Sex Differences in Glutathione Peroxidase Activity and Central Obesity in Patients with Type 2 Diabetes at High Risk of Cardio-Renal Disease.

Women with type 2 diabetes (T2DM) have an increased susceptibility of developing cardio-renal disease compared to men, the reasons and the mechanisms of this vulnerability are unclear. Since oxidative stress plays a key role in the development of cardio-renal disease, we investigated the relationship between sex, plasma antioxidants status (glutathione peroxidase (GPx-3 activity), vitamin E and selenium), and adiposity in patients with T2DM at high risk of cardio-renal disease. Women compared to men had higher GPx-3 activity (p = 0.02), bio-impedance (p ≤ 0.0001), and an increase in waist circumference in relation to recommended cut off-points (p = 0.0001). Waist circumference and BMI were negatively correlated with GPx-3 activity (p ≤ 0.05 and p ≤ 0.01, respectively) and selenium concentration (p ≤ 0.01 and p ≤ 0.02, respectively). In multiple regression analysis, waist circumference and sex were independent predictors of GPx-3 activity (p ≤ 0.05 and p ≤ 0.05, respectively). The data suggest that increased central fat deposits are associated with reduced plasma antioxidants which could contribute to the future risk of cardio-renal disease. The increased GPx-3 activity in women could represent a preserved response to the disproportionate increase in visceral fat. Future studies should be aimed at evaluating if the modulation of GPx-3 activity reduces cardio-renal risk in men and women with T2DM

Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. // Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). // Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. // Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics

We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10−9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients’ fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: −2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: −1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients

Support for smoke-free policy, and awareness of tobacco health effects and use of smoking cessation therapy in a developing country

BACKGROUND: Preventing an epidemic increase in smoking prevalence is a major challenge for developing countries. Ghana, has maintained a low smoking prevalence despite the presence of cigarette manufacturing for many decades. Some of this success may have been contributed by cultural factors and attitudes. We have studied public awareness of health risks, attitudes to smoke-free policy, tobacco advertising/promotion and other factors in a Ghanaian population sample. METHODS: We used two-stage cluster randomized sampling to study household members aged 14 and over in a representative household sample in the Ashanti Region of Ghana. RESULTS: 6258 people, 88% of those eligible, took part in the study. Knowledge of health risks of smoking and passive smoking was high; radio was the main source of such information. Most people work and/or spend time in places where smoking is permitted. There was very strong support (97%) for comprehensive smoke-free legislation, particularly among Christians and Muslims. Despite the advertising ban, a third of respondents (35%), particularly in urban areas, had noticed advertising of tobacco or tobacco products, on the radio (72%) and television (28%). Among smokers, 76% had attempted to quit in the last 6 months, with the main sources of advice being friends and spouses. Use of nicotine replacement therapy was very rare. Low levels of health awareness were seen in females compared with males (Adjusted Odds Ratio (AOR); 0.51, 95% CI 0.39-0.69, p < 0.001). High levels of health awareness was seen among Traditionalists compared with Christians AOR; 2.16 95% CI 0.79-5.94, p < 0.05) and the relatively well educated (AOR; 1.70 95% CI 1.12-2.58, p < 0.05) and those living in rural areas (AOR 1.46 95% CI 1.14-1.87, p = 0.004). CONCLUSION: Awareness of health risks and support for smoke-free policy are high in Ghana. Exposure to tobacco advertising or promotion is limited and most smokers have tried to quit. Whether these findings are cause or effect of current low smoking prevalence is uncertain

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

An updated view of hypothalamic-vascular-pituitary unit function and plasticity

The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic–pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment

Anti-inflammatory Components from Functional Foods for Obesity

Obesity, defined as excessive fat accumulation that may impair health, has been described throughout human history, but it has now reached epidemic proportions with the WHO estimating that 39% of the world’s adults over 18 years of age were overweight or obese in 2016. Obesity is a chronic low-grade inflammatory state leading to organ damage with an increased risk of common diseases including cardiovascular and metabolic disease, non-alcoholic fatty liver disease, osteo-arthritis and some cancers. This inflammatory state may be influenced by adipose tissue hypoxia and changes in the gut microbiota. There has been an increasing focus on functional foods and nutraceuticals as treatment options for obesity as drug treatments are limited in efficacy. This chapter summarises the importance of anthocyanin-containing fruits and vegetables, coffee and its components, tropical fruit and food waste as sources of phytochemicals for obesity treatment. We emphasise that preclinical studies can form the basis for clinical trials to determine the effectiveness of these treatments in humans