Screening for primary aldosteronism- normal ranges for aldosterone and renin in three South African population groups

Objective. To establish normal ranges for plasma aldosterone, renin and aldosterone / renin (A/ R) ratio in South African normotensives under typical ou tpatient conditions, and to estimate the prevalence of primary aldosteronism (PA) among hypertensives in primary care settings.Design and methods. One hundred and thirty-six normotensive subjects and 154 sex- and age-matched hypertensives at three primary care clinics had measurements of blood pressure, plasma creatinine, K+, aldosterone, plasma renin activity, and spot urine for urinary Na+/ creatinine ratio. Medication was not withdrawn before testing.Results. Mean plasma renin activity in black normotensive subjects (0.95 ± 1.25 ng/ ml/ h, mean± standard deviation (SD)) was significantly lower than in white (2.09 ± 1.12 ng/ ml/ h; P < 0.0001) and coloured (1.81 ± 1.86 ng/ ml/ h, P = 0.013) normotensives. Mean plasma aldosterone in black normotensives (306 ± 147 pmol/ 1) was also significantly lower than in white (506 ± 324 pmol/1, P = 0.0002) and coloured (418 ± 304 pmol/1, P = 0.0148) normotensives. In hypertensives, there were no significant differences in renin or aldosterone levels between the three population groups. Urinary Na+ /creatinine ratios, an index of Na+ intake, were not significantly different in the three population groups. None of the normotensives had an A/R ratio ≥ 1 000 plus aldosterone ≥ 750, while 7.1% of hypertensives exceeded these levels, suggesting that they are appropriate criteria for screening for PA.Conclusions. A large fraction of black normotensive subjects had low renin and aldosterone levels compared with whites, suggesting a salt-retaining tendency in black subjects. These results have important implications for the interpretation of plasma renin and aldosterone levels in hypertensive patients. In primary care settings, 7.1% of hypertensives had biochemical results indicating the need for investigation of PA

Donor-recipient HLA-A mismatching is associated with hepatic artery thrombosis, sepsis, graft loss and reduced survival after liver transplantation

HLA matching is not routinely performed for liver transplantation as there is no consistent evidence of benefit, however the impact of HLA mismatching remains uncertain. We explored the effect of class I and II HLA mismatching on graft failure and mortality. 1042 liver transplants performed at a single centre, between 1999 and 2016 with available HLA typing data were included. Median follow up period was 9.38 years (IQR 4.9-14) and 350/1042 (33.6%) transplants resulted in graft loss and 280/1042 (26.9%) in death. Graft loss and mortality were not associated with the overall number of mismatches at HLA-A, -B, -C, -DR and -DQ loci. However, graft failure and mortality were both increased in the presence of one (p = 0.004 and p = 0.01) and two (p = 0.01 and p = 0.04) HLA-A mismatches. Elevated hazard ratios for graft failure and death were observed with HLA-A mismatches in univariate and multivariate Cox proportional hazard models. Excess graft loss with HLA-A mismatch (138/940 (14.7%) of mismatched compared to 6/102 (5.9%) matched transplants) occurred within the first-year following transplantation (OR 2.75, p = 0.02). Strikingly, all grafts lost due to hepatic artery thrombosis were in HLA-A mismatched transplants (31/940 vs. 0/102), as were those lost due to sepsis (35/940 vs. 0/102). In conclusion, HLA-A mismatching was associated with increased graft loss and mortality. The poorer outcome for The HLA mismatched group was due to hepatic artery thrombosis and sepsis and these complications occurred exclusively with HLA-A mismatched transplants. This suggests that HLA-A mismatching is important for post-transplant outcomes and knowledge of HLA-A status may enable enhanced surveillance and interventions to reduce risk of complications or stratified HLA-A matching in high-risk recipients

Down-regulation of the caffeic acid \u3cem\u3eO\u3c/em\u3e-methyltransferase gene in switchgrass reveals a novel monolignol analog

Background Down-regulation of the caffeic acid 3-O-methyltransferase EC 2.1.1.68 (COMT) gene in the lignin biosynthetic pathway of switchgrass (Panicum virgatum) resulted in cell walls of transgenic plants releasing more constituent sugars after pretreatment by dilute acid and treatment with glycosyl hydrolases from an added enzyme preparation and from Clostridium thermocellum. Fermentation of both wild-type and transgenic switchgrass after milder hot water pretreatment with no water washing showed that only the transgenic switchgrass inhibited C. thermocellum. Gas chromatography–mass spectrometry (GCMS)-based metabolomics were undertaken on cell wall aqueous extracts to determine the nature of the microbial inhibitors. Results GCMS confirmed the increased concentration of a number of phenolic acids and aldehydes that are known inhibitors of microbial fermentation. Metabolomic analyses of the transgenic biomass additionally revealed the presence of a novel monolignol-like metabolite, identified as trans-3, 4-dimethoxy-5-hydroxycinnamyl alcohol (iso-sinapyl alcohol) in both non-pretreated, as well as hot water pretreated samples. iso-Sinapyl alcohol and its glucoside were subsequently generated by organic synthesis and the identity of natural and synthetic materials were confirmed by mass spectrometric and NMR analyses. The additional novel presence of iso-sinapic acid, iso-sinapyl aldehyde, and iso-syringin suggest the increased activity of a para-methyltransferase, concomitant with the reduced COMT activity, a strict meta-methyltransferase. Quantum chemical calculations were used to predict the most likely homodimeric lignans generated from dehydration reactions, but these products were not evident in plant samples. Conclusions Down-regulation of COMT activity in switchgrass resulted in the accumulation of previously undetected metabolites resembling sinapyl alcohol and its related metabolites, but that are derived from para-methylation of 5-hydroxyconiferyl alcohol, and related precursors and products; the accumulation of which suggests altered metabolism of 5-hydroxyconiferyl alcohol in switchgrass. Given that there was no indication that iso-sinapyl alcohol was integrated in cell walls, it is considered a monolignol analog. Diversion of substrates from sinapyl alcohol to free iso-sinapyl alcohol, its glucoside, and associated upstream lignin pathway changes, including increased phenolic aldehydes and acids, are together associated with more facile cell wall deconstruction, and to the observed inhibitory effect on microbial growth. However, iso-sinapyl alcohol and iso-sinapic acid, added separately to media, were not inhibitory to C. thermocellum cultures

Representations of mental health and arts participation in the national and local British press, 2007-2015

We analysed news articles published in national and local British newspapers between 2007 and 2015 to understand 1) how mental health and arts participation were framed and 2) how the relationships between participants in arts initiatives were conceptualised. Using corpus-assisted qualitative frame analysis, we identified frames of recovery, stigma and economy. The recovery frame, which emphasised that mental illness can be treated similarly to physical illness, positioned arts participation as a form of therapy that can complement or substitute medication. The stigma frame presented arts participation as a mechanism for challenging social conceptions that mentally ill individuals are incapable of productive work. The economy frame discussed the economic burden of mentally ill individuals and portrayed arts participation as facilitating their return to employment. Using thematic analysis, which paid attention to the representation of social actors, we found that service users were identified as the prime beneficiaries of arts initiatives and arts participation was conceptualised as a way to bring people with mental health issues together. We discuss these findings against existing research on media representations of mental health and the concept of ‘mutual recovery’ and suggest what wider concurrent developments in the areas of mental health and the media may account for the uncovered frames and themes

A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, ratelimiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12)United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208)American Society for Radiation Oncology (Resident Seed Grant RA-2011-1)European Molecular Biology Organization (Long-Term Fellowship)National Institutes of Health (U.S.) (R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389)United States. Department of Defense (W81XWH-14-PRCRP-IA)Alexander and Margaret Stewart Trus

Pre-Training Muscle Characteristics of Subjects Who Are Obese Determine How Well Exercise Training Will Improve Their Insulin Responsiveness

Pre-training muscle characteristics of subjects who are obese determine how well exercise training will improve their insulin responsiveness. J Strength Cond Res 31(3): 798–808, 2017—Only half of prediabetic subjects who are obese who underwent exercise training without weight loss increased their insulin responsiveness. We hypothesized that those who improved their insulin responsiveness might have pretraining characteristics favoring a positive response to exercise training. Thirty nondiabetic subjects who were obese volunteered for 8 weeks of either strength training or endurance training. During training, subjects increased their caloric intake to prevent weight loss. Insulin responsiveness by euglycemic clamps and muscle fiber composition, and expression of muscle key biochemical pathways were quantified. Positive responders initially had 52% higher intermediate muscle fibers (fiber type IIa) with 27% lower slow-twitch fibers (type I) and 23% lower expression of muscle insulin receptors. Whether after weight training or stationary bike training, positive responders\u27 fiber type shifted away from type I and type IIa fibers to an increased proportion of type IIx fibers (fast twitch). Muscle insulin receptor expression and glucose transporter type 4 (GLUT4) expression increased in all trained subjects, but these moderate changes did not consistently translate to improvement in whole-body insulin responsiveness. Exercise training of previously sedentary subjects who are obese can result in muscle remodeling and increased expression of key elements of the insulin pathway, but in the absence of weight loss, insulin sensitivity improvement was modest and limited to about half of the participants. Our data suggest rather than responders being more fit, they may have been less fit, only catching up to the other half of subjects who are obese whose insulin responsiveness did not increase beyond their pretraining baseline