Mercury based drug in ancient India: The red sulfide of mercury in nanoscale.

Mercury is one of the elements which had attracted the attention of the chemists and physicians of ancient India and China. Among the various metal based drugs which utilize mercury, we became interested in the red sulfide of mercury which is known in ancient Indian literature as rasasindur (alias rasasindura, rasasindoor, rasasinduram, sindur, or sindoor) and is used extensively in various ailments and diseases. Following various physico-chemical characterizations it is concluded that rasasindur is chemically pure α-HgS with Hg:S ratio as 1:1. Analysis of rasasindur vide Transmission Electron Microscopy (TEM) showed that the particles are in nanoscale. Bio-chemical studies of rasasindur were also demonstrated. It interacts with Bovine Serum Albumin (BSA) with an association constant of (9.76 ± 0.56) × 103 M-1 and behaves as a protease inhibitor by inhibiting the proteolysis of BSA by trypsin. It also showed mild antioxidant properties.

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM-INSULIN trial.

AIMS: The coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. METHODS: ODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening≥70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C≥70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. RESULTS: This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. CONCLUSION: The ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.

Cardiovascular risk prevention and all-cause mortality in primary care patients with an abdominal aortic aneurysm.

BACKGROUND: Perioperative mortality is low for patients undergoing abdominal aortic aneurysm (AAA) repair, but long-term survival remains poor. Although patients diagnosed with AAA have a significant burden of cardiovascular disease and associated risk factors, there is limited understanding of the contribution of cardiovascular risk management to long-term survival. METHODS: General practice records within The Health Improvement Network (THIN) were examined. Patients with a diagnosis of AAA and at least 1 year of registered medical history were identified from 2000 to 2012. Medical therapies for cardiovascular risk were classified as antiplatelet, statin or antihypertensive agents. Progression to death was investigated using the G-computation formula with time-dependent co-variables to account for differences in exposure to cardiovascular risk-modifying treatments and the confounding between exposure, co-morbidities and death. RESULTS: Some 12 485 patients had a recorded diagnosis of AAA. From 2000 to 2012, prescription of medications that modify cardiovascular risk increased: from 26·6 to 76·7 per cent for statins, from 56·5 to 73·9 per cent for antiplatelet agents and from 75·3 to 84·0 per cent for antihypertensive drugs. Adjusted Kaplan-Meier curves demonstrated a better 5-year survival rate in patients receiving statins (68·4 versus 42·2 per cent), antiplatelet agents (63·6 versus 39·7 per cent) or antihypertensive agents (61·5 versus 39·1 per cent), compared with rates in patients not receiving each therapy. CONCLUSION: Appropriate risk factor modification could significantly reduce long-term mortality in patients with AAA. In the UK, up to 30 per cent of patients are not currently receiving these medications.

Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials.

The full licensing of dipeptidyl peptidase-4 (DPP-4) inhibitors in the USA and Europe requires demonstration of cardiovascular (CV) safety with an upper boundary of harm of <30%. We report a total of 3334 CV events during 86,716 person-years of follow-up in 36,543 patients, when combining data from three trials with formal and prospectively assessed endpoints. Fixed-effect meta-analysis showed that, compared with placebo, DPP-4 inhibition did not increase the upper boundary of risk for the composite endpoint, nor for any individual component by >30%. Relative risks (RRs) were: 0.99 [confidence interval (CI) 0.93-1.06] for composite CV-specific death, non-fatal myocardial infarction (MI) and non-fatal stroke; 1.01 (CI 0.91-1.12) for CV-specific death; 0.98 (CI 0.89-1.09) for non-fatal MI; and 1.00 (CI 0.86-1.16) for non-fatal stroke. The risk of acute pancreatitis was increased (RR 1.79; CI 1.13-2.81), equating to 5.5 extra cases/10,000 patients/year (weighted mean) and a number needed to harm of 1940/year. These data provide reassurance about the safety of DPP-4 inhibitors with regard to individual atherothrombotic events and a safety signal for pancreatitis.

Chronic fatigue syndrome and circulating cytokines: A systematic review.

There has been much interest in the role of the immune system in the pathophysiology of chronic fatigue syndrome (CFS), as CFS may develop following an infection and cytokines are known to induce acute sickness behaviour, with similar symptoms to CFS. Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls. Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation. Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-ß) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines. Following physical exercise there were no differences in circulating cytokine levels between cases and controls and exercise made no difference to already elevated TGF-ß concentrations. The finding of elevated TGF-ß concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue.

A meta-analysis of published studies of endothelial dysfunction does not support its routine clinical use.

BACKGROUND: Endothelial dysfunction is a marker of future cardiovascular disease (CVD) risk, yet epidemiological studies have yielded inconsistent results. We therefore studied the association between endothelial dysfunction and CVD under diverse circumstances. METHODS AND RESULTS: Literature-based meta-analysis of prospective observational studies with ≥ 12 months of follow-up published in Medline and having information on endothelial function and CVD outcomes. Tabular data on participant characteristics, endothelial function assessments and incident CVD outcomes were abstracted from individual studies. Random-effects meta-analysis was used to quantify pooled associations, and I(2) statistic to evaluate between-study heterogeneity. Potential sources of heterogeneity were explored by subgroup analyses and meta-regression. Thirty five studies involving 17,206 participants met the inclusion criteria. During more than 80,000 person-years of observation, up to 2755 CVD events were accrued, yielding a pooled relative risk (RR) of 1.25 (95% confidence interval 1.15-1.35) for CVD comparing top (i.e. more severe) vs. bottom (less severe) third of endothelial dysfunction. There was significant between-study heterogeneity and evidence of publication bias. RRs varied importantly according to the method used to ascertain endothelial function, and were higher among older individuals and among participants with risk factors for CVD or established CVD at baseline. CONCLUSIONS: Although endothelial dysfunction is an important determinant of cardiovascular outcomes in people with pre-existing CVD, current evidence base does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD.

Cardiovascular safety of the glucagon-like peptide-1 receptor agonist taspoglutide in people with type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials.

AIMS: To study the short-term cardiovascular effects of the once-weekly glucagon-like peptide-1 receptor agonist taspoglutide. METHODS: We conducted a meta-analysis of individual-participant data from nine randomized controlled trials in the T-Emerge programme, which assessed the efficacy and safety of taspoglutide in type 2 diabetes. Our primary outcome was a composite of death from cardiovascular disease (CVD) and acute myocardial infarction, stroke and hospitalization for unstable angina. RESULTS: Overall, 7056 individuals were included in the analysis, and there were 67 primary endpoint events during 7478 person-years of follow-up (40 vs 27 events in the intervention vs control groups, respectively). The odds ratio for the composite endpoint among people randomized to taspoglutide was 0.94 (95% confidence interval 0.57-1.56), which was robust across multiple subgroups. Longer-term data were not available as the development of taspoglutide was stopped because of gastrointestinal intolerance and serious hypersensitivity reactions. CONCLUSIONS: The available data suggest that short-term, once-weekly administration of taspoglutide was not associated with an excess risk of CVD, and provide insights relevant to the development of other novel once-weekly incretin mimetics.

The shortfall in long-term survival of patients with repaired thoracic or abdominal aortic aneurysms: retrospective case-control analysis of hospital episode statistics.

OBJECTIVE: To report the contemporary life expectancy of patients undergoing abdominal (AAA) or thoracic aortic aneurysm (TAA) repair in England, relative to a healthy control population. METHODS: A retrospective observational case-control study was carried out of Hospital Episode Statistics (HES) data, an administrative dataset covering the entire English National Health Service. Patients undergoing elective repair of an abdominal or thoracic aortic aneurysm in an English NHS hospital between April 2006 and March 2011 were included. Outcome measures were 5-year all-cause mortality (in- and out-of-hospital) and adverse cardiovascular events (myocardial infarction, stroke, emergency amputation or limb revascularisation). RESULTS: 19,505 AAA and 730 TAA repairs were identified, with 75,260 and 2,721 control participants, respectively, and 27.5 (1.0-60.0) months' median (range) follow-up. Five-year survival was 67.4% for AAA against 81.1% for control participants, and 65.3% for TAA against 89.1% for control participants (p < .001). Freedom from adverse cardiovascular events was 86.1% for AAA against 93% for control participants and 89.1% for TAA against 94.4% for control participants (p < .001). CONCLUSION: Long-term survival remains poor after aneurysm repair and adverse cardiovascular events are common relative to the wider population. Further research is required to characterise and optimise cardiovascular risk prevention in patients with aortic aneurysms.

The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: a meta-analysis.

AIMS/HYPOTHESIS: It is well established that diabetes mellitus increases the risk of cardiovascular disease (CVD) and all-cause mortality. Observational studies suggest that a history of diabetic foot ulceration (DFU) may increase this risk further still. We sought to determine to what extent DFU is associated with excess risk over and above diabetes. METHODS: We identified studies reporting on associations of DFU with CVD and all-cause mortality. We obtained data on incident events of all-cause mortality, fatal myocardial infarction and fatal stroke. Study-specific estimates were pooled using a random-effects meta-analysis and the statistical heterogeneity of included studies was assessed using the I (2) statistic. RESULTS: The eight studies included reported on 3,619 events of all-cause mortality during 81,116 person-years of follow-up. DFU was associated with an increased risk of all-cause mortality (RR 1.89, 95% CI 1.60, 2.23), fatal myocardial infarction (2.22, 95% CI 1.09, 4.53) and fatal stroke (1.41, 95% CI 0.61, 3.24). CVD mortality accounted for a similar proportion of deaths in DFU and non-DFU patients. CONCLUSIONS/INTERPRETATION: Patients with DFU have an excess risk of all-cause mortality, compared with patients with diabetes without a history of DFU. This risk is attributable, in part, to a greater burden of CVD. If this result is validated in other studies, strategies should evaluate the role of further aggressive CVD risk modification and ulcer prevention in those with DFU.

Identification of motion from multi-channel EMG signals for control of prosthetic hand.

The authors in this paper propose an effective and efficient pattern recognition technique from four channel electromyogram (EMG) signals for control of multifunction prosthetic hand. Time domain features such as mean absolute value, number of zero crossings, number of slope sign changes and waveform length are considered for pattern recognition. The patterns are classified using simple logistic regression (SLR) technique and decision tree (DT) using J48 algorithm. In this study six specific hand and wrist motions are identified from the EMG signals obtained from ten different able-bodied. By considering relevant dominant features for pattern recognition, the processing time as well as memory space of the SLR and DT classifiers is found to be less in comparison with neural network (NN), k-nearest neighbour model 1 (kNN-Model-1), k-nearest neighbour model 2 (kNN-Model-2) and linear discriminant analysis. The classification accuracy of SLR classifier is found to be 91 ± 1.9%.

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

In-vitro and in-vivo correlation for two gliclazide extended-release tablets.

The aim of this study was to perform an in-vitro-in-vivo correlation (IVIVC) for two 60-mg gliclazide extended-release formulations (Fast and Slow release) given once a day and to compare their plasma concentrations over time. In-vitro release rate data were obtained for each formulation using the USP apparatus II, paddle stirrer at 50 and 100 rev min(-1) in 0.1 M HCl and pH 7.4 phosphate buffer. The similarity factor (f2) was used to analyse the dissolution data. Eighteen healthy subjects participated in the study, conducted according to a completely randomized, two-way crossover design. The formulations were compared using area under the plasma concentration-time curve, AUC(0-infinity), time to reach peak plasma concentration, Tmax, and peak plasma concentration Cmax, while correlation was determined between in-vitro release and in-vivo absorption. A linear correlation model was developed using percent absorbed data versus percent dissolved data from the two formulations. Predicted gliclazide concentrations were obtained by use of a curve fitting equation. Prediction errors were estimated for Cmax and area under the curve AUC(0-infinity) to determine the validity of the correlation. 0.1 M HCl at 50 rev min(-1) was found to be the most discriminating dissolution method. Linear regression analysis of the mean percentage of dose absorbed versus the mean percentage of in-vitro release resulted in a significant correlation (r2 > 0.98) for the two formulations. An average percent prediction error for Cmax was 4.15% for Fast release and 3.99% for Slow release formulation whereas for AUC(0-infinity) it was 6.36% and 4.66% for Fast release and Slow release formulation, respectively.

WITHDRAWN: Caregiver support for postpartum depression.

BACKGROUND: Supportive relationships during the perinatal period may enhance a mother's feeling of wellbeing and control. Support to women during labour and after birth has shown benefits and this may also be the case for mothers with postpartum depression. OBJECTIVES: The objective of this review was to assess the effect of professional and/or social support interventions for the treatment of postpartum depression. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. Date of last search: January 2001. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing additional support from caregivers with usual forms of care in the postpartum period, in women who were clinically depressed in the six months after giving birth. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted by both reviewers. Study authors were contacted for additional information. MAIN RESULTS: Two studies involving 137 women were included. There is potential for bias in at least one study, due to large numbers of women refusing to take part in the trial as well as significant losses to follow-up during the trial. Treatment of postpartum depression with support was associated with a reduction in depression at 25 weeks after giving birth (odds ratio 0.34, 95% confidence intervals 0.17 to 0.69). AUTHORS' CONCLUSIONS: There is some indication that professional and/or social support may help in the treatment of postpartum depression. The types of support should be investigated to assess which models are most effective.

Recent trials of lipid lowering.

The global burden of coronary artery disease has pushed lipid-lowering therapy to the forefront of medical management of this condition. Recent clinical trials have compared the efficacy of more intensive lipid lowering with statins against the normal standard of care. Other agents such as fibrates, glitazones, which also favourably modify lipid levels have also been assessed recently. This narrative review summarises the key recent clinical trials of lipid lowering since 2004 and their implications for future patient care.