Disturbed glutathione antioxidative defense is associated with structural brain changes in neuroleptic-naïve first-episode psychosis patients.

BACKGROUND: Oxidative stress and impaired antioxidant defense are reported in schizophrenia and are thought to be associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, negative symptomatology, and cognitive impairment. To test some of these assumptions we investigated the glutathione (GSH) antioxidant defense system (AODS) and brain structural abnormalities in drug-naïve individuals with first acute episode of psychosis (FEP). METHOD: The study involved 27 drug-naïve FEP patients and 31 healthy controls (HC). GSH AODS markers and TBARS (thiobarbituric acid reactive substances) were measured in blood plasma and erythrocytes. High-resolution T1-weighted 3T MRI were acquired from all subjects. To investigate brain structural abnormalities and effects of illness on interactions between GSH metabolites or enzyme activities and local grey matter density, voxel-based morphometry (VBM) with the computational anatomy toolbox (CAT12) was used. Symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Symptom Checklist 1990 revised (SCL-90-R). RESULTS: (i) In FEP patients, glutathione reductase activity (GSR) was lower than in the HC group. GSR activity in plasma was inversely correlated with SCL-90-R scores of depression and PANSS scores of the negative symptom subscale. (ii) A reduction of GM was observed in left inferior frontal, bilateral temporal, as well as parietal cortices of FEP patients. (iii) Interaction analyses revealed an influence of illness on GSR/GM associations in the left orbitofrontal cortex (BA 47). CONCLUSION: Our findings support the notion of altered GSH antioxidative defense in untreated acute psychosis as a potential pathomechanism for localized brain structural abnormalities. This pathology relates to a key brain region of social cognition, affective motivation control and decision making, and is clinically accompanied by depressive and negative symptoms.

Erythrocyte glutathione levels as long-term predictor of transition to psychosis.

A high proportion of individuals deemed at elevated risk for psychosis will actually never progress to develop the illness. Pharmaceutical intervention may not be necessary in these cases, and may in fact be damaging depending on the invasiveness of the treatment strategy. This highlights the need for biomarkers that are better able to reliably differentiate between at-risk individuals who will subsequently transition to psychosis and those who will not. Low glutathione (GSH) levels have been observed in schizophrenia and in patients with first-episode psychosis. The aim of this study was to determine the predictive value of erythrocyte GSH levels on the transition to psychosis in individuals at risk of developing the illness. Erythrocyte GSH levels were measured in 36 at-risk individuals, 15 of whom had transitioned to psychosis at the 7-year follow-up. Univariate Cox regression analysis showed that transition to psychosis at the 7-year time point was significantly associated with low GSH levels at baseline. The area under the receiving operating characteristic curve was 0.819, indicating that GSH can be considered a good predictor of outcome. Although these results need to be replicated, adding the criterion 'low erythrocyte GSH' to the set of criteria used to identify individuals at risk of psychosis may be indicated.

The growing number of hemophilia registries: Quantity vs. quality.

Registries for rare diseases provide a tool for obtaining an overview of the clinical situation and can be used to discover points of improvement and to monitor long-term safety. Registries could also become a powerful tool to provide supporting information for marketing authorization. There is an urgent need for a pan-European or global strategy that supports consistent data. Therefore, transparency in data collection, harmonization of the database structures, and the convergence of scientific approaches are required.

[New data from the German Haemophilia Registry]. / Neue Daten aus dem Deutschen Hämophilieregister.

UNLABELLED: The German Haemophilia Registry records online data from patients with haemophilia A, haemophilia B, von Willebrand`s disease and other coagulation factor deficiency disorders since 2009. Patient's pseudonymised data will only be enrolled in the German Haemophilia Registry if the patient signs an informed consent. Without the informed consent, only aggregated data according to §21 German Transfusion Law are reported. These data include the number of persons with congenital haemostasis disorders classified to type of disease and severity as well as patients' age, and the consumption of clotting factor according to each group. RESULTS: The highest number of patients with haemophilia was reported in 2010: 3375 patients with haemophilia A and 614 with haemophilia B respectively; the highest number of patients with von Willebrand's disease was 1473, reported in 2011. CONCLUSION: In comparison to data from registries in Austria and Switzerland it can be assumed that most of the patients with severe haemophilia are registered in the German Haemophilia Registry whereas patients with moderate and mild forms are still missing.

[Report on notifications pursuant to §21 German Transfusion Act for 2010 and 2011]. / Bericht zur Meldung nach § 21 TFG für die Jahre 2010 und 2011.

This report covers the blood supply situation in Germany over the past 12 years and provides detailed data on the years 2010 and 2011. Nearly 7.6 million donations, thereof 4.9 million whole blood donations, were reported in 2011 - the highest number since 1998. At the same time, 4.8 million red blood cell concentrates (RBC) were produced, the highest amount per year to date. While the RBC loss rate increased for both the manufacturers and the users, the RBC transfusion rate decreased for the first time since 2003. The number of platelet concentrates increased again to 0.57 million. About 60 % of this originated from apheresis donations. An amount of 3.4 million liters of plasma for fractionation was provided. Around 60 % was processed in Germany. The number of hematopoietic stem cell transplantations increased from 5,922 in 2009 to 7,093 in 2011. More than 99 % of the 16,364 transplants derived from peripheral blood and marrow; 43 % of the preparations were transplanted in Germany and 27 % were exported. Overall, the supply of blood products is considered to be good. However, because data are collected on an annual basis, seasonal shortages cannot be detected.

[Documentation of haemophilia treatment supported by the German Hemophilia Registry]. / Dokumentation in der Hämophilietherapie mit Unterstützung des Deutschen Hämophilieregisters.

The DHR (Deutsches Hämophilieregister, German Haemophilia Register) records patient data on haemophilia A, haemophilia B, von Willebrand disease, and other coagulation factor deficiency disorders. The DHR has been online since 2009. The participation in the DHR leads to additional administrative workload for the hospitals and physicians, but provides many advantages as well: A standard of documentation will be developed to give evidence for the hospitals. They may use their own data as well as with new possibilities for data processing at any time. Reports in accordance with Section21 TFG (Transfusionsgesetz, German Transfusion Act) are compiled automatically and transmitted to the Paul-Ehrlich-Institut. The DHR may support the searching for patients fulfilling the requirements for participation in a study.

[Report on notifications pursuant to Section 21 of the German Transfusion Act for the years 2008 and 2009]. / Bericht zur Meldung nach § 21 TFG für die Jahre 2008 und 2009.

This report contains the data collected in 2008 and 2009, pursuant to Section 21 of the German Transfusion Act (Transfusionsgesetz), as well as an overview of the supply situation during the last 10 years. In 2009, blood donation services reported a total of 7.5 million donations--the largest amount since 2000. At the same time, more than 4.7 million red blood cell concentrates and more than 500,000 platelet concentrates were available. The number of therapeutic single plasma units decreased to 1.1 million units in 2009. The loss rate for red blood cell concentrates is still between 3% and 4% for the users, while for the manufacturers, it has decreased slightly to 1.4%. The loss rate, for platelet concentrates, on the other hand, increased in 2009, and--what is noteworthy--especially for manufacturers of pooled platelet concentrates. The loss rate for apheresis platelet concentrates accounted for 5.2% compared to 17.5% for pooled platelet concentrates. As far as the users were concerned, loss rates for platelet concentrates largely remained unchanged with rates between 5% and 6%. Based on the data collected, the supply of blood components for transfusion can be regarded as assured. Nearly 2.9 million liters of plasma for fractionation were collected in Germany in 2009. According to reports from the pharmaceutical industry, of these, 2.6 million liters remained on the German market, of which only 56% were fractionated in this country; no statement can be made on the use of the remaining amount. Many plasma derivatives are not manufactured in Germany, despite the large amount of plasma collected. The supply with these products, however, is assured by imports. Overall, 16,409 autologous and 9,435 allogeneic hematopoietic stem cell preparations were manufactured in 2009, of which 3,382 allogeneic preparations were exported. A total of 3,181 autologous and 2,374 allogeneic preparations were transplanted; 187 of these products from imports. The large number of exported stem cells and the small number of imported stem cells suggest that no serious shortages are to be expected for the supply with these products.

Escape of about five per cent of Lyman-alpha photons from high-redshift star-forming galaxies.

The Lyman-alpha (Lyalpha) emission line is the primary observational signature of star-forming galaxies at the highest redshifts, and has enabled the compilation of large samples of galaxies with which to study cosmic evolution. The resonant nature of the line, however, means that Lyalpha photons scatter in the neutral interstellar medium of their host galaxies, and their sensitivity to absorption by interstellar dust may therefore be greatly enhanced. This implies that the Lyalpha luminosity may be significantly reduced, or even completely suppressed. Hitherto, no unbiased empirical test of the escaping fraction (f(esc)) of Lyalpha photons has been performed at high redshifts. Here we report that the average f(esc) from star-forming galaxies at redshift z = 2.2 is just 5 per cent by performing a blind narrowband survey in Lyalpha and Halpha. This implies that numerous conclusions based on Lyalpha-selected samples will require upwards revision by an order of magnitude and we provide a benchmark for this revision. We demonstrate that almost 90 per cent of star-forming galaxies emit insufficient Lyalpha to be detected by standard selection criteria. Both samples show an anti-correlation of f(esc) with dust content, and we show that Lyalpha- and Halpha-selection recovers populations that differ substantially in dust content and f(esc).

[DHR--ready for take-off]. / Das Deutsche Hämophilieregister am Start.

The collaboration between the Paul-Ehrlich-Institute (PEI) and the GTH as well as the two patient organisations, DHG and IGH has been official since February 2007 with the signing of the collaboration contract. In December 2008, the University of Munich started data enrollment. The DHR is a new software development which includes matters and modules of epidemiological as well as clinical cancer registries. Instead of collaborating with a trustee for personal data the DHR is using a so called "Intermediate". Intermediate is an independent software module installed on a separate server without hard disk and with solely random access memory. It receives personal data from the treaters over the internet, calculates the pseudonyms, which are then forwarded to the database. The Intermediate needs to be protected from data access by the PEI and its operating system and software has to be started afresh with each start. These facts require the involvement of a trustworthy third party. It shuts Intermediate off from the PEI without itself coming into the possession of personal data.

Increase in double-stranded DNA break-related foci in early-stage thymocytes of aged mice.

Cellular and molecular mechanisms involved in aging are notoriously complex. Aging-related immune decline of T lymphocyte function is partly caused by attrition of thymic T cell development, which involves programmed creation and repair of DNA breaks for generating T cell receptors. Aging also leads to significant alterations in the cellular DNA repair ability. We show that higher levels of gamma-phosphorylated H2AX (pH2AX), which marks DNA double-stranded breaks (DSBs), were detectable in early thymocyte subsets of aged as compared to young mice. Also, while only 1-2 foci of nuclear accumulation of pH2AX were detectable in these early thymocytes from young mice, cells from aged mice showed higher numbers of pH2AX foci. In CD4-CD8- double-negative (DN) thymocytes of aged mice, which showed the highest levels of DSBs, there was a modest increase in levels of the DNA repair protein MRE11, but not of either Ku70, another DNA repair protein, or the cell cycle checkpoint protein p53. Thus, immature thymocytes in aged mice show a marked increase in DNA DSBs with only a modest enhancement of repair processes, and the resultant cell cycle block could contribute to aging-related defects of T cell development.

[Report on notifications pursuant to Section 21 German Transfusion Act for 2007]. / Bericht zur Meldung nach section sign 21 TFG für das Jahr 2007.

The present report contains the data collected in 2007, pursuant to Section 21 Transfusionsgesetz (German Transfusion Act), and an analysis of the supply situation over the past eight years. The recording of the data by online reporting is in the meantime well established and generally accepted. As in previous years, all blood donation centers located in Germany transmitted data on the collection, manufacture, import and export of blood components for transfusion, so that meaningful data are available. According to these data, a total of 6.7 million blood collections were performed in 2007. The number of whole blood donations was at the level of previous years, with 4.7 million, whereas the number of apheresis donations rose again, to 1.9 million. The portion of autologous blood collections accounts for only 1.1% and thus continues to decline. Since 2003, the number of red blood cell concentrates prepared has been a constant 4.5 million transfusion units. The decrease in the portion of decay of red blood cell concentrates on the user side is particularly good news. In 2000, it accounted for 5% and in 2007, it was just above 3%, referred to the total quantity of data reported as transfused and decayed. The manufacture of platelet concentrates rose from 366,000 to 480,000 transfusion units between 2003 and 2007. The production of therapeutic single plasmas also markedly increased in 2007 compared with previous years, accounting for 1.2 million transfusion units. In 2007, 2.2 million liters of plasma for fractionation were collected in Germany. This trend went hand in hand with the increasing number of apheresis donations that year. In addition, 1.0 million liters were imported, and, at the same time, 1.8 million liters were exported. The quantity available in Germany from a pure arithmetic point of view of 1.4 million liters was almost entirely allocated to basic fractionation, so that a sufficient plasma supply can be assumed. The assessment of the degree of self-sufficiency is made difficult because of the influence of imports and exports; however, the results show no deficit for plasma derivatives. Due to the fact that manufacturing capacities are still lacking in Germany, recombinant factors need to be imported in their entirety. Since 2003, Germany has by far been the leader in Europe with more than 20 liters of fractionation plasma collected per 1,000 inhabitants. Furthermore, regarding the manufacturing figures of red blood cell concentrates, platelet concentrates, and therapeutic single plasma, Germany is in the top third for all these products compared with other European countries. The manufacture of allogeneic stem cell products for hematopoietic reconstitution, obtained by apheresis, has continuously risen to 4,700 in the reporting year. A large portion of this, 1,810 transplants could be exported while only a small number, 179 preparations, had to be imported. The manufacture of autologous stem cell preparations from cord blood also rose drastically compared with 2006, to more than 10,000 in 2007. It must be emphasized that these products were entirely placed into stock; none were transplanted in the reporting year. The interest in the figures collected in compliance with Section 21, Transfusion Act remains high both in Germany and at the international level. Reliable data are available thanks to the evaluations of trends over years, above all on the availability of blood components for transfusion. In addition, the Paul Ehrlich Institute will continue to strive to meet the demands for high-quality information on the supply situation in the future.

Two-stage focus-hold system for rapid ultra-sensitive read-out of large-area biochips.

We report here the development of a method for holding the focal plane in a fluorescence-based biochip scanner. The fast read-out of large (multiple cm(2)) glass slides as used in modern chip technology imposes severe constraints on the focal system. The limited focal depth of high-NA objectives together with the demand for single-molecule sensitivity challenges traditional focus-hold systems. Various long- and short-term effects disturb the often multiple hour-long data-acquisitioning process and cause blurred or unusable image data. Traditional focus-hold systems were often limited in terms of range, reaction time, sensitivity or demanded a large number of additional components. Our system uses the back-reflected illumination beam always present in total internal reflection fluorescence microscopy to generate an error proportional electrical signal, which in turn drives an actuator correcting the objective-sample distance. The latter consists of a fast but range-limited piezo drive attached to the objective and a slower motor coupled to the microscope's z-drive. With this combination, fast reaction times and virtually unlimited correction distances are possible. We show the applicability by scanning DNA microarrays on 27 x 18-mm(2) glass slides with single-molecule sensitivity over the whole array. Single-fluorescence dyes are imaged as diffraction-limited spots.

[The German haemophilia register]. / Aufbau des Deutschen Hämophilieregisters.

Since December 2004, the Paul-Ehrlich-Institut (PEI) has stepped up its efforts to develop the Deutsche Hämophilieregister (DHR, German Haemophilia Register). In February 2007, during the annual conference of the GTH, the collaboration contract for the establishment and operation of the German Haemophilia Register was signed as a joint project of the patient organisations DHG and IGH, the GTH, and the PEI. The parties involved conferred the responsibility for establishing the German Haemophilia Register to the PEI. They also decided that the German Haemophilia Register should be located at the PEI. Two representatives from each of the four parties involved formed as the steering committee. Since the DHR will collect personal health data, special importance must be attached to the protection of the patients' personal rights and data security. The PEI contacted the data protection representative of the Federal Republic of Germany and the federal states with the aim of a data protection concept acceptable to all parties involved. A favourable opinion from all data protection representatives was formulated in May 2007 so thus programming the database was accepted in February 2008. In the following testing period enlargements and adaptations were detected and projected. The security measures demanded by the data protection representatives will delay the official launching of the German Haemophilia Register as online register for some months.

[Report on notifications pursuant to Section 21 German Transfusion Act for 2005 and 2006]. / Bericht zur Meldung nach SS 21 TFG für die Jahre 2005 und 2006.

In 2007, for the first time since the introduction of reporting pursuant to Section 21 of the German Transfusion Act, a timely report including data collected concerning the previous year can be published. In this report on the years 2005 and 2006, a trend analysis over the 7 years since 2000 can be presented. Thereby the favourable result is confirmed that, thanks to sustained reliable reporting on collection, manufacture, import and export of blood and blood products, interesting and meaningful data on the amount of available medicinal products are provided. The amount of heterologous donations increased in 2006 again up to 6.4 million, after a decrease observed since 2003. The share of whole blood donations during the past three years was constantly about 4.7 million, out of which ca. 4.5 million erythrocyte concentrates are manufactured. While in 2005 with 1.8 million Litres plasma for fractionation the lowest amount since 2002 had been collected, the figure increased again in 2006 up to 2.1 million Litres, as a consequence of enhanced apheresis donations. About 40 % thereof are exported. On average, 1.75 million Litres are available on the German market; up to 1.4 million Litres are used for basis fractionation in Germany. After introduction of on-line submission as the obligatory way of reporting, the response rate concerning collection of blood and blood components from allergenic donors, and manufacture, import and export as well is 95 %. In contrast, in 2006 only 64 % of consuming institutions reported; this means 8 % less than in 2005. Hence, with regard to the collection of data on the usage of blood products, an unacceptably high rate of missing report from the side of health care facilities persists. Therefore, regrettably even after 7 years, it was not possible to generate a solid basis for the assessment of the demand to be met and thus the supply situation. As a potential approach to a tentative judgement of the supply situation concerning plasma derivatives, a query on the sales figures was performed. A comparison with the reported figures on consumption, however, was of little relevance in many cases. The reported number of haemophilia patients has to be regarded as considerably too low. With the upcoming introduction of a German Haemophilia Register, an improvement of the data base is intended.

[Report on notifications with respect to section sign 21 German Transfusion Act for 2003 and 2004]. / Bericht zur Meldung nach [section sign] 21 TFG für die Jahre 2003 und 2004.

Data with respect to the section sign 21 Transfusion Act concerning collection, manufacture, imports and exports show consolidation, but a non-plausible discrepancy due to the considerably lower figures of product consumption. Failure of numerous institutions to report their consumption precludes an interpretation as surplus supply. Homologous blood donations peaked in 2003 (6.8 million) with 2.4 million thereof being apheresis, which decreased to 1.6 million in 2004. Manufacture of red cells reached a peak of 4.52 million in 2004, with 74% attributable to the Red Cross. Reported consumption differs so significantly that the PEI considers utilising the legal possibility to compare the distribution lists of blood services with submitted user data. The 2.4 million litres plasma for fractionation in 2003 constitute the hitherto highest value, with a 62% share of apheresis; the latter decreased in 2004 to 50% of 1.9 million litres, paralleled by a decrease in commercial plasma centres. The new request (2004) for figures of fractionation in Germany revealed 734,224 litres, i.e. 45% of the calculated available amount on the German market. Isolated consideration of the German situation concerning plasma derivatives is impossible due to complex trade and manufacture in various federal states. Assessment of the supply situation is further impaired by missing data from users. Regarding haemophilia treatment, an improvement is intended by establishing a German Haemophilia Register.

Haploinsufficiency of the SERPINA6 gene is associated with severe muscle fatigue: A de novo mutation in corticosteroid-binding globulin deficiency.

Corticosteroid-binding globulin (SERPINA6) deficiency is an extremely rare hereditary disorder characterized by reduced corticosteroid-binding capacity with normal or low plasma corticosteroid-binding globulin concentration, and normal or low basal cortisol levels associated with hypo-/hypertension and muscle fatigue. Here, we present a patient with severe muscle fatigue, normal blood pressure, and abnormal high saliva cortisol levels following a standardized stress test. This patient was found heterozygous for a de novo 367 asparagine-encoding variant of the corticosteroid-binding globulin gene, previously described as "transcortin Lyon". Both parents were homozygous for the ("wildtype") 367 aspartate-encoding allele. To the best of our knowledge, this case represents the first de novo mutation reported for corticosteroid-binding globulin deficiency, implicating a pathogenic role of variants of SERPINA6 in some cases of muscle fatigue.

[Working hours and job satisfaction among physicians in hospitals and general practice in Munich. Results of an anonymous questionnaire]. / Arbeitszeit und Arbeitszufriedenheit angestellter und beamteter Arzte in München. Ergebnisse einer anonymen Befragung.

PURPOSE: In autumn 2004 the local association of physicians (Arztlicher Kreis- und Bezirksverband München) performed a survey among employed physicians in Munich on working hours and working conditions. The aim of the study was to assess the extent to which the German law on working hours is actually implemented in employed physicians, and to obtain information about their work satisfaction. METHODS: A questionnaire was sent to all employed physicians in hospitals and medical practices. Participants were asked to give anonymous information and send it back per mail. RESULTS: In total, 2450 out of 5461 physicians took part in the survey. 45% reported that their working hours do not meet the German law on working hours of 1994. 44.4% stated that overtime is not fully recognized by their employers. 43.5% think the job would become more attractive if the law was implemented. 63.3% expect an income loss with the implementation. 53.7% are thinking about quitting their job. For 59.9% the burden of long working hours is an important reason for this. Women are more likely to be given a limited employment contract than men, and their overtime is more rarely recognized in full. CONCLUSION: Many employed physicians in Munich are dissatisfied with their job. The high burden of long working hours is a main reason for this.

Frontotemporal dementia progresses to death faster than Alzheimer disease.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood. METHODS: This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings. RESULTS: The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 +/- 1.2 vs 11.8 +/- 0.6 years, p < 0.0001; median survival from initial clinic presentation, 3.0 +/- 0.5 vs 5.7 +/- 0.1 years, p < 0.0001). Survival was similarly reduced in the related conditions corticobasal degeneration and progressive supranuclear palsy. Survival in the semantic dementia subtype of FTLD (11.9 +/- 0.2 years from onset and 5.3 +/- 0.4 years from presentation), however, was significantly longer than in FTD and did not differ from AD. Hazards analysis to determine factors affecting survival in FTLD showed no effect of age at onset, sex, education, family history, or neuropsychiatric profile. Among neuropsychological measures examined, impaired letter fluency had a significant association with reduced survival. Associated ALS significantly reduced survival in FTLD. The presence of tau-positive inclusions was associated with the slowest progression. CONCLUSIONS: Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.