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With an overall prevalence of 10–20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries 1 , 2 . We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P CCA = 4.1 × 10 −9 ), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German ( P = 2.8 × 10 −7 ) and 167 Chilean subjects ( P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8–2.6, P = 1.4 × 10 −14 ) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.

Hans Eichel, finance minister, criticised aspects of the reforms - aimed at cutting health costs by Euros 23bn (Dollars 27bn, Pounds 16bn) by 2007 - at a Social Democratic party meeting on Monday, it emerged yesterday. An uncommonly broad alliance of critics, including economists, business groups, trade unions and consumer lobbies, was forming last night against the reforms. They complained that the reforms were \"socially unjust\", as ordinary patients and employees would have to bear the main cost burden of the cuts.

Gravitational stress occurs during space flights or certain physical activities including extreme sports, where the change in experienced gravitational acceleration can reach large magnitudes. These changes include reduction and increase in the physical forces experienced by the body and may potentially induce pathogenic alterations of physiological processes. The immune system is known to regulate most functions in the human organism and previous studies suggest an impairment of the immune function under gravitational stress. However, systematic studies aiming to investigate the effect of gravitational stress on cellular immune response in humans are lacking. Since parabolic flights are considered as feasible model to investigate a short-term impact of gravitational changes, we evaluated the influence of gravitational stress on the immune system by analyzing leukocyte numbers before and after parabolic flight maneuvers in human blood. To correct for circadian effects, samples were taken at the corresponding time points on ground the day before the flight. The parabolic flight maneuvers led to changes in numbers of different leukocyte subsets. Naïve and memory T and B cell subsets decreased under gravitational stress and lower numbers of basophils and eosinophils were observed. Only circulating neutrophils increased during the parabolic flight. The observed changes could not be attributed to stress-induced cortisol effects, since cortisol levels were not affected. Our data demonstrate that the gravitational stress by parabolic flights can affect all parts of the human immune system. Consequently, it is possible that gravitational stress can have clinically relevant impacts on the control of immune responses.

Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference −20·10 μm, 95% CI −22·76 to −17·44; p<0·0001) and in MSNON eyes (–7·41 μm, −8·98 to −5·83; p<0·0001). The macula showed RNFL thinning of −6·18 μm (–8·07 to −4·28; p<0·0001) in MSON eyes and −2·15 μm (–3·15 to −1·15; p<0·0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was −16·42 μm (–19·23 to −13·60; p<0·0001) for MSON eyes and −6·31 μm (–7·75 to −4·87; p<0·0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0·77 μm, 0·25 to 1·28; p=0·003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1·21 μm, 0·24 to 2·19; p=0·01). The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. None.

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analyzed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: −11.8 ± 4.3 ml min −1 ·1.73 m −2 , p = 0.006). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Further randomized controlled studies are necessary to confirm this potential negative effect.

A common hypothesis on the etiopathology of schizophrenia is that the failure of segregation of right from left hemisphere functions is a core deficit in psychosis. It has even been proposed that schizophrenia symptoms in general may reflect a hemispheric ‘dominance failure’ for language and that the corresponding predisposition is genetic. Here, we show that reduced asymmetries of cytoarchitectonic Broca’s subareas link to the degree of specific psychopathology and that specific gray matter reductions of subareas are related to a cognitive and a negative subtype of schizophrenia. Gene expression analyses indicate an upregulation of the MET gene in these particular areas, which has been implicated in neurodevelopment as well as neurocognition and influences the risk for schizophrenia. Our integrative findings suggest that variations of MET are associated with distinct structural alterations at the subregional level in key language regions, which may contribute to development of specific psychopathology in schizophrenia.In this paper, the authors present findings demonstrating that variations of the MET gene are associated with specific structural differences in key language regions in individuals with schizophrenia.

In classic concentric/eccentric exercise, the same absolute load is applied in concentric and eccentric actions, which infers a smaller relative eccentric load. We compared the effects of 6 weeks of classic concentric/eccentric quadriceps strength training (CON/ECC, 11 subjects) to eccentric overload training (CON/ECC+, 14 subjects) in athletes accustomed to regular strength training. The parameters determined included functional tests, quadriceps and fibre cross-sectional area (CSA), fibre type distribution by ATPase staining, localisation of myosin heavy chain (MHC) isoform mRNAs by situ hybridization and the steady-state levels of 48 marker mRNAs (RT-PCR) in vastus lateralis biopsies taken before and after training. Both training forms had anabolic effects with significant increases in quadriceps CSA, maximal strength, ribosomal RNA content and the levels of mRNAs involved in growth and regeneration. Only the CON/ECC+ training led to significantly increased height in a squat jump test. This was accompanied by significant increases in IIX fibre CSA, in the percentage of type IIA fibres expressing MHC IIx mRNA, in the level of mRNAs preferentially expressed in fast, glycolytic fibres, and in post-exercise capillary lactate. The enhanced eccentric load apparently led to a subtly faster gene expression pattern and induced a shift towards a faster muscle phenotype plus associated adaptations that make a muscle better suited for fast, explosive movements.

The aim of this paper is to examine signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and image quality of cardiac CINE imaging at 1.5 T and 3.0 T. Twenty volunteers underwent cardiac magnetic resonance imaging (MRI) examinations using a 1.5-T and a 3.0-T scanner. Three different sets of breath-held, electrocardiogram-gated (ECG) CINE imaging techniques were employed, including: (1) unaccelerated SSFP (steady state free precession), (2) accelerated SSFP imaging and (3) gradient-echo-based myocardial tagging. Two-dimensional CINE SSFP at 3.0 T revealed an SNR improvement of 103% and a CNR increase of 19% as compared to the results obtained at 1.5 T. The SNR reduction in accelerated 2D CINE SSFP imaging was larger at 1.5 T (37%) compared to 3.0 T (26%). The mean SNR and CNR increase at 3.0 T obtained for the tagging sequence was 88% and 187%, respectively. At 3.0 T, the duration of the saturation bands persisted throughout the entire cardiac cycle. For comparison, the saturation bands were significantly diminished at 1.5 T during end-diastole. For 2D CINE SSFP imaging, no significant difference in the left ventricular volumetry and in the overall image quality was obtained. For myocardial tagging, image quality was significantly improved at 3.0 T. The SNR reduction in accelerated SSFP imaging was overcompensated by the increase in the baseline SNR at 3.0 T and did not result in any image quality degradation. For cardiac tagging techniques, 3.0 T was highly beneficial, which holds the promise to improve its diagnostic value.

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analysed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -12.0±4.2 mL·min-1·1.73m-2, P=0.005). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Footnotes * An improved method for the variable selection in multivariable regression was employed with the goal of increasing the specificity of the analysis; the results and discussion have been modified accordingly.

Abstract The β-lactamase of Mycobacterium smegmatis mc2155 has been purified to protein homogeneity. Its N-terminal sequence and catalytic properties are similar to those of the β-lactamase produced by Mycobacterium fortuitum D316 and establish this new enzyme as a member of molecular class A.