Biomechanical Analysis of Stoop and Free-Style Squat Lifting and Lowering with a Generic Back-Support Exoskeleton Model

Musculoskeletal disorders (MSDs) induced by industrial manual handling tasks are a major issue for workers and companies. As flexible ergonomic solutions, occupational exoskeletons can decrease critically high body stress in situations of awkward postures and motions. Biomechanical models with detailed anthropometrics and motions help us to acquire a comprehension of person- and application-specifics by considering the intended and unintended effects, which is crucial for effective implementation. In the present model-based analysis, a generic back-support exoskeleton model was introduced and applied to the motion data of one male subject performing symmetric and asymmetric dynamic manual handling tasks. Different support modes were implemented with this model, including support profiles typical of passive and active systems and an unconstrained optimal support mode used for reference to compare and quantify their biomechanical effects. The conducted simulations indicate that there is a high potential to decrease the peak compression forces in L4/L5 during the investigated heavy loaded tasks for all motion sequences and exoskeleton support modes (mean reduction of 13.3% without the optimal support mode). In particular, asymmetric motions (mean reduction of 14.7%) can be relieved more than symmetric ones (mean reduction of 11.9%) by the exoskeleton support modes without the optimal assistance. The analysis of metabolic energy consumption indicates a high dependency on lifting techniques for the effectiveness of the exoskeleton support. While the exoskeleton support substantially reduces the metabolic cost for the free-squat motions, a slightly higher energy consumption was found for the symmetric stoop motion technique with the active and optimal support mode

Influence of lipid profile and statin administration on arterial stiffness in renal transplant recipients

Background: Hyperlipidemia is one of the major risk factors for developing a cardiovascular disease (CVD) and it is a frequent post-transplant complication, occurring in up to 60% of the renal transplant recipients (RTRs). Lipid lowering therapy with HMG-CoA reductase inhibitors (statins) is generally recommended and may reduce the overall cardiovascular risk. The aim of this study was to evaluate the lipid profile, statin administration and their relationship with arterial stiffness parameters in renal transplant recipients. Methods: Three hundred and forty-four stable RTRs (62.5% male) transplanted between 1994 and 2018 were randomly enrolled to the study. The following parameters of arterial stiffness was measured in each patient: carotid femoral pulse wave velocity (baPWV left and right, cfPWV) and pulse pressure (PP right and left). The study group was divided based on the use statins: 143 (41.6%) and 201 (58.4%). RTRs were qualified to the statin (+) and the statin (–) group, respectively. Results: In the statin (+) as compared to statin (–) group there were more patients with a CVD (32.9% vs. 14.9%) and diabetes (25.2% vs. 14.4%). In the whole study group, CVD was associated with a significant increase of both baPWV and cfPWV as well as PP (8.5 mmHg). There were significant differences in arterial stiffness parameters (baPWV, cfPWV, PP) between the statin (+) and the statin (–) group. Conclusions: Arterial stiffness was increased in RTRs with CVD and hyperlipidemia. The control of hyperlipidemia was poor in RTRs

Ion channels in control of pancreatic stellate cell migration

Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all “hallmarks of cancer” such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of K(Ca)3.1 channels in PSCs. K(Ca)3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of K(Ca)3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of K(Ca)3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2(+) concentration ([Ca(2+)](i)). K(Ca)3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca(2+)](i) and calpain activity. K(Ca)3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of K(Ca)3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology

Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families.

BackgroundThe age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA).MethodsGenomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs.ResultsThis family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10(-9)) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10(-8)) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10(-8)) that were associated with age at onset of AD.ConclusionsThis extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD

Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort

Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however, these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships

CYP2A6 metabolism in the development of smoking behaviors in young adults

Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones. A total of 1209 European American young adults enrolled in the Collaborative Study on the Genetics of Alcoholism were genotyped for CYP2A6 variants to calculate a previously well-validated metric that estimates nicotine metabolism. This metric was not associated with the transition from never smoking to smoking initiation nor with the transition from initiation to daily smoking (P > 0.4). But among young adults who had become daily smokers (n = 506), decreased metabolism was associated with increased risk of nicotine dependence (P = 0.03) (defined as Fagerström Test for Nicotine Dependence score ≥4). This finding was replicated in the Collaborative Genetic Study of Nicotine Dependence with 335 young adult daily smokers (P = 0.02). Secondary meta-analysis indicated that slow metabolizers had a 53 percent increased odds (OR = 1.53, 95 percent CI 1.11-2.11, P = 0.009) of developing nicotine dependence compared with normal metabolizers. Furthermore, secondary analyses examining four-level response of time to first cigarette after waking (>60, 31-60, 6-30, ≤5 minutes) demonstrated a robust effect of the metabolism metric in Collaborative Study on the Genetics of Alcoholism (P = 0.03) and Collaborative Genetic Study of Nicotine Dependence (P = 0.004), illustrating the important role of this measure of dependence. These findings highlight the complex role of CYP2A6 variation across different developmental stages of smoking behaviors

Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40

BACKGROUND: Alzheimer’s disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ(42) ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ(42)) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers. METHODS: We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer’s Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ(42) ratio, Aβ(42), tau, and phosphorylated tau (ptau(181)). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ(42) ratio, Aβ(42), tau, and ptau(181). RESULTS: We found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau(181) (r = 0.521) and the strength of the correlation significantly increased with the addition of genetic information (r = 0.573, p = 0.006). CONCLUSIONS: CSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau(181) levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12883-016-0742-9) contains supplementary material, which is available to authorized users

Variants Located Upstream of CHRNB4 on Chromosome 15q25.1 Are Associated with Age at Onset of Daily Smoking and Habitual Smoking

Several genome-wide association and candidate gene studies have linked chromosome 15q24–q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking theCHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28CHRNB4 with onset of chronic smoking behaviors in adolescents and young adults and may improve genetic information that will lead to better prevention and intervention for substance use disorders among adolescents and young adults

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder