Using Incongruent Equilibrium Hydration Reactions to Model Latter-Stage Crystallization in Plutons: Examples from the Bell Island Tonalite, Alaska

Models using hydration crystallization reactions (the reverse of dehydration melting reactions such as amph + qtz = px + melt) for the Bell Island pluton define incongruent equilibrium crystallization paths from hydrous + melt + pyroxene + Fe-Ti oxides + calcic andesine (30%-50% solid) to a solid tonalite consisting mostly of hornblende, lower temperature end of Bowen\u27s discontinuous reaction series and apply it to natural samples. Hydration crystallization provides an alternative to crystal fractionation for explaining variations in pluton chemistry, especially the compositions of late plutonic melts. Another characteristic of hydration crystallization is that the reactions have the potential to buffer the water content of the melt during crystallization. Two closed-system models, representing different sets of starting conditions and phases, are considered, based on least squares, mass-balance calculations of reactions and constrained by the petrography of the rocks. Model 1 starts with an average modified Bell Island leucotonalite melt coexisting with two pyroxenes, two Fe-Ti oxides, and plagioclase at the beginning of hydration crystallization. The starting assemblage of model 2 omits orthopyroxene and magnetite, includes amphibole, and uses a calculated melt composition. Both models generally predict, via different series of hydration crystallization reactions, the observed subsolidus mode. Model 2, however, is preferred based on petrographic observations of the Bell Island rocks, specifically the lack of magnetite and orthopyroxene, as well as certain textural features

A total diet replacement weight management programme for difficult-to-treat asthma associated with obesity: a randomised controlled feasibility trial

Background: Obesity is often associated with uncontrolled, difficult-to-treat asthma and increased morbidity and mortality. Previous studies suggest that weight loss may improve asthma outcomes but with heterogenous asthma populations studied and unclear consensus on optimal method of weight management. The Counterweight-Plus weight management programme (CWP) is an evidence-based, dietitian-led, total diet replacement (TDR) programme. Research question: Can use of the CWP compared to usual care (UC) improve asthma control and quality of life in patients with difficult-to-treat asthma and obesity? Study design and methods: We conducted a 1:1 (CWP:UC) randomised, controlled single centre trial in adults with difficult-to-treat asthma and body mass index ≥30kg/m2. CWP: 12-week TDR phase (800kcal/day low-energy formula); stepwise food reintroduction and weight loss maintenance up to 1 year. Primary outcome: change in asthma control questionnaire (ACQ6) score over 16 weeks. Secondary outcome: change in asthma quality of life questionnaire (AQLQ) score. Results: 35 participants were randomised (36 screened) and 33 attended 16-week follow-up (17 CWP, 16 UC). Overall, mean (95%CI) ACQ6 at baseline was 2.8 (2.4, 3.1). Weight loss was greater in CWP than UC (mean difference -12.1kg; 95%CI -16.9, -7.4; p<0.001). ACQ6 improved more in CWP than UC (mean difference -0.69; 95%CI -1.37, -0.01; p=0.048). A larger proportion of participants achieved minimal clinically important difference in ACQ6 with CWP than UC (53% vs 19%; p=0.041; NNT 3 (95%CI 1.5, 26.9)). AQLQ improvement was greater in CWP than UC (mean difference 0.76; 95%CI 0.18, 1.34; p=0.013). Interpretation: Utilising a structured weight management programme results in clinically important improvements in asthma control and quality of life over 16 weeks compared to usual care, in adults with difficult-to-treat asthma and obesity. This generalisable programme is easy to deliver for this challenging phenotype. Longer-term outcomes continue to be studied

Dietary weight-management for type 2 diabetes remissions in South Asians: the South Asian diabetes remission randomised trial for proof-of-concept and feasibility (STANDby)

Background: We aimed to assess whether a structured weight management programme incorporating a total diet replacement (TDR) (3–5 months ∼850 kcal/day formula diet) weight loss phase is acceptable to people of South Asian ethnicity and can achieve type 2 diabetes (T2D) remissions similarly to other populations. Methods: Adults of South Asian ethnicity, aged 18–65 years, with T2D for ≤4 years, and BMI 25–45 kg/m2 were recruited from primary care and social media, and randomised to commence TDR either immediately (iTDR), or delayed (dTDR) for 3–5 months as a usual care control arm during this period. Intervention effects were tested in randomised comparisons powered to detect significant weight loss, and in an expanded observational analysis to determine remission effect size, including both iTDR and dTDR groups. Acceptability in those recruited was explored by questionnaire and weight change. Trial registration: Current Controlled Trials, ISRCTN10720065. Date of Registration 27/09/2017. Findings: Twenty-five eligible individuals were recruited. Mean baseline (SD) age was 45.8 (11.1) years, weight 88.2 (13.7) kg, BMI 32.1 (3.8) kg/m2, HbA1c 60.4 (11.3) mmol/mol, liver fat by MRI 15.6 (9.4)%. In the RCT, mean(SD) weight change after TDR was −7.7 (7.2)% in the intervention group (n = 13), and −1.2 (1.4)% in the usual-care control group (n = 12) (p = 0.005), with T2D remission achieved by 5/13, compared to 0/12 respectively (p = 0.039). In the observational study, 23/25 started TDR and 19/23 participants completed the TDR phase. Median time spent in TDR was 105 days (IQR 77–134 days). T2D remission was achieved in 10/23 (43%), and weight changes were concordant with the RCT. Overall, 8/23 (35%) lost over 10% bodyweight. Absolute liver fat proportion near halved from 15.3% at the start of TDR to 8.6% (p < 0.001). Interpretation: In UK-based South Asians, TDR-led weight loss and T2D remission rates are comparable to those observed in white cohorts, and the intervention was acceptable in most of those recruited. There is potential to further improve outcomes, but one-third lost >10% body weight, and the mechanism underpinning T2D remission appears similar, driven by weight change with loss of excess ectopic body-fat. Funding: We gratefully acknowledge funding for the MRI scans from the, Miss MJM Smith Trust (registered charity: SC040586). No other external funds were provided for this trial. NS is supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217)

Dystrophin Is Required for the Normal Function of the Cardio-Protective KATP Channel in Cardiomyocytes

Duchenne and Becker muscular dystrophy patients often develop a cardiomyopathy for which the pathogenesis is still unknown. We have employed the murine animal model of Duchenne muscular dystrophy (mdx), which develops a cardiomyopathy that includes some characteristics of the human disease, to study the molecular basis of this pathology. Here we show that the mdx mouse heart has defects consistent with alteration in compounds that regulate energy homeostasis including a marked decrease in creatine-phosphate (PC). In addition, the mdx heart is more susceptible to anoxia than controls. Since the cardio-protective ATP sensitive potassium channel (KATP) complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including KATP ion channel complex presence, its functionality and interaction with dystrophin. We found that this channel complex is present in the dystrophic cardiac cell membrane but its ability to sense a drop in the intracellular ATP concentration and consequently open is compromised by the absence of dystrophin. We further demonstrate that the creatine kinase muscle isoform (CKm) is displaced from the plasma membrane of the mdx cardiac cells. Considering that CKm is a determinant of KATP channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the KATP channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective KATP system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients