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Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3′-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.
Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.
Background: Detailed injury data are not available for international tournaments in field hockey. We investigated the epidemiology of field hockey injuries during major International Hockey Federation (Fédération Internationale de Hockey, FIH) tournaments in 2013.
Materials: and methods FIH injury reports were used for data collection. All major FIH tournaments for women (n=5) and men (n=11) in 2013 were included. The main focus of this study was to assess the pattern, time, site on the pitch, body site and mechanism of each of the injuries. We calculated the average number of injuries per match and the number of injuries per 1000 player match hours.
Results: The average number of injuries was 0.7 (95% CI 0.5 to 1.0) per match in women's tournaments and 1.2 (95% CI 0.8 to 1.7) per match in men's tournaments. The number of injuries per 1000 player match hours ranged from 23.4 to 44.2 (average 29.1; 95% CI 18.6 to 39.7) in women and 20.8 to 90.9 (average 48.3; 95% CI 30.9 to 65.8) in men. Most injuries occurred in the circle (n=25, 50%, in women, n=95, 51%, in men). The rate of injuries increased after the first quarter. Injuries to the head and face (n=20, 40%) were most common in women. The head/face (n=51, 27%) and the thigh/knee (n=52, 28%) were equally affected in men. The ball caused the most injuries, followed by the stick, collisions and tripping/falling. There were no deaths or injuries that required hospital treatment in the entire cohort.
Summary: Field hockey has a low incidence of acute injuries during competition.
Ocular gene therapy approaches have been developed for a variety of different diseases. In particular, clinical gene therapy trials for RPE65 mutations, X-linked retinoschisis, and choroideremia have been conducted at different centers in recent years, showing that adeno-associated virus (AAV)-mediated gene therapy is safe, but limitations exist as to the therapeutic benefit and long-term duration of the treatment. The technique of vector delivery to retinal cells relies on subretinal injection of the vector solution, causing a transient retinal detachment. Although retinal detachments are known to cause remodeling of retinal neuronal structures as well as significant cell loss, the possible effects of this short-term therapeutic retinal detachment on retinal structure and circuitry have not yet been studied in detail. In this study, retinal morphology and apoptotic status were examined in healthy rat retinas following AAV-mediated gene transfer via subretinal injection with AAV2/5.CMV.d2GFP or sham injection with fluorescein. Outer plexiform layer (OPL) morphology was assessed by immunohistochemical labeling, laser scanning confocal microscopy, and electron microscopy. The number of synaptic contacts in the OPL was quantified after labeling with structural markers. To assess the apoptotic status, inflammatory and pro-apoptotic markers were tested and TUNEL assay for the detection of apoptotic nuclei was performed. Pre- and postsynaptic structures in the OPL, such as synaptic ribbons or horizontal and bipolar cell processes, did not differ in size or shape in injected versus non-injected areas and control retinas. Absolute numbers of synaptic ribbons were not altered. No signs of relevant gliosis were detected. TUNEL labeling of retinal cells did not vary between injected and non-injected areas, and apoptosis-inducing factor was not delocalized to the nucleus in transduced areas. The neuronal circuits in the OPL of healthy rat retinas undergoing AAV-mediated gene transfer were not altered by the temporary retinal detachment caused by subretinal injection, the presence of viral particles, or the expression of green fluorescent protein as a transgene. This observation likely requires further investigations in the dog model for RPE65 deficiency in order to determine the impact of RPE65 transgene expression on diseased retinas in animals and men.
Hyponatremia is the most common and by far underestimated electrolyte disorder in clinical practice. Especially in elderly patients, treatment of symptomatic hyponatremia is challenging. Herein we describe the case of an octogenarian with recurrent symptomatic hyponatremia due to idiopathic syndrome of inappropriate antidiuretic hormone release (SIADH). Fluid restriction was insufficient to prevent repeated episodes of hyponatremia complicated by falls and coma. After introduction of a low-dose therapy with tolvaptan, serum sodium levels as well as the clinical condition were stable under vaptan therapy, without any relapse for more than six years now. This case demonstrates that long-term tolvaptan treatment for hyponatremia caused by SIADH is safe and well tolerated, even in the elderly.
We have developed a new in vitro skin irritation test based on an open source reconstructed epidermis (OS-REp) with openly accessible protocols for tissue production and test performance. Due to structural, mechanistic and procedural similarity, a blinded catch-up validation study for skin irritation according to OECD Performance Standards (PS) was conducted in three laboratories to promote regulatory acceptance, with OS-REp models produced at a single production site only. While overall sensitivity and predictive capacity met the PS requirements, overall specificity was only 57%. A thorough analysis of the test results led to the assumption that some of the false-positive classifications could have been evoked by volatile skin-irritating chemicals tested in the same culture plate as the non-irritants falsely predicted as irritants. With GC/MS and biological approaches the cross-contamination effect was confirmed and the experimental set-up adapted accordingly. Retesting of the affected chemicals with the improved experimental set-up and otherwise identical protocol resulted in correct classifications as non-irritants. Taking these re-test results into account, 93% overall sensitivity, 70% specificity and 82% accuracy was achieved, which is in accordance with the OECD PS. A sufficient reliability of the method was indicated by a within-laboratory-reproducibility of 85–95% and a between-laboratory-reproducibility of 90%.
Purpose: High precision radiosurgery demands comprehensive delivery-quality-assurance techniques. The use of a liquid-filled ion-chamber-array for robotic-radiosurgery delivery-quality-assurance was investigated and validated using several test scenarios and routine patient plans.
Methods and material: Preliminary evaluation consisted of beam profile validation and analysis of source–detector-distance and beam-incidence-angle response dependence. The delivery-quality-assurance analysis is performed in four steps: (1) Array-to-plan registration, (2) Evaluation with standard Gamma-Index criteria (local-dose-difference ⩽ 2%, distance-to-agreement ⩽ 2 mm, pass-rate ⩾ 90%), (3) Dose profile alignment and dose distribution shift until maximum pass-rate is found, and (4) Final evaluation with 1 mm distance-to-agreement criterion. Test scenarios consisted of intended phantom misalignments, dose miscalibrations, and undelivered Monitor Units. Preliminary method validation was performed on 55 clinical plans in five institutions.
Results: The 1000SRS profile measurements showed sufficient agreement compared with a microDiamond detector for all collimator sizes. The relative response changes can be up to 2.2% per 10 cm source–detector-distance change, but remains within 1% for the clinically relevant source–detector-distance range. Planned and measured dose under different beam-incidence-angles showed deviations below 1% for angles between 0° and 80°. Small-intended errors were detected by 1 mm distance-to-agreement criterion while 2 mm criteria failed to reveal some of these deviations. All analyzed delivery-quality-assurance clinical patient plans were within our tight tolerance criteria.
Conclusion: We demonstrated that a high-resolution liquid-filled ion-chamber-array can be suitable for robotic radiosurgery delivery-quality-assurance and that small errors can be detected with tight distance-to-agreement criterion. Further improvement may come from beam specific correction for incidence angle and source–detector-distance response.
Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.
Immunopathogenic mechanisms of autoimmune Hepatitis : how much do we know from animal models?
(2016)
Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.