α-Synuclein Attenuates Maneb Neurotoxicity through the Modulation of Redox-Sensitive Transcription Factors.

The accumulation and aggregation of α-synuclein is a pathognomonic sign of Parkinson's disease (PD). Maneb (MB) exposure has also been reported as one environmental triggering factor of this multifactorial neurodegenerative disease. In our laboratory, we have previously reported that mild overexpression of α-synuclein (200% increase with respect to endogenous neuronal levels) can confer neuroprotection against several insults. Here, we tested the hypothesis that α-synuclein can modulate the neuronal response against MB-induced neurotoxicity. When exposed to MB, cells with endogenous α-synuclein expression displayed increased reactive oxygen species (ROS) associated with diminished glutamate-cysteine ligase catalytic subunit (GCLc) and hemeoxygenase-1 (HO-1) mRNA expressions and upregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) repressor, BTB domain and CNC homolog 1 (BACH1). We found that α-synuclein overexpression (wt α-syn cells) attenuated MB-induced neuronal damage by reducing oxidative stress. Decreased ROS found in MB-treated wt α-syn cells was associated with unaltered GCLc and HO-1 mRNA expressions and decreased BACH1 expression. In addition, the increased SOD2 expression and catalase activity were associated with forkhead box O 3a (FOXO3a) nuclear compartmentalization. Cytoprotective effects observed in wt α-syn cells were also associated with the upregulation of silent information regulator 1 (SIRT1). In control cells, MB-treatment downregulated glutathione peroxidase 4 mRNA levels, which was coincident with increased ROS content, lipid peroxidation, and mitochondrial alterations. These deleterious effects were prevented by ferrostatin-1, an inhibitor of ferroptosis, under conditions of endogenous α-synuclein expression. The overexpression of α-synuclein attenuated MB toxicity by the activation of the same mechanisms as ferrostatin-1. Overall, our findings suggest that mild overexpression of α-synuclein attenuates MB-induced neurotoxicity through the modulation of NRF2 and FOXO3a transcription factors and prevents cell death probably by intervening in mechanisms associated with ferroptosis. Thus, we postulate that early stages of α-synuclein overexpression could be potentially neuroprotective against MB neurotoxicity.

The use of a novel burn dressing out of bacterial nanocellulose compared to the French standard of care in paediatric 2nd degree burns - A retrospective analysis.

PURPOSE: Paediatric burn care is a delicate discipline which benefits from special attention. Despite being highly effective, the current standard of care for second degree burns in the largest paediatric burn center in France - exposure to infrared light - involves long hospital stays, straining economic and professional resources, especially in times of a pandemic. The present study investigated this standard of care and compared it to the use of a bacterial nanocellulose dressing. MATERIALS AND METHODS: A retrospective analysis of two groups has been performed: the control group assessed thirty consecutive children treated with the standard of care, and the intervention group assessed thirty consecutive children treated with the bacterial nanocellulose dressing. Parameters evaluated were: healed wounds, additional treatments, rate of infections, hospital length of stay, pain experience and overall satisfaction. RESULTS: The two groups did not differ significantly in terms of age and TBSA. A significant reduction in hospital length of stay (p < .001) and pain experience (p < .001) could be observed. In terms of healed wounds, additional treatments and infections, the two groups were equally matched (p > .05) with satisfactory results in both groups. Tendencies towards better results could be seen in the intervention group. CONCLUSION: The use of bacterial nanocellulose wound dressings is an important tool in the armamentarium of today's burn surgeons. Satisfying results were achieved, ameliorating burn care for children. Future studies are indicated to further support its value and assess the economic impact.

Continuous pH monitoring in wounds using a composite indicator dressing - A feasibility study.

PURPOSE: Modern burn care strives for new means to guarantee optimised wound healing. Several studies have shown a correlation between the pH value in a (burn) wound and successful wound healing. A multitude of devices to monitor pH is available, all requiring direct wound contact and removal of the dressing for pH monitoring. The aim of this feasibility study was to create a sterile and easy to handle method for pH monitoring while simultaneously using an advanced wound dressing. MATERIALS AND METHODS: Dressing sheets of biotechnologically generated nanofibrillar cellulose (epicitehydro) were chemically functionalised with the indicator dye GJM-534. pH-donors with increasing pH were subsequently applied to the created indicator dressing. To investigate temporal resolution and continuous monitoring we used circular pH-donors with different pH (7 and 10) and decreasing diameters that were placed on another dressing sheet. Clinically relevant spatial resolution was checked by a wound bed simulation with small areas (8 mm) of higher pH (10) on a field of lower pH (7) and vice versa. RESULTS: The indicator dressing showed a gradual colouring from yellow to dark orange with increasing pH in steps of 0.3. After conversion of digital pictures to greyscale values, a sigmoidal distribution with a pKa-value of 8.4 was obtained. A ring-like pattern with alternating colour change corresponding to the pH was observed in the continuous monitoring experiment and the wound bed simulation delivered excellent local resolution. CONCLUSION: Since the pH of a (burn) wound can have a significant influence on wound healing, a pH indicator was successfully linked to an advanced, temporary, alloplastic wound dressing material. We were able to show the possibility of pH monitoring by the dressing itself. Additional testing, including studies with large case numbers for optimisation are necessary before clinical implementation.

Timing and predictors of severe rotavirus gastroenteritis among unvaccinated infants in low- and middle-income countries.

Delays in rotavirus vaccine schedule could improve performance in low- and middle-income countries (LMICs). However, delaying the first dose could be detrimental if infants experience severe rotavirus gastroenteritis (RVGE) early in life. Our objective was to describe the timing and predictors of severe RVGE in unvaccinated children in LMICs. We analysed the placebo arms from two clinical trials (cohort 1: NCT00241644; cohort 2: NCT00362648). We estimated the rate, cumulative incidence (per 1000 infants) and age distribution of severe RVGE episodes. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CI) for the association between baseline factors and severe RVGE. Cumulative incidence at 6 months of age was 23/1000 (95% CI 15-30) in cohort 1 and 6/1000 (95% CI 3-8) in cohort 2. Early antibiotic use (compared with no use) was associated with 2.03 (95% CI 1.18-3.48) and 1.41 (95% CI 0.80-2.51) times the rate of severe RVGE in cohorts 1 and 2, respectively. The cumulative incidence of severe RVGE was low at 6 months of age, suggesting that a 4-week delay in the vaccination schedule may not result in a large number of severe RVGE episodes prior to vaccine receipt.

Reorganization of mental health services: from institutional to community-based models of care.

Mental health services in the Eastern Mediterranean Region are predominantly centralized and institutionalized, relying on scarce specialist manpower. This creates a major treatment gap for patients with common and disabling mental disorders and places an unnecessary burden on the individual, their family and society. Six steps for reorganization of mental health services in the Region can be outlined: (1) integrate delivery of interventions for priority mental disorders into primary health care and existing priority programmes; (2) systematically strengthen the capacity of non-specialized health personnel for providing mental health care; (3) scale up community-based services (community outreach teams for defined catchment, supported residential facilities, supported employment and family support); (4) establish mental health services in general hospitals for outpatient and acute inpatient care; (5) progressively reduce the number of long-stay beds in mental hospitals through restricting new admissions; and (6) provide transitional/bridge funding over a period of time to scale up community-based services and downsize mental institutions in parallel.

[Overweight in primary school-age children. Prevalence and risk factors]. / Gewichtsentwicklung im frühen Grundschulalter. Prävalenz, Inzidenz und Risikofaktoren für Übergewicht und Adipositas.

BACKGROUND: Various studies show that pre-school age is a sensitive period for the development of overweight and obesity. During a longitudinal study between 2010 and 2013, the municipal health authority (city of Frankfurt) in cooperation with the university children's hospital investigated the development of weight in children aged 5 to 8. MATERIALS AND METHODS: The weight and height of a collective of 5720 children were measured (2010/11). In addition, nutritional and exercise habits, as well as media consumption was documented for 4758 children through a questionnaire during the school enrolment procedure. The weight and height of 3481 children were measured again in the second grade (2012/13). RESULTS: Over a period of 24 months, the percentage of overweight (not obese) children increased from 7.5 to 9.4 % and that of obese children from 4.5 to 5.0 %. 164 of 2818 children with a normal initial weight (5.8 %) changed to percentile class overweight or obese. 79 of 260 children who were initially overweight, not obese (30 %), changed to the group of normal weight, but only 4 out of 156 obese children (3 %). Increased TV consumption (> 1 h per day), availability of their own television, lack of physical activity, and consumption of high-calorie drinks were risk factors for the development of overweight during the primary school age. 72 % of parents of overweight children and 22 % of obese children falsely classified their children as normal weight. CONCLUSIONS: Targeted education about the risk of obesity in the primary school age and offers for early intervention should be established in the healthcare services concerned.

Intravitreal bevacizumab (Avastin) versus triamcinolone (Volon A) for treatment of diabetic macular edema: one-year results.

PURPOSE: The objective was to compare retinal morphology and function following intravitreal injections of bevacizumab (Avastin) or triamcinolone (Volon A) in patients with early diabetic macular edema (DME). PATIENTS AND METHODS: The study was planned as a randomized, prospective, interventional clinical trial. A total of 30 diabetic patients with treatment-naïve, clinically significant macular edema were included in this study and randomized to two equal groups. One group initially received three injections of 2.5 mg bevacizumab in monthly intervals. The second group received a single injection of 8 mg triamcinolone, followed by two sham interventions. Functional and anatomic results were evaluated monthly using ETDRS vision charts and spectral-domain optical coherence tomography. According to the study protocol, retreatment after 3 months was dependent on functional and anatomic outcome in a PRN regimen. RESULTS: Baseline best corrected visual acuity (BCVA) was 0.30 logMAR and central retinal subfield thickness (CSRT) was 505 µm in the bevacizumab group and 0.32 logMAR and 490 µm CSRT in the triamcinolone group. After 3 months, BCVA improved to 0.23 logMAR (bevacizumab) and 358 µm CRST and 0.26 logMAR (triamcinolone) and 308 µm CSRT. After 12 months, BCVA further recovered in the bevacizumab group (0.18 logMAR) but slightly decreased in the triamcinolone group (0.36 logMAR). CONCLUSION: Intravitreal bevacizumab and triamcinolone are both equally effective in reducing CSRT in early DME. After 6 months, rehabilitation of vision was comparable in both treatment arms, whereas at the final follow-up at month 12, BCVA was superior in the bevacizumab than in the triamcinolone sample. This may be related to cataract development following steroid treatment, as well as to substance-specific mechanisms within the angiogenic versus the inflammatory cascade.

Thromboembolic events associated with immunoglobulin treatment.

OBJECTIVE: Due to an increasing number of reported thromboembolic events (TEE) after the administration of one intravenous immunoglobulin (IVIG) and one subcutaneous immunoglobulin (SCIG), pharmacovigilance and laboratory data were collected to analyse the root cause and assess the reporting frequency of TEEs for various IG products. METHODS: Paul-Ehrlich-Institut retrospectively analysed 228 reports of TEEs associated with six different IG products and estimated annual TEE-reporting rates based on worldwide sale figures over a period of 6 years (2006-2011). In addition, non-activated partial thromboplastin time (NAPTT) testing was performed to capture pro-coagulant potential of six IG products (four IVIG and two SCIG). RESULTS: For three IVIGs, the drug-related TEE-reporting rates remained stable from 2006 to 2011 (0-0·83 cases per 1000 kg IVIG distributed). In contrast, the TEE rate of one IVIG increased significantly from 0·33 cases in 2006 to nearly nine cases in 2010 (P < 0·001). The NAPTT testing of IG products with a low TEE rate revealed a NAPTT time >200 s and a NAPTT ratio >0·8, whereas TEE-associated batches of IG products with an increased TEE rate had a NAPTT ratio <0·8. After modifications of manufacturing processes, a normalization of NAPTT results and a decrease in TEE rates could be demonstrated.

[Spiroergometric reference values for the sociomedical assessment of performance in adults aged over 60 years]. / Spiroergometrische Referenzwerte für die sozialmedizinische Leistungsbeurteilung bei Erwachsenen im Alter über 60 Jahre.

BACKGROUND: In order to determine physical capability, objective methods for the assessment of performance are required. Spiroergometry is well established in occupational and social medicine. The existing standard values are defined for younger adults; however patients have predominantly an older age. To determine the age-related physical capability healthy men and women at the age over 60 years were studied. METHODS AND PATIENTS: 43 persons (21 ♀/22 ♂), aged 60 - 79 years were examined spiroergometrically, including lactate measurements. The results were compared with previously published standard values. RESULTS: The maximum capacity in watts (W) for women was 98 W, and for men 155 W and declined with increasing age (♀ 60 - 69 years 100 W, ♀ 70 - 79 years 93 W; ♂ 60 - 69 years 165 W. ♂ 70 - 79 years 139 W). The maximum oxygen uptake (♀ 1476 ±â€†275 mL/min, ♂ 2292 ±â€†245 mL/min), the weight-specific oxygen uptake (♀ 21.6 ±â€†4.9 mL/kg/min, ♂ 28.4 ±â€†4.6 mL/kg/min) and the oxygen pulse (♀ 10.7 ±â€†2.8 mL, ♂ 16.4 ±â€†2.1 mL) were significantly lower in woman compared to men (p < 0.001). The maximum lactate was achieved in women with a mean value of 5.83 mmol/L, and for men of 6.58 mmol/L (p = 0.76). CONCLUSIONS: Studies for the collection of normal values have mainly involved young people. The physiological performance parameters cannot be referred to elderly persons. In the socio-medical assessment age-related normative values should be used to determine residual capacity.

Benefit of transfusion-related acute lung injury risk-minimization measures--German haemovigilance data (2006-2010).

OBJECTIVE: Based on the frequency of immune-mediated and non-immune-mediated transfusion-related acute lung injury (TRALI), the effect of risk-minimization measures was evaluated during a period of 5 years (2006-2010). Risk-minimization measures were implemented in 2008/2009, consisting of exclusion of female donors with a history of pregnancy or exclusion of female donors with human leucocyte antigen (HLA)/human neutrophil alloantigen (HNA) antibodies. METHODS: TRALI was confirmed according to the criteria of the International Haemovigilance Network. Based upon the results of donor testing of white-blood-cell antibodies (WBC-Ab) against HLA or HNAs, confirmed cases were classified as immune- or non-immune-mediated TRALI. Reporting rates were calculated on the basis of the annually transfused blood components, and pre- and post-implementation periods were compared. RESULTS: In total, 60 immune-mediated (75%) and 20 non-immune-mediated (25%) TRALI reactions were confirmed. A total of 68 (64 women and four men) donors were involved: seven red-blood-cell concentrates donors (13%), six platelet concentrate donors (10%), and 48 fresh frozen plasma (FFP) donors (77%). The reporting rate of immune-mediated TRALI caused by FFP decreased continuously; from 12·71 per million units in 2006/2007 to 6·81 per million units in 2008/2009 and no case in 2010. CONCLUSION: The comparison of the pre- and the post-implementation period demonstrated a significantly reduced risk of TRALI events comparing 2006/2007 with 2010 (P-value: <0·01). Furthermore, no case of TRALI-induced fatality occurred after the implementation of risk-minimization measures.

Evaluation of the PC-1 K121Q and G2906C variants as independent risk factors for ischaemic stroke.

UNLABELLED: Overexpression of plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor tyrosine kinase activity and thus favours insulin resistance and atherosclerotic vascular disease. Recent findings indicate that the minor variant K121Q in the PC-1 gene confers an increased risk for early myocardial infarction independent of other established risk factors. We hypothesized that genetic variants in PC-1 may also influence the risk for cerebrovascular disease. AIM: Therefore, we assessed the association of the PC-1 K121Q variant in the coding region and a polymorphism (G2906C) in the 3' untranslated region of the PC-1 gene with the risk of stroke. PATIENTS: We analyzed 1014 patients with a history of ischaemic stroke from the Vienna stroke registry and 1001 control individuals without vascular disease. RESULTS, CONCLUSION: Genotype frequencies of both genetic variants were similar in patients and controls in the total study population. By multivariate analysis, no interactions were observed between the PC-1 genotype and established vascular risk factors. However, the PC-1 2906C allele was significantly more frequent in patients who suffered from stroke before the age of 40 years. In these patients the risk for ischaemic stroke was increased four-fold.

[Evaluation of measures aimed to reduce serious adverse transfusion reactions (hemovigilance data from 1997 to 2008)]. / Bewertung der Massnahmen zur Reduktion schwerwiegender Transfusionsreaktionen (Hämovigilanzdaten von 1997 bis 2008).

On the basis of reports of serious transfusion reactions, measures aimed to improve the safety standard of the manufacturing process of blood components were evaluated from 1997-2008. Measures of the Paul-Ehrlich-Institut (PEI) as well as recommendations of the Advisory Committee "Blood" were considered. Reporting frequencies before and after the implementation of measures were compared. After the implementation of NAT pool testing, a reduction of virus transmission was seen for red blood cell concentrates (RBC) from 1.0/10(6) to 0.5/10(6) units and for platelet concentrates (PC) from 3.0/10(6) to 0.0/10(6) units. After the implementation of a pre-donation sampling, however, no reduction of bacterial infections associated with PC administration (>9.0/10(6)) was identified. To reduce the frequency of TRALI associated with FFP administration (11.2/10(6) units), the use of plasma from male donors or female donors without a history of pregnancy was established in September 2009. Without specific measures of risk reduction, the reporting frequency of severe allergic transfusion reaction increased for all blood components during the investigation period (from 0.8/10(6) to 6.2/10(6) RBC units). The benefit of measures to improve safety standards should be evaluated repeatedly by collecting precise hemovigilance data.

Frequency and severity of transfusion-related acute lung injury--German haemovigilance data (2006-2007).

OBJECTIVE: In an observational cohort study (2006-2007) the Paul-Ehrlich-Institut collected epidemiological data to investigate the frequency and causes of TRALI. METHODS: Diagnosis of TRALI was confirmed according to criteria of the European Haemovigilance Network. Subsequent testing of white blood cell antibodies (WBC-Ab) against HLA or human neutrophil alloantigens was performed. RESULTS: Of a total of 187 reported TRALI cases, 44 could be confirmed consisting of 35 cases of antibody-mediated TRALI and nine cases of non-immune-mediated TRALI. Eight of 44 affected patients (18%) had a fatal outcome, seven cases with WBC-Ab positive plasma donors and one case with red blood cell donors. WBC antibodies were found in one male and 39 female donors. In 34 female donors, a history of pregnancy was confirmed. WBC-Ab positive donors presented four HLA class I antibodies, 15 HLA class II antibodies, 13 HLA class I and class II antibodies, one HNA-2a, and seven HNA-3a antibodies. WBC antibodies matching with recipient antigens were found exclusively in 28 female donors; 26 FFP donors, one platelet donor and one red blood cell donor. Reporting frequency of immune-mediated TRALI was 1:66,000 for fresh frozen plasma, 1:2.86 million for red blood cell concentrates and 1:420,000 for platelet concentrates. Reporting frequency of TRALI-related fatalities was 1:285,000 for FFP. SUMMARY: Haemovigilance data show the significance of female donors with a history of pregnancy for the development of antibody-mediated TRALI. Manufacturing of FFP from male plasma and female donor screening for WBC-Ab could represent preventive measures.

Improving the quality of mental health care.

OBJECTIVE: To develop international guidance for improving the quality of mental health care in low- and middle-income countries. DESIGN: A panel developed recommendations based on a comprehensive literature review, consultation with over 100 experts from 46 countries and an analysis of international best practices. Recommendations A 5-pronged approach to improving the quality of mental health care is recommended. Quality improvement requires the alignment of policy and legislation with the attainment of good quality mental health outcomes. Key partners must be brought into the quality improvement process. Funding can be an important tool for promoting good quality but needs to be correctly aligned to meet policy objectives and to promote evidence-based interventions. Accreditation procedures and quality standards need to be carefully developed and resources allocated for their implementation. Finally, quality improvement must be brought into routine service management and delivery. CONCLUSIONS: Through a systematic approach to quality improvement, it is possible to ensure that the best possible interventions are provided within the constraints of each country and that the rights and well-being of people with mental disorders is optimally promoted. Quality improvement is not a luxury but an integral part of ensuring that the best possible services are provided to all who need them.

The German Haemovigilance System--reports of serious adverse transfusion reactions between 1997 and 2007.

Data of the German Haemovigilance System were collected from 1997 to 2007 and assessed on the basis of pre-defined safety standards. Suspected cases of serious adverse reactions following transfusions reported to the Paul-Ehrlich-Institut were evaluated on the basis of national criteria, and the definitions of International Society of Blood Transfusion (ISBT) in compliance with defined causality criteria. The suspected cases were rated as confirmed and unconfirmed transfusion reactions. Assessment of causality took into consideration the clinical course of the adverse reaction and, if necessary, information about donation and manufacturing. Of the 5128 suspected serious adverse reactions, 1603 could be confirmed. Referring to the absolute figures, acute transfusion reactions (e.g. allergic reactions, hypotension and dyspnoea) were recorded most frequently, followed by transfusion-related acute lung injury (TRALI), haemolytic reactions, transfusion-related bacterial infections and virus infections. The majority of the 52 transfusion-related fatalities (14 each) were due to TRALI and acute transfusion reactions (mostly severe allergic reactions). Referred to the blood products administered, immune TRALI cases and TRALI-related fatal courses were most frequently reported after administration of fresh frozen plasma (FFP) (15/10(6) and 3.5/10(6) units, respectively), transfusion-related bacterial infections after administration of platelet concentrates (7/10(6) units), acute haemolytic transfusion reactions after administration of red blood cell concentrates (2.3/10(6)units) and acute transfusion reactions after administration of red blood cell or platelet concentrates (7.8/10(6) and 13/10(6) units, respectively). Despite the high safety standard required for blood products in Germany, there is still room for reducing the frequency of isolated cases of transfusion reactions by targeted action.

Effect of P6 acustimulation on post-operative nausea and vomiting in patients undergoing a laparoscopic cholecystectomy.

BACKGROUND: Non-pharmacologic techniques such as electrical acustimulation may mitigate post-operative nausea and vomiting (PONV). The primary purpose of this study was to investigate the effectiveness of acustimulation on attenuating PONV. Moreover, we tested whether a pre- or a post-induction application of acustimulation results in differences in PONV reduction. METHODS: In this prospective, double-blind, randomized, controlled trial, we studied 200 patients undergoing a laparoscopic cholecystectomy during propofol (induction) fentanyl/isoflurane/atracurium (maintenance) anaesthesia. In the acustimulation group (n=101), subdivided into groups with pre-induction (n=57) and post-induction (n=44) acustimulation, an active ReliefBand device was placed at the P6 acupoint. In the sham group (n=99), also subdivided into pre-induction (n=55) or post-induction (n=44) groups, an inactive device was applied instead. The ReliefBand remained in place for 24 h after surgery. Nausea and vomiting/retching were recorded at 2, 6, and 24 h post-operatively. RESULTS: The incidence of early nausea (up to 2 h) was significantly lower in the acustimulation than in the sham group (29% vs. 42%; P=0.043). No significant effect could be detected for retching/vomiting. Moreover, acustimulation showed no effect on PONV after 6 and 24 h. Risk factor analysis (female gender, non-smoker, history of PONV/motion sickness, and post-operative morphine usage) revealed a relative reduction in risk of 40% for nausea (P=0.021) and 55% for retching/vomiting (P=0.048) in patients with three or four risk factors present. The timing of (pre- vs. post-induction) acustimulation had no significant effect on PONV reduction. CONCLUSION: Acustimulation at the P6 acupoint reduces early nausea, but not vomiting, after laparoscopic cholecystectomy, irrespective of its pre- or post-induction application.