'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

Study protocol: a randomised controlled trial of supervised resistance training versus aerobic training in Sri Lankan adults with type 2 diabetes mellitus: SL-DART study

Background: The prevalence of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) is rising globally. T2DM is particularly problematic in South Asia with an estimated 10–15% of Sri Lankans diagnosed with the disease. Exercise is known to improve blood glucose, lipid profiles, blood pressure and adiposity, key goals in the management of T2DM. However, much of the evidence to date has been gained from white Caucasians who have a different body composition and disease profile compared to South Asians. Similarly, the recreational exercise culture is new to Sri Lankans and the effects of exercise on T2DM has not been studied in this population. Methods: The Sri Lanka Diabetes Aerobic and Resistance Training (SL-DART) Study will be comprised of 2 components. Component 1 is a 12-week randomized controlled trial (RCT) to compare the effects of a supervised progressive resistance exercise program (RT) and aerobic exercise program (AT) with standard treatment/control (CN). Sedentary Sri Lankan adults with T2DM (aged 35–65 years) and with no contraindications to exercise will be randomized into one of 3 groups (AT, RT, CN). Exercise sessions will be conducted 2 days/week for 3 months. Baseline and post-intervention biochemical (glycemic control, lipid and liver profiles, inflammatory markers), anthropometric (height, weight, body circumferences), body composition, physical fitness, food preference (liking and wanting food) and quality of life parameters will be measured and compared between groups. Component 2 will be a qualitative study conducted immediately post-intervention via in-depth interviews to assess the barriers and facilitators for adherence to each exercise program. Discussion: SL-DART Study represents one of the first adequately powered methodologically sound RCTs conducted in South Asia to assess the effects of resistance and aerobic exercise in participants with T2DM. Triangulation of quantitative and qualitative outcomes will enable the design of a culturally appropriate therapeutic physical activity intervention for Sri Lankans with T2DM, and the initiation of a professionally driven and specialized clinical exercise prescription service

An Audit of Pre-Pregnancy Maternal Obesity and Diabetes Screening in Rural Regional Tasmania and Its Impact on Pregnancy and Neonatal Outcomes.

Maternal obesity in pregnancy, a growing health problem in Australia, adversely affects both mothers and their offspring. Gestational diabetes mellitus (GDM) is similarly associated with adverse pregnancy and neonatal complications. A low-risk digital medical record audit of antenatal and postnatal data of 2132 pregnant mothers who gave birth between 2016-2018 residing in rural-regional Tasmania was undertaken. An expert advisory group guided the research and informed data collection. Fifty five percent of pregnant mothers were overweight or obese, 43.6% gained above the recommended standards for gestational weight gain and 35.8% did not have an oral glucose tolerance test. The audit identified a high prevalence of obesity among pregnant women and low screening rates for gestational diabetes mellitus associated with adverse maternal and neonatal pregnancy outcomes. We conclude that there is a high prevalence of overweight and obesity among pregnant women in rural regional Tasmania. Further GDM screening rates are low, which require addressing

Effect of a 4-week weight maintenance diet on circulating hormone levels: implications for clinical weight loss trials

Summary The majority of weight loss studies fail to standardize conditions such as diet and exercise via a weight maintenance period prior to commencement of the trial. This study aimed to determine whether a weight stabilization period is necessary to establish stable baseline hormone concentrations. Fifty-one obese male participants with a body mass index of 30–40 kg m−2 and aged 25–54 years underwent 4 weeks on an energy balance diet that was designed to achieve weight stability. Blood samples were collected in the fasting state at commencement and completion of the 4-week period, and circulating concentrations of 18 commonly measured hormones were determined. During the 4-week weight maintenance period, participants achieved weight stability within −1.5 ± 0.2 kg (−1.4 ± 0.2%) of their initial body weight. Significant reductions in serum insulin (by 18 ± 6.5%) and leptin (by 21 ± 6.0%) levels occurred, but no significant changes were observed for gut-derived appetite-regulating hormones (ghrelin and peptide YY), nor thyroid, adrenal, gonadal or somatotropic hormones. There were no significant correlations between the change in body weight and the change in circulating concentrations of insulin or leptin over the 4-week period, indicating that the observed changes were not due to weight loss, albeit significant negative correlations were observed between the changes in body weight and plasma ghrelin and peptide YY levels. This study demonstrates the need for baseline weight maintenance periods to stabilize serum levels of insulin and leptin in studies specifically investigating effects on these parameters in the obese. However, this does not apply to circulating levels of gut-derived appetite-regulating hormones (ghrelin and peptide YY), nor thyroid, adrenal, gonadal or somatotropic hormones

Intermittent energy restriction improves weight loss efficiency in obese men: the MATADOR study

Background/Objectives:The MATADOR (Minimising Adaptive Thermogenesis And Deactivating Obesity Rebound) study examined whether intermittent energy restriction (ER) improved weight loss efficiency compared with continuous ER and, if so, whether intermittent ER attenuated compensatory responses associated with ER.Subjects/Methods:Fifty-one men with obesity were randomised to 16 weeks of either: (1) continuous (CON), or (2) intermittent (INT) ER completed as 8 × 2-week blocks of ER alternating with 7 × 2-week blocks of energy balance (30 weeks total). Forty-seven participants completed a 4-week baseline phase and commenced the intervention (CON: N=23, 39.4±6.8 years, 111.1±9.1 kg, 34.3±3.0 kg m−2; INT: N=24, 39.8±9.5 years, 110.2±13.8 kg, 34.1±4.0 kg m−2). During ER, energy intake was equivalent to 67% of weight maintenance requirements in both groups. Body weight, fat mass (FM), fat-free mass (FFM) and resting energy expenditure (REE) were measured throughout the study.Results:For the N=19 CON and N=17 INT who completed the intervention per protocol, weight loss was greater for INT (14.1±5.6 vs 9.1±2.9 kg; PConclusions:Greater weight and fat loss was achieved with intermittent ER. Interrupting ER with energy balance ‘rest periods’ may reduce compensatory metabolic responses and, in turn, improve weight loss efficiency

Prevalence and trends of metabolic syndrome among adults in the asia-pacific region: a systematic review

Background: The Asia-Pacific region is home to nearly half of the world’s population. The region has seen a recentrapid increase in the prevalence of obesity, type-2 diabetes and cardiovascular disease. The present systematicreview summarizes the recent prevalence and trends of Metabolic Syndrome (MetS) among adults in countries ofthe Asia-Pacific Region.Methods: Data on MetS in Asia-Pacific countries were obtained using a stepwise process by searching the onlineMedline database using MeSH terms ‘Metabolic Syndrome X’ and ‘Epidemiology/EP’. For the purpose of describingprevalence data for the individual countries, studies that were most recent, nationally representative or with thelargest sample size were included. When evaluating secular trends in prevalence in a country we only consideredstudies that evaluated the temporal change in prevalence between similar populations, prospective studies basedon the same population or National surveys conducted during different time periods.Results: This literature search yielded a total of 757 articles, and five additional article were identified by screeningof reference lists. From this total, 18 studies were eligible to be included in the final analysis. Of the 51 Asia-Pacificcountries (WHO) we only located data for 15. There was wide between country variation in prevalence of MetS.A national survey from Philippines conducted in 2003 revealed the lowest reported prevalence of 11.9% accordingto NCEP ATP III criteria. In contrast, the highest recorded prevalence in the region (49.0%) came from a studyconducted in urban Pakistan (Karachchi, 2004). Most studies reported a higher prevalence of MetS in females andurban residents. Data on secular trends were available for China, South Korea and Taiwan. An increase in theprevalence of MetS was observed in all three countries.Conclusion: Despite differences in methodology, diagnostic criteria and age of subjects studied, the Asia-Pacificregion is facing a significant epidemic of MetS. In most countries nearly 1/5th of the adult population or morewere affected by MetS with a secular increase in prevalence. Strategies aimed at primary prevention are requiredto ameliorate a further increase in the epidemic and for the reduction of the morbidity and mortality associatedwith MetS

Clinical implications of gait analysis in the rehabilitation of adult patients with "Prader-Willi" Syndrome: a cross-sectional comparative study ("Prader-Willi" Syndrome vs matched obese patients and healthy subjects)

<p>Abstract</p> <p>Background</p> <p>Being severely overweight is a distinctive clinical feature of Prader-Willi Syndrome (PWS). PWS is a complex multisystem disorder, representing the most common form of genetic obesity. The aim of this study was the analysis of the gait pattern of adult subjects with PWS by using three-Dimensional Gait Analysis. The results were compared with those obtained in a group of obese patients and in a group of healthy subjects.</p> <p>Methods</p> <p>Cross-sectional, comparative study: 19 patients with PWS (11 males and 8 females, age: 18–40 years, BMI: 29.3–50.3 kg/m²); 14 obese matched patients (5 males and 9 females, age: 18–40 years, BMI: 34.3–45.2 kg/m²); 20 healthy subjects (10 males and 10 females, age: 21–41 years, BMI: 19.3–25.4 kg/m²). Kinematic and kinetic parameters during walking were assessed by an optoelectronic system and two force platforms.</p> <p>Results</p> <p>PWS adult patients walked slower, had a shorter stride length, a lower cadence and a longer stance phase compared with both matched obese, and healthy subjects. Obese matched patients showed spatio-temporal parameters significantly different from healthy subjects.</p> <p>Furthermore, Range Of Motion (ROM) at knee and ankle, and plantaflexor activity of PWS patients were significantly different between obese and healthy subjects. Obese subjects revealed kinematic and kinetic data similar to healthy subjects.</p> <p>Conclusion</p> <p>PWS subjects had a gait pattern significantly different from obese patients. Despite that, both groups had a similar BMI. We suggest that PWS gait abnormalities may be related to abnormalities in the development of motor skills in childhood, due to precocious obesity. A tailored rehabilitation program in early childhood of PWS patients could prevent gait pattern changes.</p