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Background The ultra-high risk (UHR) paradigm allows early contact with patients developing acute psychosis and the study of treatment effects on the underlying pathology. Methods 29 patients with first acute psychosis according to CAARMS criteria (transition patients, TP) (T0) and thereof 22 patients after two-year follow-up (mean 788 d) (T1) underwent 1H-/31P-MR spectroscopy of the prefrontal (DLPFC) and anterior midcingulate (aMCC) cortices and the thalamus. N-acetylaspartate (NAA), glutamate (Glu, Glx), energy (PCr, ATP) and phospholipid metabolites (PME, PDE) were compared to 27 healthy controls by ANCOVA and correlated with patients' symptom ratings (BPRS-E, SCL-90R). For longitudinal analysis, linear mixed model (LMM) and ANCOVA for repeated measures were used. Results DLPFC : In patients, NAA and PME were decreased bilaterally and Glu on the left side at T0. Left-sided Glu and NAA (trend) and bilateral Glx increased during follow-up. Thalamus : In TP, bilateral NAA, left-sided Glu and right-sided Glx were decreased at T0; bilateral NAA and left-sided Glx increased during follow-up. aMCC : In TP, bilateral NAA, right-sided Glu, and bilateral PME and PDE were decreased, while left-sided PCr was increased at T0. No changes were observed during follow-up. Conclusion Regardless of the long-term diagnosis, the psychotic state of illness includes disturbed neuronal function in the DLPFC, thalamus and aMCC. Treatment-as-usual (TAU), including antipsychotic/antidepressant medication and supportive psychotherapy, had an effect on the thalamo-frontal area but not or less pronounced on the neurometabolic deficits of the aMCC.

Objective Regulatory guidelines for preclinical cartilage repair studies suggest large animal models (e.g., sheep, goat, [mini]-pig, or horse) to obtain results representative for humans. However, information about the 3-dimensional thickness of articular cartilage at different implantation sites in these models is limited. Design To identify the most suitable site for experimental surgery, cartilage thickness at the medial femoral condyle (MFC), lateral femoral condyle (LFC), and trochlea in ovine, caprine, and porcine cadaver stifle joints was systematically measured using hematoxylin-eosin staining of 6 µm paraffin sections and software-based image analysis. Results Regarding all ventral-dorsal regions of the MFC, goat showed the thickest articular cartilage (maximal mean thickness: 1299 µm), followed by sheep (1096 µm) and mini-pig (604 µm), with the highest values in the most ventral and dorsal regions. Also for the LFC, the most ventral regions showed the thickest cartilage in goat (maximal mean thickness: 1118 µm), followed by sheep (678 µm) and mini-pig (607 µm). Except for the mini-pig, however, the cartilage thickness on the LFC was consistently lower than that on the MFC. The 3 species also differed along the transversal measuring points on the MFC and LFC. In contrast, there were no consistent differences for the regional cartilage thickness of the trochlea among goat and sheep (≥780 µm) and mini-pig (≤500 µm). Conclusions Based on their cartilage thickness, experimental defects on goat and sheep MFC may be viable options for preclinical cartilage repair studies, in addition to well-established horse models.

There is conflicting evidence about the comparative diagnostic accuracy of the Agatston score versus computed tomography angiography (CTA) in patients with suspected obstructive coronary artery disease (CAD).To determine whether CTA is superior to the Agatston score in the diagnosis of CAD.In total 2452 patients with stable chest pain and a clinical indication for invasive coronary angiography (ICA) for suspected CAD were included by the Collaborative Meta-analysis of Cardiac CT (COME-CCT) Consortium. An Agatston score of400 was considered positive, and obstructive CAD defined as at least 50% coronary diameter stenosis on ICA was used as the reference standard.Obstructive CAD was diagnosed in 44.9% of patients (1100/2452). The median Agatston score was 74. Diagnostic accuracy of CTA for the detection of obstructive CAD (81.1%, 95% confidence interval [CI]: 77.5 to 84.1%) was significantly higher than that of the Agatston score (68.8%, 95% CI: 64.2 to 73.1%, p0.001). Among patients with an Agatston score of zero, 17% (101/600) had obstructive CAD. Diagnostic accuracy of CTA was not significantly different in patients with low to intermediate (1 to100, 100-400) versus moderate to high Agatston scores (401-1000,1000).Results in our international cohort show CTA to have significantly higher diagnostic accuracy than the Agatston score in patients with stable chest pain, suspected CAD, and a clinical indication for ICA. Diagnostic performance of CTA is not affected by a higher Agatston score while an Agatston score of zero does not reliably exclude obstructive CAD.• CTA showed significantly higher diagnostic accuracy (81.1%, 95% confidence interval [CI]: 77.5 to 84.1%) for diagnosis of coronary artery disease when compared to the Agatston score (68.8%, 95% CI: 64.2 to 73.1%, p0.001). • Diagnostic performance of CTA was not affected by increased amount of calcium and was not significantly different in patients with low to intermediate (1 to100, 100-400) versus moderate to high Agatston scores (401-1000,1000). • Seventeen percent of patients with an Agatston score of zero showed obstructive coronary artery disease by invasive angiography showing absence of coronary artery calcium cannot reliably exclude coronary artery disease.

Objective To quantify the effects of annuloplasty rings designed to treat ischemic/functional mitral regurgitation on left ventricular septal-lateral (S-L) and commissure-commissure (C-C) dimensions. Methods Radiopaque markers were placed as opposing pairs on the S-L and C-C aspects of the mitral annulus and the basal, equatorial, and apical level of the left ventricle (LV) in 30 sheep. Ten true-sized Carpentier-Edwards Physio (PHY), Edwards IMR ETlogix (ETL), and GeoForm (GEO; all from Edwards Lifesciences, Irvine, Calif) annuloplasty rings were inserted in a releasable fashion. After 90 seconds of left circumflex artery occlusion with the ring implanted (RING), 4-dimensional marker coordinates were obtained using biplane videofluoroscopy. After ring release, another data set was acquired after another 90 seconds of left circumflex artery occlusion (NO RING). S-L and C-C diameters were computed as the distances between the respective marker pairs at end-diastole. Percent change in diameters was calculated between RING versus NO RING as 100 × (diameter in centimeters [RING] − diameter in centimeters [NO RING])/diameter in centimeters [NO RING]). Results Compared with NO RING, all ring types (PHY, ETL, and GEO) reduced mitral annular S-L dimensions by −20.7 ± 5.6%, −26.8 ± 3.9%, and −34.5 ± 3.8%, respectively. GEO reduced the S-L dimensions of the LV at the basal level only by −2.3 ± 2.4%, whereas all other S-L dimensions of the LV remained unchanged with all 3 rings implanted. PHY, ETL, and GEO reduced mitral annular C-C dimensions by −17.5 ± 4.8%, −19.6 ± 2.5, and −8.3 ± 4.9%, respectively, but none of the rings altered the C-C dimensions of the LV. Conclusions Despite radical reduction of mitral annular size, disease-specific ischemic/functional mitral regurgitation annuloplasty rings do not induce relevant changes of left ventricular dimensions in the acutely ischemic ovine heart.

Objective Papillary muscle (PM) displacement contributes to ischemic/functional mitral regurgitation (IMR/FMR). The displaced PMs pull the mitral leaflets into the left ventricle (ie, toward the apex) thus hampering leaflet coaptation. Intuitively apical leaflet tethering results from apical PM displacement. The 3-dimensional directions of PM displacement are, however, incompletely characterized. Methods Data from in vivo ovine models of IMR (6-8 weeks of posterolateral infarction, n = 12) and FMR (9-21 days of rapid left ventricular pacing, n = 11) were analyzed. All sheep had radiopaque markers implanted on the anterior and posterior PM (PPM) tips, around the mitral annulus, and on the left ventricular apex. To explore 3-dimensional PM displacement directions, differences in marker coordinates were calculated at end-systole before and during IMR/FMR using a right-handed coordinate system centered on the mitral annular “saddle horn” with the y-axis passing through the apical marker. Results No apical PM displacement was observed during either IMR or FMR. The anterior PM displaced laterally during FMR. Posterolateral PPM displacement was observed during IMR and FMR. Conclusions Experimental in vivo ovine models suggest posterolateral PPM displacement as a predominant pathomechanism leading to apical leaflet tethering during IMR/FMR.

Background Prosthesis-patient mismatch (PPM) after aortic valve replacement (AVR) may affect survival but data are conflicting. It is assessed by relating effective orifice area (EOA) to body surface area (EOAi). EOA is patient-specific as the result of flow-velocity times area at the individual patient's outflow tract levels (LVOTA) divided by trans-prosthetic flow velocity. However, some studies use projected EOAs (i.e., valve size associated EOAs from other patient populations) to assess how PPM affects outcome. Methods We analyzed 76 studies addressing hemodynamic outcome and/or mortality after bioprosthetic AVR. Results In 48 studies, projected or measured EOA for calculation of EOAi and PPM assessment was used (of which 25 demonstrated an effect on survival). We identified 28 additional studies providing measured EOA values and the corresponding Bernoulli's pressure gradients after AVR. Despite EOA being a patient-specific parameter, 77% of studies assessing a PPM impact on survival used projected EOAs. The 28 studies are providing measured EOA values and the corresponding Bernoulli's pressure gradients in patients after AVR showed a highly significant, linear relationship between EOA and Bernoulli's gradient. Considering this relationship, it is surprising that relating EOA to body surface area (BSA) (EOAi) is standard but relating pressure gradients to BSA is not. Conclusion We conclude that the majority of studies assessing PPM have used false assumptions because EOA is a patient-specific parameter and cannot be transferred to other patients. In addition, the use of EOAi to assess PPM may not be appropriate and could explain the inconsistent relation between PPM and survival in previous studies.

Respiratory tract infections (RTI) can take a serious course under immunosuppression. Data on the impact of the underlying pathogens are still controversial. Samples from the upper (n = 322) and lower RT (n = 169) were collected from 136 children and 355 adults; 225 among them have been immunocompromised patients. Exclusion criteria were presence of relevant cultivable microorganisms, C-reactive protein > 20 mg/dl, or procalcitonin > 2.0 ng/ml. Samples were tested by PCR for the presence of herpesviruses (HSV-1/-2; VZV; CMV; HHV6; EBV), adenoviruses, bocaviruses, entero-/rhinoviruses (HRV), parechoviruses, coronaviruses, influenza viruses (IV), parainfluenza viruses as well as for pneumoviruses (HMPV and RSV), and atypical bacteria (Mycoplasma pneumoniae, M.p.; Chlamydia pneumoniae, C.p.). Viral/bacterial genome equivalents were detected in more than two-thirds of specimens. Under immunosuppression, herpesviruses (EBV 30.9%/14.6%, p p p = 0.012) were frequently observed, mainly through their reactivation in adults. Immunocompromised adults tended to present a higher RSV prevalence (6.4%/2.4%, p = 0.078). Immunocompetent patients were more frequently tested positive for IV (15.0%/5.8%, p = 0.001) and M.p. (6.4%/0.4%, p

Aims High concentrations of air pollutants are associated with increased risk for myocardial infarction. The European Union has defined statutory limits for air pollutants based on upper absolute concentrations. We evaluated the association between rapid changes in air pollutants and the risk of myocardial infarction independently of absolute concentrations. Methods and results Using a hospital-based case-crossover study, effects of 24h changes of nitrogen oxides (NOX/2), particulate matter (PM10), and ozone on the risk of myocardial infarction was assessed in 693 patients. In the overall population, increases of NOX of more than 20 µg/m3 within 24 h were associated with an increase in the risk of myocardial infarction by up to 121% (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.19–4.08). Comparably, rapid increases of NO2 of more than 8 µg/m3 tended to increase myocardial infarction risk by 73% (OR 1.73, 95% CI 0.91–3.28) while myocardial infarction risk decreased by 60% after a decrease of NO2 concentration of more than 8 µg/m3 (OR 0.4, 95% CI 0.21–0.77), suggesting a close-to-linear association. While results for ozone concentrations were ambiguous, rapid change in PM10 was not associated with myocardial infarction risk. Conclusion Dynamics and extent of increase in nitrogen oxide concentrations may be an independent risk factor for myocardial infarction. As there are currently no European Union statutory limits reflecting this dynamic variation of air pollutants on a daily basis, the results urgently call for confirming studies in different geographical regions to verify the observations.

SummaryObjective Most epileptic seizures occur unexpectedly and independently of known risk factors. We aimed to evaluate the clinical significance of patients’ perception that weather is a risk factor for epileptic seizures. Methods Using a hospital-based, bidirectional case-crossover study, 604 adult patients admitted to a large university hospital in Central Germany for an unprovoked epileptic seizure between 2003 and 2010 were recruited. The effect of atmospheric pressure, relative air humidity, and ambient temperature on the onset of epileptic seizures under temperate climate conditions was estimated. Results We found a close-to-linear negative correlation between atmospheric pressure and seizure risk. For every 10.7 hPa lower atmospheric pressure, seizure risk increased in the entire study population by 14% (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.01–1.28). In patients with less severe epilepsy treated with one antiepileptic medication, seizure risk increased by 36% (1.36, 1.09–1.67). A high relative air humidity of >80% increased seizure risk in the entire study population by up to 48% (OR 1.48, 95% CI 1.11–1.96) 3 days after exposure in a J-shaped association. High ambient temperatures of >20°C decreased seizure risk by 46% in the overall study population (OR 0.54, 95% CI 0.32–0.90) and in subgroups, with the greatest effects observed in male patients (OR 0.33, 95% CI 0.14–0.74). Significance Low atmospheric pressure and high relative air humidity are associated with an increased risk for epileptic seizures, whereas high ambient temperatures seem to decrease seizure risk. Weather-dependent seizure risk may be accentuated in patients with less severe epilepsy. Our results require further replication across different climate regions and cohorts before reliable clinical recommendations can be made.

The ultra-high risk (UHR) paradigm allows early contact with patients developing acute psychosis and the study of treatment effects on the underlying pathology.29 patients with first acute psychosis according to CAARMS criteria (transition patients, TP) (T0) and thereof 22 patients after two-year follow-up (mean 788 d) (T1) underwentDLPFC: In patients, NAA and PME were decreased bilaterally and Glu on the left side at T0. Left-sided Glu and NAA (trend) and bilateral Glx increased during follow-up. Thalamus: In TP, bilateral NAA, left-sided Glu and right-sided Glx were decreased at T0; bilateral NAA and left-sided Glx increased during follow-up. aMCC: In TP, bilateral NAA, right-sided Glu, and bilateral PME and PDE were decreased, while left-sided PCr was increased at T0. No changes were observed during follow-up.Regardless of the long-term diagnosis, the psychotic state of illness includes disturbed neuronal function in the DLPFC, thalamus and aMCC. Treatment-as-usual (TAU), including antipsychotic/antidepressant medication and supportive psychotherapy, had an effect on the thalamo-frontal area but not or less pronounced on the neurometabolic deficits of the aMCC.

Background: To evaluate if weather or changes in weather are risk factors for Bell’s palsy (BP) as exposure to draught of cold air has been popularly associated with the occurrence of BP. Methods: Using a multicenter hospital-based case-crossover study, we analyzed the association between ambient temperature, atmospheric pressure, relative air humidity or their 24 h changes and the risk for BP in 825 patients or subgroups. Results: One day following a 24 h increase in atmospheric pressure of more than 6 hPa, the risk for BP increased by 35% (OR 1.35; 95% CI 1.03–1.78) in the overall population. The risk for BP more than doubled in patients with diabetes mellitus after rapid variations in ambient temperature, independent of the direction (temperature decrease > 2.25°C; OR 2.15; 95% CI 1.08–4.25; temperature increase between 0.75 and 2.25°C; OR 2.88; 95% CI 1.63–5.10). Conclusions: Our findings support the hypothesis of an association between certain weather conditions and the risk for BP with acute changes in atmospheric pressure and ambient temperature as the main risk factors. Additionally, contrasting results for risk of BP after temperature changes in the diabetic and non-diabetic subgroups support the paradigm of a diabetic facial palsy as a distinct disease entity.

Das thematisch sehr breite Spektrum der Digitalisierung im Offentlichen Bereich wird durch eine Vielzahl von interessierten Berufsgruppen mit Schwerpunkt auf Lehre, Forschung, Serviceangeboten und Vertretung von verbandlichen Interessen von Wirtschaft sowie Verwaltung begleitet. Gemeinsam ist diesen hinsichtlich ihrer Motive sonst sehr heterogenen Stakeholdern, dass sie die Entwicklung der Digitalisierung weiter vorantreiben, Trends erkennen, Nischen fur die eigene Profilierung bzw. Marktpositionierung nutzen und Entscheidungstrager mit eigenen Einsichten erhellen, evtl. auch von Vorschlagen fur Managemententscheidungen uberzeugen und sich selbst in ihrem Segment als Mitgestalter der Situation einbringen wollen.

Background Partial nephrectomy and radical nephrectomy are the relevant surgical therapy options for localised renal cell carcinoma. However, debate regarding the effects of these surgical approaches continues and it is important to identify and summarise high-quality studies to make surgical treatment recommendations. Objectives To assess the effects of partial nephrectomy compared with radical nephrectomy for clinically localised renal cell carcinoma. Search methods We searched CENTRAL, MEDLINE, PubMed, Embase, Web of Science, BIOSIS, LILACS, Scopus, two trial registries and abstracts from three major conferences to 24 February 2017, together with reference lists; and contacted selected experts in the field. Selection criteria We included a randomised controlled trial comparing partial and radical nephrectomy for participants with small renal masses. Data collection and analysis One review author screened all of the titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Next, two review authors independently assessed full-text reports, identified relevant studies, evaluated the eligibility of the studies for inclusion, assessed trial quality and extracted data. The update of the literature search was performed by two independent review authors. We used Review Manager 5 for data synthesis and data analyses. Main results We identified one randomised controlled trial including 541 participants that compared partial nephrectomy to radical nephrectomy. The median follow-up was 9.3 years. Based on low quality evidence, we found that time-to-death of any cause was decreased using partial nephrectomy (HR 1.50, 95% CI 1.03 to 2.18). This corresponds to 79 more deaths (5 more to 173 more) per 1000. Also based on low quality evidence, we found no difference in serious adverse events (RR 2.04, 95% CI 0.19 to 22.34). Findings are consistent with 4 more surgery-related deaths (3 fewer to 78 more) per 1000. Based on low quality evidence, we found no difference in time-to-recurrence (HR 1.37, 95% CI 0.58 to 3.24). This corresponds to 12 more recurrences (14 fewer to 70 more) per 1000. Due to the nature of reporting, we were unable to analyse overall rates for immediate and long-term adverse events. We found no evidence on haemodialysis or quality of life. Reasons for downgrading related to study limitations (lack of blinding, cross-over), imprecision and indirectness (a substantial proportion of patients were ultimately found not to have a malignant tumour). Based on the finding of a single trial, we were unable to conduct any subgroup or sensitivity analyses. Authors' conclusions Partial nephrectomy may be associated with a decreased time-to-death of any cause. With regards to surgery-related mortality, cancer-specific survival and time-to-recurrence, partial nephrectomy appears to result in little to no difference.

Objectives Hybrid composite restorations in posterior teeth were evaluated over 15 years using the semiquantitative Clinical, Photographic and Micromorphologic (CPM) index. It was a further aim to quantitate the surface morphology by three-dimensional scanning electron microscopy (3D-SEM). Methods Thirty seven hybrid composite restorations (Ketac-Bond/Visio-Molar X, ESPE, Seefeld/Germany) were longitudinally followed up. Parallel to clinical assessment replicas were taken at baseline, after 1, 5, 10 and 15 years and evaluated by SEM, and profilometrical analyses of 3D-SEM data were computed. The profilometrical results were statistically analysed by ANOVA. The level of significance was set to p Results The semiquantitative micromorphological evaluation exhibited the most considerable deterioration within the first year and up to 5 years of function. Less change was detected during the next 10 years. The profilometrical quantification showed raising depth of the negative marginal ledges with a mean of 27.2 μm (range 0.6–94.5 μm) after 10 years, with no statistically significant changes from 5 to 10 and 10 to 15 years. The 3D-SEM revealed marginal grooves beneath the level of the ledges (mean 34.5 μm after 5 years) within the bonding zone, exposing enamel margins. Leakages, marginal fractures and surface roughness did not seriously deteriorate the quality of restorations. Conclusions Hybrid composite restorations of Class I and II cavities surviving the first five years performed well over 15 years of function. Quantitative 3D-SEM profilometrical measurements revealed the dynamics of marginal behaviour over time. Clinical significance Long-term parallel clinical and micromorphological evaluation of posterior composite restorations of Class I and Class II cavities documented the clinical safety and acceptable longevity. The longitudinal 3D micromorphologic assessment of the surface changes and of the marginal behaviour revealed deteriorating as well as improving factors hidden in clinical performance.

Exercise-induced changes of transverse proton relaxation time (T2), tissue perfusion and metabolic turnover were investigated in the lower back muscles of volunteers by applying muscle functional MRI (mfMRI) and diffusion-weighted imaging (DWI) before and after as well as dynamic 31P-MRS during the exercise. Inner (M. multifidus, MF) and outer lower back muscles (M. erector spinae, ES) were examined in 14 healthy young men performing a sustained isometric trunk-extension. Significant phosphocreatine (PCr) depletions ranging from 30% (ES) to 34% (MF) and Pi accumulations between 95% (left ES) and 120%–140% (MF muscles and right ES) were observed during the exercise, which were accompanied by significantly decreased pH values in all muscles (∆pH ≈ –0.05). Baseline T2 values were similar across all investigated muscles (approximately 27 ms at 3 T), but revealed right–left asymmetric increases (T2,inc) after the exercise (right ES/MF: T2,inc = 11.8/9.7%; left ES/MF: T2,inc = 4.6/8.9%). Analyzed muscles also showed load-induced increases in molecular diffusion D (p = .007) and perfusion fraction f (p = .002). The latter parameter was significantly higher in the MF than in the ES muscles both at rest and post exercise. Changes in PCr (p = .03), diffusion (p

An increase in acute autochthonous hepatitis E virus (HEV) infections has been recorded in Germany. These are suspected to be zoonotically transmitted from wild boar, deer and domestic pig. The latter may represent a major reservoir for HEV. In this study, 537 sera from humans living in Westphalia and Lower Saxony, representing areas of high pig density in Germany, were tested for the presence of HEV-specific antibodies. Among them were 302 individuals with occupational, direct contact to pigs and 235 individuals without direct contact to pigs. Two commercial tests and one in-house assay were applied for the detection of HEV-specific immunoglobulin G (IgG) antibodies. Sera were also tested in an assay that detects all classes of HEV-specific antibodies. Depending on the test used, the seroprevalence ranged from 4.1 to 27.9 %. Exposition to pigs was found to be associated with a significantly higher seroprevalence in subjects with contact to pigs (13.2-32.8 %) compared with that in non-exposed humans (7.7-21.7 %). In particular, individuals younger than 40 years with occupational exposure exhibited a markedly higher HEV seroprevalence compared with non-exposed individuals of that age group. In general, HEV seroprevalence increased with age resulting in a similar prevalence level in the age group of ≥ 50 years for exposed and non-exposed individuals. Analysis of all sera by a commercial anti-HEV IgM ELISA revealed 35 positive and 25 borderline samples. However, only one positive serum could be confirmed by an IgM line assay. Selected samples from IgM and/or IgG as well as total HEV antibody-positive individuals were also tested for the presence of HEV RNA. In one of the 78 samples, the only IgM ELISA positive and IgM line assay confirmed sample, RNA of HEV genotype 3 was detected. This sequence has high similarity to HEV sequences obtained from wild boars and domestic pigs from Germany and The Netherlands. This study demonstrates that in addition to the consumption of raw or undercooked meat, direct contact to pigs has to be considered as an additional risk factor for HEV infection.

Quality of life (QOL) is an important issue in patients with amyotrophic lateral sclerosis (ALS). QOL measurements can help the support care team understand how to maintain or improve QOL in ALS patients. The purpose of this study was to describe the relationship between health-related QOL, disease severity and social support in ALS patients. In the current study, 49 German ALS patients were evaluated using the European quality of life score (EQ-5D), ALS Functional Rating Scale in its revised form (ALSFRS-R), Social Support Questionnaire (F-SozU K-14) and the Beck depression inventory. Data concerning patient history and socioeconomic background were collected using a semi-structured interview. Age, gender, number of children, habitation, socioeconomic status and disease duration were not significantly related to health-related QOL (EQ-5D). Positive correlations were found between the ALSFRS-R, social support and health-related QOL, whereas depression was negatively correlated with the ALSFRS-R score. A multiple linear regression model indicated a significant influence of the ALSFRS-R score on health-related QOL in ALS patients, with an additional trend for social support as a predictor. These results suggest that because of the logarithmic association between measures, compensatory therapy for loss of health-related QOL should be optimised during the course of the disease in ALS patients.

FLT3 mutations represent the most frequent molecular aberrations in acute myeloid leukemia (AML), and are associated with a higher probability of relapse and worse outcome. Activating mutations of FLT3 predominantly comprise internal tandem duplications (FLT3-ITDs), and can be detected in up to 30%

Background Glutamatergic dysfunction, deregulated mitochondrial metabolism and alterations of membrane phospholipids are considered as core pathology of psychosis, and have been studied in schizophrenic illness using magnetic resonance spectroscopy (MRS). Combining 1H- and 31P-MRS, this study investigates these aspects in Ultra-high risk (UHR-T) patients right after transition to psychosis (T0) and after a two years interval (T1) in a naturalistic longitudinal design, including treatment as usual by cognitive-behavioral therapy (CBT) and pharmacotherapy with second generation antipsychotics. Methods We applied 3 T chemical shift imaging (3D 31P-MRS, 2D 1H-MRS) and hippocampal single-voxel 1H-MRS in 29 neuroleptic-naïve UHR-T patients and 27 healthy controls matched for age and gender. Glutamate (Glu) and N-acetyl-aspartate (NAA) reflect neuronal functioning, phosphocreatine (PCr), adenosine triphosphate (ATP) and NAA indicate mitochondrial function and energy metabolism, and phosphomono- and diester indicate the balance of phospholipid synthesis (PME) and -breakdown (PDE). Psychopathology was assessed using the CAARMS, BPRS-E and SCL-90-R. Generalized linear mixed models were used to examine case-control differences in metabolite changes over time, and associations with clinical improvement. Results At T0, cross-sectional analysis revealed decreased NAA, Glu and PME levels in the left dorsolateral prefrontal cortex (DLPFC) and thalamus of UHR-T patients as well as higher PCr and lower PDE levels in the right hippocampus. (ii) Follow-up analysis (T1) showed in patients a significant increase of Glu in the bilateral DLPFC and the right thalamus, while a decrease of PCr was observed in the right hippocampus. Discussion The observed metabolite pattern at T0 likely reflects a hypofunction of glutamatergic neurons and a disturbance of membrane phospholipid turnover in fronto-thalamo-hippocampal networks during the first acute onset phase of psychotic illness. The pattern of changes at T1 is suggestive for an improvement of neuronal functioning in these networks that is caused by therapy, and presumably underlies the observed clinical improvement in terms of negative symptoms and cognitive impairment.

The risk of zoonotic human infection caused by European porcine influenza virus strains was estimated in German regions with a high pig density. Sera from 622 healthy volunteers were collected between April 2009 and November 2011, mainly in Westphalia and western Lower Saxony. These included 362 subjects with occupational contact to pigs and 260 blood donors without any direct exposition to pigs. Samples were analysed by the haemagglutination inhibition (HI) assay against a panel of six swine viruses of subtypes avian-like H1N1 and human-like H3N2 as well as against human H1N1 and H3N2 viruses including the pandemic H1N1 strain of 2009. Reciprocal HI titres ≥20 were quoted as seroreactive. Compared to the control group, a significantly higher proportion of subjects with direct contact to pigs exhibited seroreactivity against porcine antigens of the avian-like H1N1 (37.0 %/7.7 %), the human-like H3N2 (59.7 %/43.1 %), the pandemic H1N1 strain of 2009 (51.7 %/26.5 %) and against a historic seasonal H3N2 strain that is closely related antigenetically to currently circulating human-like H3N2 viruses of European pigs (57.5 %/36.5 %). This trend was also observed when a reciprocal HI titre ≥40 was chosen as cut-off. Particularly, in younger subjects, the differences in seroreactivity against porcine strains between the exposed and non-exposed group were significant. The data indicate a higher risk of infection in the exposed individuals.

Simvastatin, a cholesterol-lowering drug, is reported to have immunomodulatory properties that attenuated acute lung injury independent of their major lipid lowering effects. Based on these reports, simvastatin is expected to be used for influenza prophylaxis and treatment. The present study evaluated the efficacy of simvastatin against influenza A/PR/8/34 virus infection in a murine model. In a first study, simvastatin was administered orally. To achieve high plasma levels, intraperitoneal application was used in a second study. Survival, body weight loss, viral titers in lung and trachea, and histologic lung injury were measured. Surprisingly, treatment with simvastatin resulted in lower survival rates and in more distinct body mass loss in comparison to virus-infected control mice. Furthermore, the viral load in lungs and tracheas as well as histopathological lesions were not reduced by simvastatin. Overall, these results showed that simvastatin failed to protect mice against influenza virus infection. J Med. Virol. 85:1978–1982, 2013. © 2013 Wiley Periodicals, Inc.

The hereditary kidney disease Alport syndrome (AS) has become a treatable disease: intervention with angiotensin-converting enzyme (ACE)-inhibitors delays end stage renal failure by years. The efficiency of ACE inhibition depends on the onset of therapy-the earlier the better. Therefore, early diagnosis has become increasingly important. To date, robust diagnosis requires renal biopsy and/or expensive genetic analysis, which is mostly performed late after onset of the profound clinical symptoms of this progressive renal disease. Thus, disease biomarkers enabling low-invasive screening are urgently required.Fourteen potential proteomic candidate markers (proteins) identified in a previous study in sera from patients exhibiting manifest AS were evaluated in the plasma, serum, and urine collected from a cohort of 132 subjects, including patients with AS and other nephropathies and healthy controls. Quantitation was performed by immunoassays.The serum and plasma levels of none of the 14 proteins evaluated were significantly different among the three groups and therefore could not be used to discriminate between the groups. In contrast, the levels of various biomarker combinations in the urine were significantly different between AS patients and healthy controls. Importantly, some combinations had the potential to discriminate between AS and other nephropathies.These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients.

The collection and analysis of applied forces is an essential part of the ergonomic evaluation of workplaces. In industrial companies, direct measurements and estimates are currently considered to be accepted methods. The present study identifies alternatives to the accepted procedures for the determination of action-forces and analysed one of these in detail: force-matching.

Objectives: There is a growing need for studies to measure how patients feel supported in their autonomy. The Health Care Climate Questionnaire (HCCQ) is an instrument to assess the physician’s support to motivate the patient to take personal responsibility for his/her health. The aim of this study was to translate the HCCQ into German and validate the translated version, called the HCCQ-Deutschland (HCCQ-D). Study Design and Setting: In a cross-sectional study, we translated and culturally adapted the HCCQ, then administered the questionnaire to primary care patients from nine general practices in Germany. We used the European Task Force on Patient Evaluations of General Practice questionnaire (EUROPEP) to assess convergent validity. Subsequently, we performed Cronbach a to assess internal consistency and exploratory factor analysis to evaluate the underlying factor structure of the items. Results: Of 450 questionnaires, we included 351 (78%) in the final analysis. Internal consistency was high, with Cronbach a5 0.97. We found one major underlying factor similar to the English version: all items showed a scale correlation above 0.7. The mean values of the HCCQ correlated moderately (� 0.5) with those of the EUROPEP. Conclusion: This study shows similar psychometric properties of the HCCQ-D as of the original English instrument. The HCCQ-D may be appropriate to explore German-speaking patients’ perceived autonomy support in primary care settings. 2012 Elsevier Inc. All rights reserved.

Due to the increasing number of non-travel-associated hepatitis E virus (HEV) infections observed in several industrialised countries including Germany, there is a substantial interest in the characterisation of risk factors and transmission routes relevant to autochthonous HEV infections. Autochthonous cases are believed to be the result of a zoonotic HEV transmission from pigs, wild boars and deer. Recently, a high prevalence of HEV-specific antibodies in the German domestic pig population has been demonstrated. Thus, one may assume a higher prevalence of HEV-specific antibodies in humans with occupational exposure to pigs. In this study, sera obtained from 24 slaughterers, 14 meat inspectors, 46 pig farmers and 22 veterinarians were tested for the presence of HEV-specific antibodies using a line immunoassay. For comparison, sera obtained from 116 age- and gender-matched blood donors were also included. Twenty eight per cent (28.3%; 30/106) of the swine-exposed humans and 15.5% (18/116) of the blood donors without contact to pigs exhibited IgG-antibodies determined as reactive (i.e. borderline or positive) against HEV. Thus, an increased risk of HEV infection in humans occupationally exposed to pigs and particularly for slaughterers (41.7%; 10/24) was demonstrated.

Several studies have investigated the orthonasal detection threshold for carbon dioxide (CO(2)) in humans. The aim of current study was to investigate whether 24 healthy young subjects exhibited differences of CO(2) detection thresholds during orthonasal or retronasal stimulation. As nasal mucosa is believed to desensitize to CO(2) concentrations at or below 4% (v/v) during expiration, the second aim of the study was to explore the influence during nasal versus oral breathing on the detection thresholds. CO(2) stimuli of varying concentrations and a duration of 1000 ms were applied with an air-dilution olfactometer in either the anterior nasal cavity or the nasopharynx during nasal respectively oral breathing. In these 4 conditions, the mean CO(2) detection thresholds using the staircase forced-choice procedure were between 3.9% and 5.3% (v/v). Statistical analysis revealed a significant difference between orthonasal and retronasal stimulation. The CO(2) detection threshold was lower in retronasal stimulation. The nasopharyngeal mucosa is more sensitive to perithreshold CO(2) stimuli than the nasal mucosa. The breathing route had no influence on the detection thresholds. The results of this study indicate that the natural contact of the nasal mucosa with approximately 4% (v/v) CO(2) during nasal expiration does not influence CO(2) detection thresholds.

Purpose This is the first study to evaluate the long-term effectiveness of a school-based prevention program in Germany. The aim is to determine the long-term effects of the primary prevention program PriMa (Primary prevention of anorexia nervosa in preadolescent girls) on disordered eating and body self-esteem from childhood to young adulthood. Methods PriMa was conducted and successfully evaluated in a quasi-experimental pre-post design with a control group from 2007 to 2008 consisting of 11–13 year old girls (N = 1508) from Thuringian schools in Germany. Seven to eight years after the intervention, the same cohort (mean age 19.8 years) was invited to complete an online survey. Disordered eating (EAT-26), body self-esteem (FBeK) and BMI were assessed via self-report. The response rate at seven-to-eight-year follow-up was very low (7%). Data of N = 100 girls were analyzed. Results Concerning changes in disordered eating, results revealed no significant long-term effect of PriMa seven to eight years after the intervention. During this time, disordered eating remained stable without a significant increase or decrease. Regarding changes in body self-esteem, group courses differed significantly from each other. The results revealed a significant main effect of group, indicating significant differences in changes of body self-esteem between the intervention and the control group. Following the analysis of these changes of body self-esteem over time, it was found that the intervention group revealed an increase of body self-esteem after program participation and remained stable over time. By contrast, the control group revealed a decrease of body self-esteem over time. Conclusions Long-term intervention effects of PriMa could be found for body self-esteem but not for disordered eating. The findings suggest that PriMa prevented a decrease of body self-esteem from childhood to young adulthood. For a broader dissemination it is necessary to implement prevention programs consistently in school settings. In order to maintain the prevention effects, it would be interesting to investigate the effects of booster sessions which refresh the programs content on a regular basis. Furthermore, the results of this study revealed the implementation difficulties of primary prevention programs especially concerning the retention of the sample size.

Glutamatergic dysfunction and altered membrane lipid and energy metabolism have been repeatedly demonstrated in the frontal/prefrontal and anterior cingulate cortex (ACC) in schizophrenia. Though having been already studied in animals, the presumed link between glutamatergic function and structural plasticity has not been investigated directly in the human brain yet. We measured glutamate (Glu), focal energy metabolism, and membrane phospholipid turnover to investigate main pathologies in those key brain regions of schizophrenia.(1)H- and (31)P-Chemical Shift Imaging (CSI) was combined in a single session to assess Glu and markers of energy (PCr, ATP) and membrane lipid (PME, PDE) metabolism in 31 neuroleptic-naïve first acute onset psychosis patients and 31 matched healthy controls. Multivariate analyses of covariance were used to assess disease effects on Glu and to investigate the impact of Glu alterations on phospholipid and energy metabolites.Glu levels of patients were increased in the frontal and prefrontal cortex bilaterally and in the ACC. Higher Glu was associated with increased left frontal/prefrontal PME and right frontal/prefrontal PDE in patients, which was not observed in healthy controls. In contrast, higher Glu levels were associated with lower PCr or ATP values in the frontal/prefrontal cortex bilaterally and in the right ACC of controls. This was not observed in the right ACC and left frontal/prefrontal cortex of patients.Frontal glutamatergic hyperactivity is disconnected from physiologically regulated energy metabolism and is associated with increased membrane breakdown in right and increased membrane restoration in left frontal and prefrontal cortical regions. As indicated by previous findings, this pathology is likely dynamic during the course of first acute illness and possibly associated with negative symptoms and cognitive impairment. Our findings underline the importance of further research on neuroprotective treatment options during the early acute or even better for the ultra-high risk state of psychotic illness.

During aging declining maximum force capacity with more or less unchanged fatigability is observed with the underlying mechanisms still not fully understood. Therefore, we compared morphology and function of skeletal muscles between different age groups. Changes in high-energy phosphate turnover (PCr, Pi and pH) and muscle functional MRI (mfMRI) parameters, including proton transverse relaxation time (T 2 ), diffusion (D) and vascular volume fraction (f), were investigated in moderately exercised low back muscles of young and late-middle-aged healthy subjects with 31 P-MR spectroscopy, T 2 - and diffusion-weighted MRI at 3 T. In addition, T 1 -weighted MRI data were acquired to determine muscle cross-sectional areas (CSA) and to assess fat infiltration into muscle tissue. Except for pH, both age groups showed similar load-induced MR changes and rates of perceived exertion (RPE), which indicates comparable behavior of muscle activation at moderate loads. Changes of mfMRI parameters were significantly associated with RPE in both cohorts. Age-related differences were observed, with lower pH and higher Pi/ATP ratios as well as lower D and f values in the late-middle-aged subjects. These findings are ascribed to age-related changes of fiber type composition, fiber size and vascularity. Interestingly, post exercise f was negatively associated with fat infiltration with the latter being significantly higher in late-middle-aged subjects. CSA of low back muscles remained unchanged, while CSA of inner back muscle as well as mean T 2 at rest were associated with maximum force capacity. Overall, applying the proposed MR approach provides evidence of age-related changes in several muscle tissue characteristics and gives new insights into the physiological processes that take place during aging.

To judge a person’s maximum trunk extension performance as either age-appropriate or deconditioned is challenging. The current study aimed at determining age and anthropometrically adjusted maximum voluntary contraction (MVC) of back extensors considering the number and recovery time between trials. Thirty-one younger (20–30 years) and 33 older (50–60 years) healthy males performed five repetitions of maximal isometric trunk extensions in an upright standing position with randomized recovery times ranging between one to five minutes at one minute intervals. Torque values were normalized according to the individual’s upper body mass resulting in upper body torque ratios (UBTR). To evaluate the impact of age, recovery time, and fatigue on UBTR we applied a linear mixed-effects model. Based on surface EMG data muscular fatigue could be excluded for both groups. For all MVC trials, UBTR levels differed significantly between age groups (range of mean values: younger: 2.26–2.28, older: 1.78–1.87, effect size: 1.00) but were independent from recovery time. However, the older males tended to exert higher UBTR values after shorter recovery periods. The study provides normative values of anthropometrically and age-group adjusted maximum back extensor forces. For the investigated groups, only two MVC trials with a recovery time of about one minute seem appropriate.

Exercise-induced changes of transverse proton relaxation time (T2 ), tissue perfusion and metabolic turnover were investigated in the lower back muscles of volunteers by applying muscle functional MRI (mfMRI) and diffusion-weighted imaging (DWI) before and after as well as dynamic (31) P-MRS during the exercise. Inner (M. multifidus, MF) and outer lower back muscles (M. erector spinae, ES) were examined in 14 healthy young men performing a sustained isometric trunk-extension. Significant phosphocreatine (PCr) depletions ranging from 30% (ES) to 34% (MF) and Pi accumulations between 95% (left ES) and 120%-140% (MF muscles and right ES) were observed during the exercise, which were accompanied by significantly decreased pH values in all muscles (∆pH ≈ -0.05). Baseline T2 values were similar across all investigated muscles (approximately 27 ms at 3 T), but revealed right-left asymmetric increases (T2 ,inc ) after the exercise (right ES/MF: T2 ,inc = 11.8/9.7%; left ES/MF: T2 ,inc = 4.6/8.9%). Analyzed muscles also showed load-induced increases in molecular diffusion D (p = .007) and perfusion fraction f (p = .002). The latter parameter was significantly higher in the MF than in the ES muscles both at rest and post exercise. Changes in PCr (p = .03), diffusion (p .01) and perfusion (p = .03) were strongly associated with T2,inc , and linear mixed model analysis revealed that changes in PCr and perfusion both affect T2,inc (p .001). These findings support previous assumptions that T2 changes are not only an intra-cellular phenomenon resulting from metabolic stress but are also affected by increased perfusion in loaded muscles.

Introduction. The aim of this retrospective study was to examine effect of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) in second-line and further therapy in daily clinical practice.Methods. Patients with histologically or cytologically proven NSCLC (n=84) treated with erlotinib in second-line (n=34), third-line (n=36), and more-line therapy (n=14) were examined for progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of therapy, and adverse effects.Results. Median PFS of all lines was 83 days (CI 70.0–96.0), OS was 7 months (CI 4.7–9.3), DCR was 66.2% (CI 55–77%), and 1-year survival rate was 33% (CI 22–43%), with no significant difference between therapy lines. Median duration of treatment was 76 days (IQR 39–139.5). Patients with epidermal growth factor receptor mutation (EGFR-M) reached the highest PFS (204 days), as did patients with good performance status (ECOG 0-1: 94 versus ECOG 2-3: 65 days,P=0.035). Patients with EGFR-M also revealed a DCR of 100%. The most frequent side effects were rash (69%) and diarrhoea (41%), without any significant difference between therapy lines. In 24 patients, the treatment dose was reduced and in 18, the therapy was paused.Conclusion. Erlotinib works in all therapy lines without any significant differences in efficacy and side effects.

Picornaviruses have been isolated from a variety of hosts, mainly mammals and birds. Here, we describe the sequence analysis of carp picornavirus 1 (CPV-1) F37/06 that was isolated from an organ pool (heart, brain, liver) of a common carp (Cyprinus carpio). This carp perished after an accidental discharge of liquid manure into a fish pond and presented without obvious clinical symptoms. Experimental intraperitoneal infection of young carp with CPV-1 revealed no clinical signs, but the virus was re-isolated from various organs. Sequence analysis of almost the complete genome (7632 nt excluding the poly-A tract) revealed a novel picornavirus clade. In phylogenetic trees, the polymerase sequence clusters with parechoviruses, duck hepatitis A virus, eel picornavirus and aquamavirus A. The ORF includes 6807 nt and encodes a polyprotein of 2269 amino acids. CPV-1 has a genome layout like that of picornaviruses except for the presence of two aphthovirus 2A-like NPGP sequence motifs: VPg+5′UTR[1AB-1C-1D-2A1npgp/2A2npgp-2B-2CATPase/3A-3BVPg-3Cpro-3Dpol]3′UTR-poly-A. 2A1npgp and 2A2npgp are separated by 133 amino acids. The proteins 2A2npgp, 2B, 3A and 3BVPg have no significant similarity to the corresponding proteins of other picornaviruses. Amino acid identities of the orthologous proteins P1, 2C, 3Cpro and 3Dpol range from 16.4 to 40.8 % in the eel picornavirus/CPV-1 comparison. 3Dpol shows the closest similarity to eel picornavirus, with an amino acid identity of 40.8 %, followed by human parechovirus (36.5 %), duck hepatitis A virus (32.7 %) and swine pasivirus (29.3 %). Both the unique genome organization and low sequence similarity support the assignment of CPV-1 to a novel picornavirus species within a novel genus.

Objectives Bivariate linear and generalized linear random effects are frequently used to perform a diagnostic meta-analysis. The objective of this article was to apply a finite mixture model of bivariate normal distributions that can be used for the construction of componentwise summary receiver operating characteristic (sROC) curves. Study Design and Setting Bivariate linear random effects and a bivariate finite mixture model are used. The latter model is developed as an extension of a univariate finite mixture model. Two examples, computed tomography (CT) angiography for ruling out coronary artery disease and procalcitonin as a diagnostic marker for sepsis, are used to estimate mean sensitivity and mean specificity and to construct sROC curves. Results The suggested approach of a bivariate finite mixture model identifies two latent classes of diagnostic accuracy for the CT angiography example. Both classes show high sensitivity but mainly two different levels of specificity. For the procalcitonin example, this approach identifies three latent classes of diagnostic accuracy. Here, sensitivities and specificities are quite different as such that sensitivity increases with decreasing specificity. Additionally, the model is used to construct componentwise sROC curves and to classify individual studies. Conclusion The proposed method offers an alternative approach to model between-study heterogeneity in a diagnostic meta-analysis. Furthermore, it is possible to construct sROC curves even if a positive correlation between sensitivity and specificity is present.

Background: The aim of this retrospective study was to examine the effect of oral trofosfamide in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: Patients with histologically or cytologically proven NSCLC, who had received at least 2 other therapies, were enrolled. The primary clinical end point was progression-free survival (PFS); secondary end points included overall survival (OS), response rate and toxicity. Results: 23 patients were enrolled, 1 of whom was excluded due to non-compliance. The patients had received a median of 3 prior therapies (range 2-4). Regarding all 22 patients, median PFS was 14 weeks (95% confidence interval (CI) 9.96-18.04). The median OS was 32 weeks (95% CI 17.12-46.88). The median duration of trofosfamide therapy was 10.5 weeks (interquartile range 6.5-17.3). 20 patients (90.9%) had stable disease; 2 were not assessable. Trofosfamide therapy was stopped in 4 patients (18.2%) due to side effects. Conclusion: Trofosfamide is an orally applicable, well-tolerated and cost-effective drug that works in patients with advanced NSCLC, who have undergone at least 2 lines of therapy. Trofosfamide seems to be a therapeutic option in NSCLC as a further therapy line. These preliminary data need to be confirmed in a larger trial.

OBJECTIVE: We compared the haemodynamic performance of two pericardial aortic prostheses with the stent either on the outside (Perimount), or the inside (Mitroflow) of the valve cusps, with regard to sizing strategies and valve dimensions. METHODS: We analysed discharge echoes from all patients who received an isolated Perimount (n= 537) or Mitroflow (n= 164) between January 2007 and November 2010. We obtained outer valve diameters from the manufacturers, and measured sizer dimensions. We compared pressure gradients (ΔP) and maximum velocity across the valve (Vmax). RESULTS: The majority of implanted valves had a size label 23 (39.7% of the Perimount; 56.1% of the Mitroflow). The metric outer diameter for size label 23 was 31 mm for Perimount, and 26 mm for Mitroflow. Despite the smaller outer diameter of the Mitroflow compared with the Perimount, peak gradients were lowest in the Mitroflow (ΔP mmHg: 22.3 ± 7.8 for Mitroflow vs 23.9 ± 7.3 for Perimount, n.s.), suggesting a design advantage for the Mitroflow. However, the 23 Mitroflow sizer was 26 mm and the 21 sizer was 23 mm. In contrast, the 23 Perimount sizer was indeed 23 mm. Thus, an intrannular sizing strategy for a patient with a 23 mm annulus most likely results in the selection of 21 Mitroflow and 23 Perimount. Haemodynamic comparison of the 21 Mitroflow with the 23 Perimount reversed the abovedescribed difference (ΔP mmHg: 26.0 ± 10.2 for Mitroflow vs 23.9 ± 7.3 for Perimount, P< 0.05). Multivariate analysis identified a 21 valve as a predictor of high pressure gradients, but found no differences between both valve types. CONCLUSIONS: The potential haemodynamic advantage of the Mitroflow is lost due to the different sizing strategy. The results underscore the importance of an optimal sizing strategy, possibly by replica sizing.

An increasing number of acute autochthonous human hepatitis E virus (HEV)-infections was noticed in Germany and other developed countries, most likely the result of a zoonotic virus transmission from pig, wild boar and deer. Currently there is still a lack of profound data concerning the actual prevalence of HEV-specific antibodies in domestic pig herds in Germany, in particular for regions with high pig density, and its age-dependency. 2273 domestic pig sera were collected in 2011 mainly from Bavaria, North Rhine-Westphalia and Lower Saxony from areas having a high pig density. Initially, 420 randomly selected pig sera were tested in three commercially available and in two in-house HEV-antibody ELISAs. 43.6% (183/420) to 65.5% (275/420) of the sera were demonstrated to be reactive against human pathogenic HEV genotypes 1 and/or 3. The majority of sera reacted only weakly or not at all with the rat HEV antigen with very few sera showing a stronger reactivity to this antigen compared to the genotype 3 antigen. The results of all three HEV-IgG tests, i.e. the PrioCHECK® HEV Ab porcine ELISA kit, the ID Screen® Hepatitis E Indirect Multi-species ELISA kit and the genotype 3 in-house ELISA were in good accordance. Therefore, the remaining sera were tested using the PrioCHECK® HEV Ab porcine ELISA kit. Samples with a borderline result were finally determined by application of the conjugate-modified recomLine HEV IgG assay. A total of 1065 of the 2273 sera (46.9%) were found to be anti-HEV IgG-positive. While 38.4% (306/796) of fatteners (age between 3 and 9 months) exhibited HEV-specific antibodies, 51.4% (759/1477) of sows (age older than 9 months) exhibited anti-HEV antibodies (P < 0.001). Fatteners kept in Southern Germany had a significantly higher HEV IgG prevalence compared to fatteners kept in the high pig density federal states North Rhine-Westphalia and Lower Saxony but also in German federal states with a low pig density. In conclusion, the present study clearly demonstrates that a high percentage of domestic pigs in Germany have had contact with HEV. Seroprevalence depends on the pig's age and herd origin with the most significant regional variations for fatteners. The presence of anti-HEV-free herds may indicate that it is feasible to establish and sustain HEV-free pig herds. HEV seroprevalence still depends on the assay used for testing. This demonstrates an urgent need for test validation.

Simvastatin, a cholesterol-lowering drug, is reported to have immunomodulatory properties that attenuated acute lung injury independent of their major lipid lowering effects. Based on these reports, simvastatin is expected to be used for influenza prophylaxis and treatment. The present study evaluated the efficacy of simvastatin against influenza A/PR/8/34 virus infection in a murine model. In a first study, simvastatin was administered orally. To achieve high plasma levels, intraperitoneal application was used in a second study. Survival, body weight loss, viral titers in lung and trachea, and histologic lung injury were measured. Surprisingly, treatment with simvastatin resulted in lower survival rates and in more distinct body mass loss in comparison to virus-infected control mice. Furthermore, the viral load in lungs and tracheas as well as histopathological lesions were not reduced by simvastatin. Overall, these results showed that simvastatin failed to protect mice against influenza virus infection.

This study aimed at the identification of histone deacetylase (HDAC) isoforms relevant for childhood acute lymphoblastic leukemia (ALL). Expression of HDAC1-11 was determined in 93 primary ALL and eight healthy donor samples. HDAC1, HDAC2 and HDAC8 showed significantly higher expressions in ALL samples. Correlation analysis of HDAC expression with clinicopathological parameters revealed that high HDAC1, HDAC2, HDAC4 and HDAC11 levels were significantly associated with unfavorable prognostic factors. Particularly, high HDAC4 expression was associated with high initial leukocyte count, T cell ALL and prednisone poor-response. siRNA-mediated inhibition of HDAC4 sensitized a T-ALL cell line to etoposide-induced cell death. In conclusion, our data point to HDAC4 as drug target in childhood ALL, especially in prednisone poor-responders.

Background— We hypothesized that annuloplasty ring implantation alters mitral annular strains in a normal beating ovine heart preparation. Methods and Results— Sheep had 16 radiopaque markers sewn equally spaced around the mitral annulus. Edwards Cosgrove partial flexible band (COS; n=12), St Jude complete rigid saddle-shaped annuloplasty ring (RSA; n=10), Carpentier-Edwards Physio (PHY; n=11), Edwards IMR ETlogix (ETL; n=11), and GeoForm (GEO; n=12) annuloplasty rings were implanted in a releasable fashion. Four-dimensional marker coordinates were obtained using biplane videofluoroscopy with the ring inserted (ring) and after ring release (control). From marker coordinates, a functional spatio-temporal representation of each annulus was generated through a best fit using 16 piecewise cubic Hermitian splines. Absolute total mitral annular ring strains were calculated from the relative change in length of the tangent vector to the annular curve as strains occurring from control to ring state at end-systole. In addition, average Green-Lagrange strains occurring from control to ring state at end-systole along the annulus were calculated. Absolute total mitral annular ring strains were smallest for COS and greatest for ETL. Strains for RSA, PHY, and GEO were similar. Except for COS in the septal mitral annular segment, all rings induced compressive strains along the entire annulus, with greatest values occurring at the lateral mitral annular segment. Conclusions— In healthy, beating ovine hearts, annuloplasty rings (COS, RSA, PHY, ETL, and GEO) induce compressive strains that are predominate in the lateral annular region, smallest for flexible partial bands (COS) and greatest for an asymmetrical rigid ring type with intrinsic septal-lateral downsizing (ETL). However, the ring type with the most drastic intrinsic septal-lateral downsizing (GEO) introduced strains similar to physiologically shaped rings (RSA and PHY), indicating that ring effects on annular strain profiles cannot be estimated from the degree of septal-lateral downsizing.