A genetic predisposition score for muscular endophenotypes predicts the increase in aerobic power after training: the CAREGENE study

<p>Abstract</p> <p>Background</p> <p>It is widely accepted that genetic variability might explain a large part of the observed heterogeneity in aerobic capacity and its response to training. Significant associations between polymorphisms of different genes with muscular strength, anaerobic phenotypes and body composition have been reported. Muscular endophenotypes are positively correlated with aerobic capacity, therefore, we tested the association of polymorphisms in twelve muscular related genes on aerobic capacity and its response to endurance training.</p> <p>Methods</p> <p>935 Coronary artery disease patients (CAD) who performed an incremental exercise test until exhaustion at baseline and after three months of training were included. Polymorphisms of the genes were detected using the invader assay. Genotype-phenotype association analyses were performed using ANCOVA. Different models for a genetic predisposition score (GPS) were constructed based on literature and own data and were related to baseline and response VO₂scores.</p> <p>Results</p> <p>Carriers of the minor allele in the R23K polymorphism of the glucocorticoid receptor gene (<it>GR</it>) and the ciliary neurotrophic factor gene (<it>CNTF</it>) had a significantly higher increase in peakVO₂after training (p < 0.05). Carriers of the minor allele (C34T) in the adenosine monophosphate deaminase (<it>AMPD1</it>) gene had a significantly lower relative increase (p < 0.05) in peakVO₂. GPS of data driven models were significantly associated with the increase in peakVO₂after training.</p> <p>Conclusions</p> <p>In CAD patients, suggestive associations were found in the <it>GR, CNTF </it>and the <it>AMPD1 </it>gene with an improved change in aerobic capacity after three months of training. Additionally data driven models with a genetic predisposition score (GPS) showed a significant predictive value for the increase in peakVO₂.</p

Effects of intra-operative fluoroscopic 3D-imaging on peri-operative imaging strategy in calcaneal fracture surgery

Introduction: Previous studies demonstrated that intra-operative fluoroscopic 3D-imaging (3D-imaging) in calcaneal fracture surgery is promising to prevent revision surgery and save costs. However, these studies limited their focus to corrections performed after 3D-imaging, thereby neglecting corrections after intra-operative fluoroscopic 2D-imaging (2D-imaging). The aim of this study was to assess the effects of additional 3D-imaging on intra-operative corrections, peri-operative imaging used, and patient-relevant outcomes compared to 2D-imaging alone. Patients and methods: In this before–after study, data of adult patients who underwent open reduction and internal fixation (ORIF) of a calcaneal fracture between 2000 and 2014 in our level-I Trauma center were collected. 3D-imaging (BV Pulsera with 3D-RX, Philips Healthcare, Best, The Netherlands) was available as of 2007 at the surgeons’ discretion. Patient and fracture characteristics, peri-operative imaging, intra-operative corrections and patient-relevant outcomes were collected from the hospital databases. Patients in whom additional 3D-imaging was applied were compared to those undergoing 2D-imaging alone. Results: A total of 231 patients were included of whom 107 (46%) were operated with the use of 3D-imaging. No significant differences were found in baseline characteristics. The median duration of surgery was significantly longer when using 3D-imaging (2:08 vs. 1:54 h; p = 0.002). Corrections after additional 3D-imaging were performed in 53% of the patients. However, significantly fewer corrections were made after 2D-imaging when 3D-imaging was available (Risk difference (RD) −15%; 95% Confidence interval (CI) −29 to −2). Peri-operative imaging, besides intra-operative 3D-imaging, and patient-relevant outcomes were similar between groups. Conclusion: Intra-operative 3D-imaging provides additional information resulting in additional corrections. Moreover, 3D-imaging probably changed the surgeons’ attitude to rely more on 3D-imaging, hence a 15%-decrease of corrections performed after 2D-imaging when 3D imaging was available. No substantiation for cost reduction was found through reduction in peri-operative imaging or in terms of improved patient-relevant outcomes

Development of a robust and convenient dual-reporter high-throughput screening assay for SARS-CoV-2 antiviral drug discovery.

Massive efforts on both vaccine development and antiviral research were launched to combat the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We contributed, amongst others, by the development of a high-throughput screening (HTS) antiviral assay against SARS-CoV-2 using a fully automated, high-containment robot system. Here, we describe the development of this novel, convenient and phenotypic dual-reporter virus-cell-based high-content imaging assay using the A549+hACE2+TMPRSS2_mCherry reporter lung carcinoma cell line and an ancestral SARS-CoV-2_Wuhan_mNeonGreen reporter virus. Briefly, by means of clonal selection, a host cell subclone was selected that (i) efficiently supports replication of the reporter virus with high expression, upon infection, of the NeonGreen fluorescent reporter protein, (ii) that is not affected by virus-induced cytopathogenic effects and, (iii) that expresses a strong fluorescent mCherry signal in the nucleus. The selected clone matched these criteria with an infection rate on average of 75% with limited cell death. The average (R)Z'-factors of the assay plates were all >0.8, which indicates a robust assay suitable for HTS purposes. A selection of reference compounds that inhibits SARS-CoV-2 replication in vitro were used to validate this novel dual-reporter assay and confirms the data reported in the literature. This assay is a convenient and powerful tool for HTS of large compound libraries against SARS-CoV-2

Compound heterozygous SCN5A mutations in severe sodium channelopathy with Brugada syndrome : a case report

Aims:Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in theSCN5Agene, encoding the main cardiac sodium Na(v)1.5 channel. Here we present a severe case of cardiac sodium channelopathy with BrS caused bySCN5Acompound heterozygous mutations. We performed a genetic analysis ofSCN5Ain a male proband who collapsed during cycling at the age of 2 years. Because of atrial standstill, he received a pacemaker, and at the age of 3 years, he experienced a collapse anew with left-sided brain stroke. A later ECG taken during a fever unmasked a characteristic BrS type-1 pattern. The functional effect of the detected genetic variants was investigated. Methods and Results:Next-generation sequencing allowed the detection of twoSCN5Avariants intrans: c.4813+3_4813+6dupGGGT-a Belgian founder mutation-and c.4711 T>C, p.Phe1571Leu. A familial segregation analysis showed the presence of the founder mutation in the proband's affected father and paternal aunt and thede novooccurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed a functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the beta(1)-subunit. Compared to theSCN5Awild type, p.Phe1571Leu displayed a hyperpolarizing shift in the voltage dependence of inactivation (loss-of-function), while the activation parameters were unaffected. Using the peptide toxin nemertide alpha-1, the variant's loss-of-function effect could be restored due to a toxin-dependent reduction of channel inactivation. Conclusion:This is the first report providing support for the pathogenicity of the p.Phe1571LeuSCN5Avariant which, together with the c.4813+3_4813+6dupGGGT founder mutation, explains the severity of the phenotype of cardiac sodium channelopathy with BrS in the presented case

Differential item functioning of the Functional Independence Measure in higher performing neurological patients

OBJECTIVE: When comparing outcomes of the Functional Independence Measure (FIM ) between patient groups, item characteristics of the FIM should be consistent across groups. The purpose of this study was to compare item difficulty of the FIM in 3 patient groups with neurological disorders. SUBJECTS: Patients with stroke (n=295), multiple sclerosis (n=150), and traumatic brain injury (n=88). METHODS: FIM scores were administered in each group. The FIM consists of a motor domain (13 items) and a cognitive domain (5 items). Rasch rating scale analysis was performed to investigate differences in item difficulty (differential item functioning) between groups. RESULTS: Answering categories of the FIM items were reduced to 3 (from the original 7) because of disordered thresholds and low answering frequencies. Two items of the motor domain ("bladder" and "bowel") did not fit the Rasch model. For 7 out of the 11 fitting motor items, item difficulties were different between groups (i.e. showed differential item functioning). All cognitive items fitted the Rasch model, and 4 out of 5 cognitive items showed differential item functioning. CONCLUSION: Differential item functioning is present in several items of both the motor and cognitive domain of the FIM. Adjustments for differential item functioning may be required when FIMdata will be compared between groups or will be used in a pooled data analysi

Landowners’ Сolonization of Bashkiria

The “closed city” practice, exercised in Ufa province before 1735, together with the unfavourable political situation led to the bad crisis of estate landownership of the Ufa district. The population polls of the mid-XVII — beginning of XVIII cc. justify the fact that Ufa noblemen had to succumb to the fate of socially deprived Siberian nobility, practically devoid of serf peasants. The beginning of the largest-scale Bashkir insurrection of 1735–1736 made the administration review its attitude to the former ban on Bashkir estate lands sale. In the history of Bashkir landowners’ colonization the edict dated February 11th, 1736, allowing the local officers and officials to buy lands from Bashkir communities, was of principal importance. This procedure was exercised simultaneously with the establishment of the Russian government military control over the south-eastern border, separating Bashkir estate lands from Kazakh migratory tribes. From this moment on there is a stop in diplomatic contacts of the Bashkir elite with the governors of the Middle Asia, Kazakhstan and Turkey that meant the complete loss of political subjection by the Bashkirs. Bashkir communities become active participants of economic relations with Russian landowners, plant owners and the state institutions. Russian government preserved estate dynastic rights with the Bashkirs and refused from large-scale operations on the expropriation of Bashkir lands, transferring the mission of colonization to private persons, who had to arrange the issue with the local communities by themselves. The permission to sell estate lands forced landowners to active participation in the system of Russian legal relations, to contact the Russian government and customers

Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function

Metzincin metalloproteases have major roles in intercellular communication by modulating the function of membrane proteins. One of the proteases is the a-disintegrin-and-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer\u27s disease amyloid precursor protein. ADAM10 is also required for neuronal network functions in murine brain, but neuronal ADAM10 substrates are only partly known. With a proteomic analysis of Adam10-deficient neurons we identified 91, mostly novel ADAM10 substrate candidates, making ADAM10 a major protease for membrane proteins in the nervous system. Several novel substrates, including the neuronal cell adhesion protein NrCAM, are involved in brain development. Indeed, we detected mistargeted axons in the olfactory bulb of conditional ADAM10-/- mice, which correlate with reduced cleavage of NrCAM, NCAM and other ADAM10 substrates. In summary, the novel ADAM10 substrates provide a molecular basis for neuronal network dysfunctions in conditional ADAM10-/- mice and demonstrate a fundamental function of ADAM10 in the brain

Thioguanine is Effective as Maintenance Therapy for Inflammatory Bowel Disease: A Prospective Multicentre Registry Study

Background and Aims: Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease [IBD] patients. Prospective effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD. Methods: IBD patients who previously failed azathioprine or mercaptopurine and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (Harvey-Bradshaw Index [HBI] ≤ 4 or Simple Clinical Colitis Activity Index [SCCAI] ≤ 2). The primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment [PGA] and quality of life [QoL]. Results: Sustained corticosteroid-free clinical remission at 3, 6 or 12 months was observed in 75 [69%], 66 [61%] and 49 [45%] of 108 patients, respectively. Thioguanine was continued in 86 patients [80%] for at least 12 months. Loss of response [55%] included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6%, and portal hypertension in 1% of patients. Conclusion: Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD