6 in the COP9 signalosome and RPN11 and RPN8 in the proteasome. While the mode of MPN+–MPN− interaction is conserved between these two systems  to each holoenzyme. Moreover, BRCC36 interactions with KIAA0157 or Abraxas are necessary for association with the holoenzyme specific adapter subunits, SHMT2 and RAP80, which target their respective DUB complex to sites of K63-Ub synthesis.The importance of the MPNIn this study we sought to address, (1) the general architecture of active BRCC36 DUB complexes, and (2) how subunit assembly affects enzyme function. Towards this end, we have characterized the binding architecture of BRISC and ARISC complexes and solved the X-ray crystal structures of the minimally active BRCC36–KIAA0157 heterodimer subcomplex, and an inactive BRCC36-BRCC36 homodimer complex. These studies revealed that formation of an unanticipated higher order super dimer is essential for DUB activity and for protein interactions necessary for the subcellular localization and biological function of each BRCC36 complex.A. thaliana  complexes at preparative levels, either as full length proteins or as trimmed deletion mutants optimized for crystallization To probe the assembly architecture of BRISC and ARISC complexes for downstream structure and function analyses, we surveyed the expression of complete holoenzyme complexes and subcomplexes in insect cells from a variety of metazoan orthologues, including H. sapiens, X. laevis, G. gallus, D. rerio, C. floridanus and iana see , we exprCfBRCC36 alone displayed no detectable cleavage activity against a K63-linked diUb fluorigenic substrate in vitro . HoweverC. floridanus BRISC complex  of the  complex , reveale complex  and for  complex . To iden complex . We were complex . DrBRC36 complex . These r complex  were con complex .− proteins and BRCC36, between BRCC45 and MERIT40 and between BRCC45 and BRCC36/KIAA0157, suggestive of direct binding interactions between subunits. They also indicated that both BRISC and ARISC adopt a tight higher order dimer configuration through the core BRCC36–KIAA0157 and BRCC36–Abraxas subcomplexes.Collectively, these data demonstrated several obligate protein folding relationships between MPNA. thaliana) to determine the structural basis for (1) how KIAA0157 supports the catalytic function of BRCC36, and (2) how super dimerization of the minimally active BRCC36–KIAA0157 heterodimer is mediated. Only CfBRCC36–KIAA0157 yielded initial crystals, but these diffracted poorly. Optimization of the CfKIAA0157 construct boundaries by deletion of poorly conserved C-terminal residues 290 to 471 (CfKIAA0157ΔC) yielded crystals in complex with full length CfBRCC36 (residues 1-253) that diffracted to 2.55 Å resolution.We pursued crystallization of BRCC36–KIAA0157 subcomplexes from different species . Following manual rebuilding and refinement, two highly interdigitated CfBRCC36–KIAA0157ΔC heterodimers were apparent in the asymmetric unit, arranged in the suspected super dimer configuration . The fin2. The MPN domains of each associated in a pseudo two-fold manner centered on helices α1 (+–MPN− superstructure (buried SA = 2902 Å2). Non-canonical helices α4 and α5 of CfBRCC36 interacted with helices α4 and α5 of CfKIAA0157 in the form of a coiled coil helical bundle (CCHB) , followed by two non-canonical helices α4 and α5 within the predicted coiled coil regions . CfBRCC3lices α1 , resultie (CCHB) . The hele (CCHB) .The contact surfaces between CfBRCC36 and CfKIAA0157 protomers were highly hydrophobic in nature, which may account for our inability to produce CfKIAA0157 alone and the tendency of CfBRCC36 to form aggregates when expressed in isolation . Three l+ domain monomer  and RPN11–RPN8 (buried SA = 4054 Å2 for MPN domains only)  .+ mutation Leu27Arg alone or in combination with Leu23Arg in BRCC36 disrupted binding to KIAA0157, and in addition to MERIT40, BRCC45, SHMT2, RAP80, BRCA1 and to a lesser extent Abraxas  disrupted interaction with BRCC36 and RAP80, leaving interactions with BRCC45 and MERIT40 largely intact. A second MPN− domain mutation, Phe20Ala, modestly reduced binding to BRCC36, and also to MERIT40, BRCC45 and RAP80  mutant, or the CCHB single  or triple  mutant. Similarly, BRCC36 MPN+ domain double mutant (Leu23Arg + Leu27Arg) was impaired for IR–induced foci formation as was Abraxas MPN− mutant (Gly16Arg)  infection in KIAA0157rylation , consistrylation . STAT1 ply16Arg) . Since rly16Arg) , the obsly16Arg) . Consistly16Arg)  did not ly16Arg) . Togethe2+ ion by the triad of His94, His96 and Asp107 side chains, the position of the transition state stabilizing Ser104 side chain, and water-coordinating catalytic Glu30 side chain. The active-like orientation of these key residues was supported by productive conformations of underlying secondary structure elements including strand β4 (denoted as the H-strand for positioning His94 and His96), helix α3 (denoted as the D-helix for positioning Asp107), the β4-α3 loop (denoted as the S-loop for positioning Ser104), and the α1- β2 loop (denoted E-loop for positioning Glu30).Consistent with our observation of robust catalytic function in vitro, the active site residues in BRCC36 when complexed to KIAA0157 resided in an active-like conformation shared by AMSH-LP, CSN5 and RPN11 (2) and, together with the short β4-α3 linker, the proximal ubiquitin centered on the lysine 63 linkage site (buried SA= 630 Å2) (2) with the proximal ubiquitin protomer remote from the K63 linkage site  . In BRCC 630 Å2) . In AMSHage site . In BRCCage site .To confirm our inference of the extended substrate-binding surface on BRCC36, we mutated conserved residues on the projected distal ubiquitin (Met117) and proximal (Ile99) ubiquitin contact sites and measured their effects on catalytic function . Both Me2+ ion (2+ ion (2+ coordinating residues (His94 and His96 in CfBRCC36) with Cys101 and Arg103 in CfKIAA0157. We note that the third triad position is maintained as Asp (position 115). Additional substitutions that would contribute to a lack of catalytic function include the substitution of the water-coordinating Glu side chain with Asn (residue 28) and a subtle substitution of the catalytic Ser residue with Thr (residue 112). Demonstrating that in addition to a catalytic role, that the Zn2+ ion in BRCC36 also plays a major scaffolding role, a BRCC36QSQ mutant compromised for Zn2+ ion binding  displayed by the CfBRCC36-KIAA0157ΔC heterodimer , notable differences in the active site region of DrBRCC36 were apparent that might account for its lack of DUB activity in comparison to CfBRCC36 complexed to KIAA0157. In particular, the E-loop of the DrBRCC36 inactive structure was partially disordered and shifted with respect to the CfBRCC36 active structure, giving rise to a 4-5 Å displacement of the catalytic glutamate  (+ X-ray structures that sample great variations of sequence identity (as low as 19%), species of origin  and substrate specificity (ubiquitin versus Nedd8 cleaving enzymes) (While the MPNrBRCC36) . Suggestenzymes) .− domain of CfKIAA0157  was shifted relative to the corresponding position in CfBRCC36 . Both ofKIAA0157 . We refeKIAA0157 . SupportKIAA0157 . The posKIAA0157 . IntriguKIAA0157 . These o2) with surrounding heterodimers that we reasoned could be responsible for super dimerization in solution  but not K48 linked diUb , which in turn recruits a MERIT40 subunit.Our protein expression and co-purification studies on ARISC and BRISC in insect cells, native mass spectrometry analysis of HsBRISC, crystallographic and SAXS analyses on the CfBRCC36–KIAA0157 complex, mutational and (in vitro and cellular) functional studies on ARISC and BRISC, support the minimal architecture model for BRISC shown in Figure S2B, the binding of KIAA0157 to BRCC36 is required for stabilization of (1) the CCHB, (2) the E-loop of BRCC36 and optimal positioning of the catalytic glutamate side chain for catalysis, and (3) the Ins-1 loop of BRCC36 and its proper positioning for substrate binding. Stabilization of all three elements is supported through direct interactions between KIAA0157 and BRCC36 within a single heterodimer as well as through interactions across BRCC36–KIAA0157 heterodimers within a super dimer. Despite the modeled vicinity of the proximal ubiquitin moiety to the opposing BRCC36 protomer within the super dimer  may be regulated in principle, since mutations that drive a monomer state are well tolerated in our insect cell expression studies with no evidence of protein aggregation. If BRISC transitions between an inactive monomer and active dimer states, and only the dimer state can recognize the targeting elements SHMT2 and RAP80, this would provide a tight mechanism to couple enzyme activation with the recruitment to biologically relevant substrates. How might super dimerization be regulated? Others have shown that residues in the BRCC36 E-loop and in the KIAA0157 E-loop supporting element are phosphorylated in cells (Phosida database ). Phosph− subunit. This would permit selective intervention on ARISC biological function in the DNA damage response or BRISC involvement in inflammatory cytokine signaling, even though the two holoenzymes share the same catalytic subunits. Additionally, although both complexes share a common architecture, the relative contribution and strength of the component interactions within ARISC and BRISC differ to some degree, as evidenced by our mutational studies in cells. Moreover, KIAA0157 is sufficient to impart DUB activity to BRCC36, while Abraxas and BRCC45 are both necessary for minimal DUB activity in ARISC  consortium, revealed that to date, 37 substituting mutations were mapped to BRCC36 (>15000 samples sequenced) and 35 to Abraxas (>19000 samples sequenced) while only 1 mutation was mapped to KIAA0157 (>19000 samples sequenced) . The mut+–MPN− paired DUBs. We see that BRCC36 (MPN+) heterodimerizes with the MPN− pseudo DUBs KIAA0157 or Abraxas using a mode of interaction that is very different from that of the CSN5–CSN6 and RPN8–RPN11 heterodimers. This likely reflects the fact that the mechanism by which KIAA0157/Abraxas support BRCC36 will differ from how CSN6 and RPN8 support/regulate the function of CSN5 and RPN11. As approximately 10% of DUBs are predicted to be pseudo DUBs , 300 mM NaCl, 20 mM imidazole, 5% (v/v) glycerol, 0.075% (v/v) 2-mercaptoethanol, 1 mM benzamidine, 1 mM PMSF. Lysis buffer was supplemented with SigmaFast protease inhibitors (EDTA-free) at 1 tablet/100 ml (Sigma). Wash buffer A was the same as lysis buffer without PMSF and protease inhibitors. High salt wash buffer B was the same as buffer A with 500 mM NaCl. All protein concentrations were calculated using the Beer-Lambert law by measuring the absorbance at 280 nm. Theoretical extinction coefficients were calculated using the ProtParam tool at the ExPASy proteomics server (http://www.expasy.org).Restriction enzyme digests, DNA ligations, and other recombinant DNA procedures were performed using standard protocols. Mutagenesis was performed using the QuikChange site-directed mutagenesis method (Stratagene) with the KOD polymerase (Novagen). DNA constructs used for transfection were purified from See Supp_material


Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is one of several chronic treatable acquired demyelinating neuropathies.To explore the association between the degree of demyelination in CIDP, and treatment responsiveness.A retrospective chart review of CIDP subjects assessed between 1997 and 2013 was performed to compare treatment responsiveness using different sets of criteria.99 CIDP patients were included, 34 with diabetes mellitus (DM). Treatment responsiveness was higher in CIDP-DM fulfilling 1 or more EFNS/PNS criteria, , and in CIDP+DM fulfilling 2 or more criteria . Nonetheless, treatment responsiveness in CIDP+DM had the highest odds ratio . Similar results were also shown in simplified uniform study criteria, with 10% cut off values for CIDP-DM, compared to 30% for CIDP+DM.In CIDP+DM, higher degrees of demyelination are associated with treatment responsiveness, implying the need to adjust current criteria in these patients. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is one of several chronic treatable acquired demyelinating neuropathies. There are currently 15 sets of criteria using a variable combination of clinical, electrophysiological, laboratory, and biopsy features to identify CIDP . As a reThe American Academy of Neurology (AAN) research criteria are highly specific, but lack sensitivity, so manyOur aim in this study was to further explore the association between treatment response rates and the degree of demyelination in CIDP patients with and without diabetes, as measured by number of criteria fulfilled, using different sets of criteria for CIDP diagnosis, including EFNS/PNS and AAN criteria, as well as simplified uniform study criteria with different cut off values for electrophysiological parameters of 10%, 20%, and 30%.CIDP subjects attending the Neuromuscular clinic for management of their immune-mediated polyneuropathy between 1997 and 2013 were evaluated for this study. In this retrospective review we extracted demographic data, the clinical history, physical examination, laboratory test results, and electrophysiological data from previously coded charts of CIDP patients. The Research Ethics Board of the University Health Network approved the current study protocol, based on chart review and collection of de-identified data.A cohort of CIDP+DM treated patients (n = 34), and age and gender matched CIDP-DM treated patients (n = 65) from a previous study was used . The diaCIDP patients, with or without DM, were also classified as responders (n = 53) or non- responders (n = 46) based on clinical response to treatment assessed by a combination of patient and physician evaluations in the 99 patients who were treated with immunotherapies. Responders were those who stabilized after declining progressively, or improved after treatment, and non-responders either worsened or did not change after treatment based on their clinical evaluation.Subjects were evaluated for neuropathy by neurological examination, the 19-point Toronto Clinical Neuropathy Score (TCNS), vibration perception threshold (VPT), and median, ulnar, peroneal, tibial, and sural NCS,19. NCS Median, ulnar, peroneal, tibial and sural NCS were performed using surface stimulating and recording techniques according to the standards of the Canadian Society of Clinical Neurophysiology and the American Association of Neuromuscular and Electrodiagnostic Medicine. The eleFor the purpose of this study, we compared response rates in CIDP patients with and without DM, fulfilling different criteria to diagnose CIDP from 2 different sets of previously published criteria, including the AAN, and theStatistical analysis was performed using SAS version 9.2 for Windows . Clinical and electrophysiological characteristics were expressed as means ± standard deviations (SD) for continuous data, or as frequency and percent for ordinal data. Comparisons between treatment responders and non-responders were made using the student’s t-test, the Wilcoxon rank-sum test, or the χ2-test, depending on the type and distribution of the variable. Normality was tested using the Shapiro-Wilk test. The number of criteria met for each of the EFNS/PNS, AAN, and study criteria definitions of CIDP were treated as ordinal variables, and univariable logistic regression models were run using responder status as the dependent variable, and “number of criteria met” as the independent variables. We report the regression coefficients, p-values, and odds ratios for each independent variable. Additionally, receiver operating characteristic (ROC) curves and the corresponding area-under-the-curve (AUC) using Responder Status as the gold-standard measure were generated for each independent variable. The analysis was completed for the entire cohort, as well as for the diabetes and non-diabetes subgroups. Significance was set at α-level of 0.05.We examined 99 CIDP subjects, 34 with DM, and 65 without diabetes . Their dFulfilling 2 or more criteria, was associated with statistically significant higher treatment response rates in the whole cohort for all studied criteria, including EFNS/PNS, 10%, and 30% cut off study criteria, except for the 20% cut off study criteria. In CIDP-DM patients the higher treatment response rates were observed only for those fulfilling 1 or more criteria , whereas this was demonstrated in CIDP+DM patients fulfilling 2 or more criteria . Similarly, higher treatment response rates in CIDP-DM patients were associated only for those fulfilling 2 or more 10% cut off study criteria , whereas this association was demonstrated in CIDP+DM patients fulfilling 2 or more 30% cut off study criteria .CIDP patients fulfilling any of the studied criteria (excluding the 20% cut off study criteria) had higher treatment response rates, using EFNS/PNS criteria (Odds ratio (OR) = 1.83, p = 0.003), AAN criteria , 10% cut off study criteria , and 30% cut off study criteria . Although the highest OR was found in CIDP+DM patients fulfilling EFNS/PNS criteria , with treatment response rates increasing consistently from 27% to 100% in concordance with the number of EFNS criteria fulfilled, in CIDP-DM patients only a trend was observed with a lower OR . Higher treatment response rates in patients fulfilling different study criteria were different between subgroups. In CIDP-DM patients, only those fulfilling 10% cut off study criteria , and in CIDP+DM patients, only those fulfilling 30% cut off study criteria , showed Areas under receiver operator characteristics (ROC) curves for EFNS/PNS, AAN, and study criteria, ranged from 0.53 to 0.73. Those that were statistically significant included EFNS criteria, generally the highest (0.68 (p = 0.002) whole cohort, 0.65 (p = 0.04) CIDP-DM patients subgroup, and 0.73 (p = 0.02) CIDP+DM patients), 10% and 30% cut off study criteria for the whole cohort 0.63, and 0.64 (p = 0.02), 10% cut off study criteria for CIDP-DM patients, 0.66 (p = 0.02), and a trend at the 30% cut off study criteria in CIDP+DM patients subgroup 0.7 (p = 0.05). All areas under ROC curves using AAN criteria were not statistically significant .Although CIDP+DM and CIDP-DM patients have similar treatment response rates,22–24, tThe major finding of the current study, is that fulfilling a higher number of electrophysiological criteria in CIDP patients, with and without DM, is associated with higher treatment response rates. An association between treatment responsiveness and demyelination has been reported previously, and the presence of axonal features predicted lack of response. HoweverA possible explanation for the finding that only relatively high degrees of demyelination are associated with higher treatment response rates in CIDP+DM patients, might be related to underlying DSP. The coexistence of DSP was indicated by lower sural sensory nerve action potential (SNAP) amplitudes in CIDP+DM patients compared to CIDP-DM patients . The preThe current study has several limitations. First, although only statistically significant results were considered, the patient numbers are small, especially in the CIDP+DM subgroup. In addition, misclassification and selection bias are potential errors, especially in DM patients with concomitant DSP, as there are no biomarkers to make a definitive diagnosis of CIDP. The lack of reliable biomarkers is a limitation not only for the diagnosis of CIDP, but also for assessing treatment responsiveness. Although this can be usually done reliably combining information from the clinical history, disability and functional questioners, and from clinical and electrophysiological examinations, misclassification is still a potential concern. The use of modern scales for disease severity in CIDP would have improved this study, but the scales were not available when many of these patients were evaluated. There are additional neuropathies causing proximal weakness, such as diabetic radiculoplexus neuropathies, and electrophysiological and pathologic investigations have limited capabilities for distinguishing between primary demyelinating and axonal processes. SlowingIn conclusion, fulfilling CIDP criteria is associated with higher treatment response rates. However, lower degrees of demyelination predict higher treatment response rates, in those patients without DM, then in those with DM. This observation might indicate that current criteria for CIDP need to be adjusted to predict treatment response rates in DM patients. An important consideration is that some patients not fulfilling the criteria examined still responded to treatment. As numbers are small, prospective studies with higher numbers of CIDP patients are required to confirm these findings, and to further explore the differences between CIDP-DM and CIDP+DM patients regarding treatment responsiveness and other factors.S1 FileClick here for additional data file.


Whilst ADL did not impact on the relationship between depression and HR-QOL, there was a significant (p<.001) indirect effect of depression on HR-QOL via ADL, suggesting both direct and indirect (via ADL) effects of depression on HR-QOL. The magnitude of this effect was moderate (R2 = .13). People with PD who report depression also experience greater difficulty completing ADL, which impacts upon their HR-QOL. It is recommended that clinicians adopt a multidisciplinary approach to care by combining pharmacological treatments with psycho/occupational therapy, thereby alleviating the heterogeneous impact of motor and non-motor symptoms on HR-QOL in people with PD.This study examined whether activities of daily living (ADL) mediate the relationship between depression and health-related quality of life (HR-QOL) in people with Parkinson's disease (PD). A cross-sectional, correlational research design examined data from 174 participants who completed the Geriatric Depression Scale (GDS-15), Parkinson's Disease Questionnaire-39 (PDQ-39), and Unified Parkinson's Disease Rating Scale-section 2 (UPDRS-section 2 [ADL]). Multiple Regression Analysis (MRA) was used to examine the mediator model. Depression and ADL significantly ( In addition to the cardinal motor symptoms of Parkinson's disease (PD), approximately 42% of people with PD report depressive symptoms Poor motor function, body discomfort and pain are common consequences of PD, which can lead to social isolation and negatively impact HR-QOL In an examination of the relationship between motor  and non-motor  symptoms and HR-QOL in PD, Qin et al. Activities of Daily Living (ADL) are difficult for people with PD In addition to the relationship between ADL and depression, research has identified a significant relationship between ADL and HR-QOL Despite strong evidence that both depression and ADL are important determinants of HR-QOL in PD, and that depression leads to poorer ADL, no study to date has examined the impact of ADL and depression on HR-QOL. One possibility is that depression reduces ADL, which leads to poorer HR-QOL. That is, that the effect of depression on HR-QOL is mediated by ADL. Another is that both depression and ADL independently predict HR-QOL, and a final possibility is that depression has both direct and indirect effects on HR-QOL, in part via ADL.The present study examined the relationship between depression and HR-QOL in people with PD. The following hypotheses were tested: (1) depression significantly predicts HR-QOL, (2) depression significantly predicts ADL, (3) ADL significantly predicts HR-QOL, and (4) ADL significantly mediates the relationship between depression and HR-QOL.M = 65.96, SD = 9.46). All participants provided written informed consent. Edith Cowan University's Research Ethics Committee approved this study.People with idiopathic PD in Western Australia were invited to participate in the Parkinson's Centre (ParkC) research project located at Edith Cowan University. Participants were recruited through advertising, and referrals from neurologists and physicians. To be included in the study, participants must have been formally diagnosed with PD in accordance with the United Kingdom Parkinson's Disease Society Brain Bank Clinical Criteria (UKPDSBBC). Participants were excluded from the study if they scored below 24 on the Mini Mental Status examination (MMSE) The Geriatric Depression Scale-15 (GDS-15) is a self-report measure used to detect depression in older adults and contains 15 questions that require participants to answer “no” or “yes” and are summed to a total of 15 The Parkinson's Disease Questionnaire-39 (PDQ-39) contains 39 items across eight dimensions of HR-QOL  The UPDRS-section II (ADL) is the second subscale of the UPDRS, which assesses ADL among people with PD Assessment times were scheduled during the participant's ‘on’ stage, approximately one hour post-medication. Each assessment was conducted by a trained researcher and took approximately 2.5 hours.t-tests revealed no significant gender differences for depression, ADL, and HR-QOL (p>.05). Bivariate correlations determined whether age significantly correlated with depression, ADL, and HR-QOL. Older age was associated with poorer ADL and was retained as a covariate  = 82.54, p<.001. Finally, and as predicted (Hypothesis 2) depression was a significant predictor of ADL after controlling for age, accounting for an additional 7.7% of the variance in ADL, F  = 14.62, p<.001. Age and depression combined accounted for a significant 10.5% of the variance in ADL, R2 = .11, adjusted R2 = .10, F  = 10.05, p<.001.As predicted (Hypothesis 1), depression significantly correlated with HR-QOL and ADL. After controlling for the influence of age, depression remained a significant predictor of HR-QOL, accounting for an additional 23.3% of variance. Likewise, consistent with prediction (Hypothesis 3), ADL also significantly correlated with HR-QOL. Again, after controlling for age, ADL accounted for an additional and significant 19.2% of the variance in HR-QOL. The overall model of age, depression, and ADL was significant, z = 3.58 (p<.001), indicating that ADL does have a significant, indirect effect on the relationship between depression and HR-QOL. Given the above relationships, hierarchical multiple regression analysis (MRA) was used to determine whether ADL mediates the relationship between depression and HR-QOL.A Sobel test was used to test whether ADL had a significant indirect effect on the relationship between depression and HR-QOL R2 = .40, adjusted R2 = .39, F  = 57.22, p<.001. ADL was entered at Step 3 and accounted for an additional 19.2% of the variance in HR-QOL, ΔR2 = .19, F  = 80.18, p<.001. Depression accounted for a significant 39.9% of the variance of HR-QOL at Step 2. However, when ADL was entered at Step 3, the amount of unique variance accounted for by depression reduced to 23.3% although this remained significant. Therefore, partial mediation can be inferred. A final MRA tested whether this mediation effect was complete or partial. At Step 2, age and depression accounted for 40.1% of the variance in HR-QOL, significant change z test was conducted using the unstandardized beta coefficients and corresponding standard error values to determine the significance of the indirect effect of ADL z test value of 1.65 indicates no significant difference between the two path coefficients. The change in depression when ADL was entered into the model was not a significant change, indicating that ADL does not partially mediate the relationship between depression and HR-QOL, thus hypothesis (4) was rejected. However, the Sobel test indicates that there remained a significant indirect effect of ADL on the relationship between depression and HR-QOL. Based on Cohen's R2 = .13.To declare partial mediation the change in the effect of depression on HR-QOL from Steps 2 to 3 must be a z = 3.40 (p<.001) indicated that ADL had a significant indirect effect on the depression and HR-QOL relationship R2 = .43, adjusted R2 = .42, F  = 63.40, p<.001. ADL was entered at Step 3 and accounted for an additional 14.2% (decrease of 5%) of the variance in HR-QOL, ΔR2 = .14, F  = 55.65, p<.001. Depression accounted for a significant 42.5% (increase of 1.6%) of the variance in HR-QOL at Step 2. However, when ADL was entered at Step 3, the amount of unique variance accounted for by depression reduced to 27% (increase of 3.7%) although this remained significant. This result infers partial mediation.The previous analyses were repeated to examine whether shared variance between the UPDRS-section II (ADL) and the PDQ-39  had any effect on the results. With the PDQ-39  removed from the model, a significant Sobel test z test returned a value of 1.40 to indicate that ADL does not partially mediate the relationship between depression and HR-QOL R2 = .11 (decrease of .2) With the PDQ-39  is removed from the model, a This is the first study to examine whether ADL mediates the relationship between depression and HR-QOL in people with PD. ADL demonstrated a signficant indirect effect on the depression and HR-QOL relationship, but did not reduce the relationship such that a partial mediation effect could be declared There are several implications from the present finding. Firstly, it may be valuable for clinicians to consider the non-motor factors relating to HR-QOL in people with PD Secondly, the present findings highlight the complex interaction between non-motor symptoms and daily functioning in PD. Previous research has demonstrated that people with PD with more knowledge of the disease course are less likely to be depressed Finally, the present findings suggest that depression and impaired ADL in combination lead to worse HR-QOL than the impact of the two independently. Therefore, psychotherapy interventions  for people with PD and depression may have additional benefits for those who also experience difficulty with ADL. Cognitive-behavioural therapy (CBT) can promote acceptance of assistance by a caregiver to provide help with ADL and combat feelings of dependence and helplessness for people with PD In addition to the significant indirect effect, depression was the strongest predictor of HR-QOL (Hypothesis 1). This result is consistent with findings by Schrag et al. Supporting previous research by Dissanayaka et al. ADL accounted for a significant proportion of variance in HR-QOL (Hypothesis 3). Kleiner-Fisman et al. The present results should be considered within some limitations. The participants' mean score for depressive symptoms was below the diagnostic cut off for depression, and the mean scores for ADL and HR-QOL were within the ‘normal’ to ‘slightly impaired’ range The novel nature of the indirect effect of ADL on the depression and HR-QOL relationship in PD provides opportunities for future research. Recruitment of a sample that captures the spectrum of symptom severity would provide a more accurate representation of the heterogeneity in PD and increase both the external validity of the results and the possibility of finding mediation effects In conclusion, this is the first study to demonstrate a significant indirect effect of ADL on the depression and HR-QOL relationship in PD. The moderate effect size suggests that people with PD and depressive symptoms experience greater difficulty completing ADL, which adversely impacts upon their HR-QOL. It is recommended that clinicians adopt a multidisciplinary approach when caring for people with PD and consider the relationships between depression, ADL, and HR-QOL. Undoubtedly, this significant effect warrants further investigation and accentuates the relationship between depression and HR-QOL in PD.