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Background: Adverse health effects of cadmium in adults are well documented, but little is known about the neuropsychological effects of cadmium in children, and no studies of cadmium and blood pressure in children have been conducted. Objective: We examined the potential effects of low-level cadmium exposure on intelligence quotient, neuropsychological functions, behavior, and blood pressure among children, using blood cadmium as a measure of exposure. Methods: We used the data from a multicenter randomized clinical trial of lead-exposed children and analyzed blood cadmium concentrations using the whole blood samples collected when children were 2 years of age. We compared neuropsychological and behavioral scores at 2, 5, and 7 years of age by cadmium level and analyzed the relationship between blood cadmium levels at 2 years of age and systolic and diastolic blood pressure at 2, 5, and 7 years of age. Results: The average cadmium concentration of these children was 0.21 µg/L, lower than for adults in the National Health and Nutrition Examination Survey (NHANES), but comparable to concentrations in children < 3 years of age in NHANES. Except for the California Verbal Learning Test for Children, there were no differences in test scores among children in different cadmium categories. For children with detectable pretreatment blood cadmium, after adjusting for a variety of covariates, general linear model analyses showed that at none of the three age points was the coefficient of cadmium on Mental Development Index or IQ statistically significant. Spline regression analysis suggested that behavioral problem scores at 5 and 7 years of age tended to increase with increasing blood cadmium, but the trend was not significant. We found no significant associations between blood cadmium levels and blood pressure. Conclusion: We found no significant associations between background blood cadmium levels at 2 years of age and neurodevelopmental end points and blood pressure at 2, 5, and 7 years of age. The neuropsychological or hypertensive effects from longer background exposures to cadmium need further study.

Objective The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study. Research design and methods Patients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated. Results Over 36 months, twice-daily exenatide was associated with improved body weight (−3.9 kg), waist circumference (−3.6 cm), systolic/diastolic BP (−2.5/−2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (−0.2 mmol/L), and hsCRP (−1.7 mg/L). Heart rate did not increase (−0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight ( P  < 0.0001), waist circumference ( P  < 0.001), systolic BP ( P  < 0.001), diastolic BP ( P  = 0.023), HDL-cholesterol ( P  = 0.001), and hsCRP ( P  = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4 %; P  = 0.026) or lipid-lowering medication (8.4 vs 12.8 %; P  = 0.025). Conclusions Add-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride. Clinical trial registration: NCT00359762, http://www.ClinicalTrials.gov

Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials. We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283). 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0–5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95–1·04] for ACEIs; 0·96 [0·92–1·01] for ARBs; 0·98 [0·89–1·07] for β blockers; 1·01 [0·95–1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01–1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93–1·09] for ACEIs; 0·99 [0·92–1·06] for ARBs; 0·99 [0·89–1·11] for β blockers; 1·04 [0·96–1·13] for calcium channel blockers; 1·00 [0·90–1·10] for thiazides). We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers. British Heart Foundation, National Institute for Health Research, Oxford Martin School.

Antiobesity treatment is recommended for selected patients in whom lifestyle modification is unsuccessful. Two antiobesity drugs are currently licensed for long-term use. Orlistat, a gastrointestinal lipase inhibitor, reduces weight by around 3 kg on average and decreases progression to diabetes in high-risk patients; adverse gastrointestinal effects are common. Sibutramine, a monoamine-reuptake inhibitor, results in mean weight losses of 4–5 kg, but is associated with increases in blood pressure and pulse rate. Rimonabant, the first of the endocannabinoid receptor antagonists, reduces weight by 4–5 kg on average and improves waist circumference and concentrations of HDL cholesterol and triglyceride; however, an increased incidence of mood-related disorders has been reported. To date, all antiobesity drug trials have been limited by their high attrition rates and lack of long-term morbidity and mortality data. Other promising antiobesity drugs, including those acting within the central melanocortin pathway, are in development, but are years away from clinical use. In light of the lack of successful weight-loss treatments and the public-health implications of the obesity pandemic, the development of safe and effective drugs should be a priority. However, as new drugs are developed we suggest that the assessment processes should include both surrogate endpoints (ie, weight loss) and clinical outcomes (ie, major obesity-related morbidity and mortality). Only then can patients and their physicians be confident that the putative benefits of such drugs outweigh their risks and costs.

Epigenetic mechanisms such as chromatin histone H3 lysine methylation and acetylation have been implicated in diabetic vascular complications. However, histone modification profiles at pathologic genes associated with diabetic nephropathy in vivo and their regulation by the angiotensin II type 1 receptor (AT1R) are not clear. Here we tested whether treatment of type 2 diabetic db/db mice with the AT1R blocker losartan not only ameliorates diabetic nephropathy, but also reverses epigenetic changes. As expected, the db/db mice had increased blood pressure, mesangial hypertrophy, proteinuria, and glomerular expression of RAGE and PAI-1 vs. control db/+ mice. This was associated with increased RNA polymerase II recruitment and permissive histone marks as well as decreased repressive histone marks at these genes, and altered expression of relevant histone modification enzymes. Increased MCP-1 mRNA levels were not associated with such epigenetic changes, suggesting post-transcriptional regulation. Losartan attenuated key parameters of diabetic nephropathy and gene expression, and reversed some but not all the epigenetic changes in db/db mice. Losartan also attenuated increased H3K9/14Ac at RAGE, PAI-1, and MCP-1 promoters in mesangial cells cultured under diabetic conditions. Our results provide novel information about the chromatin state at key pathologic genes in vivo in diabetic nephropathy mediated in part by AT1R. Thus, combination therapies targeting epigenetic regulators and AT1R could be evaluated for more effective treatment of diabetic nephropathy.

The prevalence of malignant hypertension has clearly fallen with the advent of anti-hypertensive medication but has remained stable over the past 30–40 years in spite of progress in diagnosis and management of hypertension. A diagnosis of malignant hypertension is usually based on the association of severely elevated blood pressure with a Keith and Wagener stage III or IV retinopathy. We believe that this definition can be reconsidered for several reasons. Although simple and pragmatic, this definition corresponds to a time when there were few techniques for assessment of hypertensive target organ involvement, and does not take into account involvement of kidney, brain and heart; whereas the overall prognosis largely depends on how much they are affected. On the contrary, the acute blood pressure level and especially diastolic should not be a hard diagnostic criterion as it does not itself constitute the prognosis of the condition. We propose to consider that malignant hypertension with retinopathy is only one of a number of possible presentation(s) of acute hypertension with multi organ damage (hypertension multi organ damage (MOD)) and that the recognition of these hypertensive emergencies, when retinopathy is lacking, be based on acute elevation of BP associated with impairment of at least three different target organs. The objective of a new and expanded definition is to facilitate recognition of these true emergencies. The condition is more common than usually perceived and would have a much worse prognosis than the usual forms of hypertension. Early recognition and management of hypertension-MOD are fundamental to any improvement in prognosis.

Angiotensin-converting-enzyme (ACE) inhibitors reduce cardiovascular mortality and morbidity in patients with heart failure or left ventricular systolic dysfunction (LVSD). Three large trials have assessed the effect of ACE inhibitors in stable patients without these conditions but with atherosclerosis. We undertook a systematic review of the Heart Outcomes Prevention Evaluation (HOPE), the European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA), and the Prevention of Events with ACE inhibition (PEACE) studies to determine the consistency with which ACE inhibitors reduce total mortality and fatal and non-fatal cardiovascular events. We computed cardiovascular outcomes and total mortality in the 29 805 patients of these three trials, randomly assigned an ACE inhibitor or placebo and followed up for a mean of about 4·5 years. The results were also analysed within the context of five large trials of ACE inhibitors in patients with heart failure or LVSD. When the findings of the HOPE, EUROPA, and PEACE trials were combined, ACE inhibitors significantly reduced all-cause mortality (7·8 vs 8·9%, p=0·0004), cardiovascular mortality (4·3 vs 5·2%, p=0·0002), non-fatal myocardial infarction (5·3 vs 6·4%, p=0·0001), all stroke (2·2 vs 2·8%, p=0·0004), heart failure (2·1 vs 2·7%, p=0·0007), coronary-artery bypass surgery (6·0 vs 6·9%, p=0·0036) but not percutaneous coronary intervention (7·4 vs 7·6%, p=0·481). The composite outcomes of cardiovascular mortality, non-fatal myocardial infarction, or stroke occurred in 1599 (10·7%) of the patients allocated ACE inhibitor and in 1910 (12·8%) of those allocated placebo (odds ratio, 0·82; 95% CIs 0·76–0·88; p<0·0001). Except for stroke and revascularisation, these results were similar to those of the five trials in patients with heart failure or LVSD. ACE inhibitors reduce serious vascular events in patients with atherosclerosis without known evidence of LVSD or heart failure. Results showing these benefits in intermediate-risk patients complement existing evidence of similar benefit in higher-risk patients with LVSD or heart failure. Therefore, use of ACE inhibitors should be considered in all patients with atherosclerosis.

The prevalence of hypertension is increasing globally, while strategies for prevention and treatment of hypertension remain limited. FG-4592 (Roxadustat) is a potentially novel, orally active small-molecule hypoxia-inducible factor (HIF) stabilizer and is being used clinically to treat chronic kidney disease (CKD) anemia. In the present study, we evaluate the effects of FG-4592 on hypertension. In an angiotensin II (Ang II) hypertension model, FG-4592 abolished hypertensive responses; prevented vascular thickening, cardiac hypertrophy, and kidney injury; downregulated AGTR1 expression; and enhanced AGTR2, endothelial NO synthase (eNOS), and HIF1α protein levels in the aortas of mice. Additionally, the levels of thiobarbituric acid reactive substances (TBARs) in blood and urine were diminished by FG-4592 treatment. In vascular smooth muscle cells, FG-4592 treatment reduced angiotensin receptor type 1 (AGTR1) and increased AGTR2 levels, while preventing Ang II-induced oxidative stress. In vascular endothelial cells, FG-4592 upregulated total and phosphorylated eNOS. Moreover, FG-4592 treatment was hypotensive in L-NAME-induced hypertension. In summary, FG-4592 treatment remarkably ameliorated hypertension and organ injury, possibly through stabilizing HIF1α and subsequently targeting eNOS, AGTR1, AGTR2, and oxidative stress. Therefore, in addition to its role in treating CKD anemia, FG-4592 could be explored as a treatment for hypertension associated with high renin angiotensin system (RAS) activity or eNOS defects.