Effects of Aging on the Biomechanics of Slips and Falls

Although much has been learned in recent decades about the deterioration of muscular strength, gait adaptations, and sensory degradation among older adults, little is known about how these intrinsic changes affect biomechanical parameters associated with slip-induced fall accidents. In general, the objective of this laboratory study was to investigate the process of initiation, detection, and recovery of inadvertent slips and falls. We examined the initiation of and recovery from foot slips among three age groups utilizing biomechanical parameters, muscle strength, and sensory measurements. Forty-two young, middle-age, and older participants walked around a walking track at a comfortable pace. Slippery floor surfaces were placed on the track over force platforms at random intervals without the participants’ awareness. Results indicated that younger participants slipped as often as the older participants, suggesting that the likelihood of slip initiation is similar across all age groups; however, older individuals’ recovery process was much slower and less effective. The ability to successfully recover from a slip (thus preventing a fall) is believed to be affected by lower extremity muscle strength and sensory degradation among older individuals. Results from this research can help pinpoint possible intervention strategies for improving dynamic equilibrium among older adults

Migrant participation in Norwegian health care. A qualitative study using key informants

Background Little is known about how migrants adapt to first-world public health systems. In Norway, patients are assigned a registered general practitioner (RGP) to provide basic care and serve as gatekeeper for other medical services. Objectives: To explore determinants of migrant compliance with the RGP scheme and obstacles that migrants may experience. Methods: Individuals in leadership positions within migrant organizations for the 13 largest migrant populations in Norway in 2008 participated in this qualitative study. Semi-structured interviews, with migrants serving as key informants, were used to elucidate possible challenges migrant patients face in navigating the local primary health-care system. Conversations were structured using an interview guide covering the range of challenges that migrant patients meet in the health-care system. Results: According to informants, integration into the RGP scheme and adequacy of patient-physician communication varies according to duration of stay in Norway, the patient's country of origin, the reason for migration, health literacy, intention to establish permanent residence in Norway, language proficiency, and comprehension of information received about the health system. Informants noted as obstacles: doctor-patient interaction patterns, conflicting ideas about the role of the doctor, and language and cultural differences. In addressing noted obstacles, one strategy would be to combine direct intervention by migrant associations with indirect intervention via the public-health system

Analysis of gender equality competence present in cultural positions

Articulating the gender dimension in organizations is not easy because their members have to be trained to adopt positions that facilitate the implementation of solutions that help to combat inequalities. The aim of this article was to identify the gender equality competence present in the three types of cultural positions Castells proposed in members of a City Council in Sevilla-Spain, who wanted to implement gender mainstreaming. The participants were 27 people (16 women and 11 men). The method used was discourse analysis. The obtained results show that, while all competences were present in the project position, in the resistance position, there was none. In the legitimizers, we observed inconsistency in the discourse presented. This arouses considerations on the importance of knowing the gender equality competences in order to implement gender mainstreaming in organization

Analgesic and Anti-Inflammatory Effects of the Novel Semicarbazide-Sensitive Amine-Oxidase Inhibitor SzV-1287 in Chronic Arthritis Models of the Mouse.

Semicarbazide-sensitive amine oxidase (SSAO) catalyses oxidative deamination of primary amines. Since there is no data about its function in pain and arthritis mechanisms, we investigated the effects of our novel SSAO inhibitor SzV-1287 in chronic mouse models of joint inflammation. Effects of SzV-1287 (20 mg/kg i.p./day) were investigated in the K/BxN serum-transfer and complete Freund's adjuvant (CFA)-evoked active immunization models compared to the reference SSAO inhibitor LJP-1207. Mechanonociception was assessed by aesthesiometry, oedema by plethysmometry, clinical severity by scoring, joint function by grid test, myeloperoxidase activity by luminescence, vascular leakage by fluorescence in vivo imaging, histopathological changes by semiquantitative evaluation, and cytokines by Luminex assay. SzV-1287 significantly inhibited hyperalgesia and oedema in both models. Plasma leakage and keratinocyte chemoattractant production in the tibiotarsal joint, but not myeloperoxidase activity was significantly reduced by SzV-1287 in K/BxN-arthritis. SzV-1287 did not influence vascular and cellular mechanisms in CFA-arthritis, but significantly decreased histopathological alterations. There was no difference in the anti-hyperalgesic and anti-inflammatory actions of SzV-1287 and LJP-1207, but only SzV-1287 decreased CFA-induced tissue damage. Unlike SzV-1287, LJP-1207 induced cartilage destruction, which was confirmed in vitro. SzV-1287 exerts potent analgesic and anti-inflammatory actions in chronic arthritis models of distinct mechanisms, without inducing cartilage damage

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

BACKGROUND:DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS:Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS:Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS:Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes

Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation

Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate beta -oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD. Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.We thank Douglas Taatjes and Nicole Bouffard for help with confocal microscopy analysis (Microscopy Imaging Center) at the University of Vermont. We also thank the University of Vermont Medical Center's Department of Pathology and Laboratory Medicine Histology and Clinical Laboratories for assistance with liver section staining and AST/ALT measurement, respectively. This work was supported by NIH STTR R41DK112429 (M.R.), NIH PO GM103496 (M.R.), Mitotherapeutix LLC (M.R., K.F, and M.L.M.-C.), MINECO/Feder SAF2015-65327-R and RTI2018-096494-B-100 (J.A.), MINECO/Feder SAF2017-87301-R (M.L.M-C.), BIOEF (M.L.M.-C.), EITB Maratoia BIO15/CA/014 (M.L.M-C), BBVA (M.L.M.-C.), La Caixa Foundation (M.L.M.-C.), Basque Country Health Department 2013111114 (M.L.M-C), MINECO/Feder SAF2015-64352-R (P.A.) and MINECO-Feder RTI2018-095134-B-100 (P.A.). ISCIII-Feder PI17/00535 (C.G.-M.), ISCIII-Feder CP14/00181, and PI16/00823 (A.G-R.), and Francisco Cobos Foundation (A.G.-R.). CIC bioGUNE is the recipient of a Severo Ochoa Excellence Accreditation (SEV-2016-0644) by the Ministry of Science, Innovation and Universities

A prebiotic intervention study in children with autism spectrum disorders (ASDs)

Different dietary approaches, such as gluten and casein free diets, or the use of probiotics and prebiotics have been suggested in autistic spectrum disorders in order to reduce gastrointestinal (GI) disturbances. GI symptoms are of particular interest in this population due to prevalence and correlation with the severity of behavioural traits. Nowadays, there is lack of strong evidence about the effect of dietary interventions on these problems, particularly prebiotics. Therefore, we assessed the impact of exclusion diets and a 6-week Bimuno® galactooligosaccharide (B-GOS®) prebiotic intervention in 30 autistic children. RESULTS: The results showed that children on exclusion diets reported significantly lower scores of abdominal pain and bowel movement, as well as lower abundance of Bifidobacterium spp. and Veillonellaceae family, but higher presence of Faecalibacterium prausnitzii and Bacteroides spp. In addition, significant correlations were found between bacterial populations and faecal amino acids in this group, compared to children following an unrestricted diet. Following B-GOS® intervention, we observed improvements in anti-social behaviour, significant increase of Lachnospiraceae family, and significant changes in faecal and urine metabolites. CONCLUSIONS: To our knowledge, this is the first study where the effect of exclusion diets and prebiotics has been evaluated in autism, showing potential beneficial effects. A combined dietary approach resulted in significant changes in gut microbiota composition and metabolism suggesting that multiple interventions might be more relevant for the improvement of these aspects as well as psychological traits

Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution

We show that epigenome- and transcriptome-wide association studies (EWAS and TWAS) are prone to significant inflation and bias of test statistics, an unrecognized phenomenon introducing spurious findings if left unaddressed. Neither GWAS-based methodology nor state-of-the-art confounder adjustment methods completely remove bias and inflation. We propose a Bayesian method to control bias and inflation in EWAS and TWAS based on estimation of the empirical null distribution. Using simulations and real data, we demonstrate that our method maximizes power while properly controlling the false positive rate. We illustrate the utility of our method in large-scale EWAS and TWAS meta-analyses of age and smoking

Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.Peer reviewe

The immunobiology of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease histologically characterized by the presence of intrahepatic and/or extrahepatic biliary duct concentric, obliterative fibrosis, eventually leading to cirrhosis. Approximately 75% of patients with PSC have inflammatory bowel disease. The male predominance of PSC, the lack of a defined, pathogenic autoantigen, and the potential role of the innate immune system suggest that it may be due to dysregulation of immunity rather than a classic autoimmune disease. However, PSC is associated with several classic autoimmune diseases, and the strongest genetic link to PSC identified to date is with the human leukocyte antigen DRB01*03 haplotype. The precise immunopathogenesis of PSC is largely unknown but likely involves activation of the innate immune system by bacterial components delivered to the liver via the portal vein. Induction of adhesion molecules and chemokines leads to the recruitment of intestinal lymphocytes. Bile duct injury results from the sustained inflammation and production of inflammatory cytokines. Biliary strictures may cause further damage as a result of bile stasis and recurrent secondary bacterial cholangitis. Currently, there is no effective therapy for PSC and developing a rational therapeutic strategy demands a better understanding of the disease