Hemodynamic and metabolic responses to valsartan and atenolol in obese hypertensive patients

OBJECTIVE: None of the current hypertension guidelines provides specific guidance regarding pharmacological management of obese hypertensive patients. Treatment recommendations for lean hypertensives may not be simply extrapolated to obese hypertensive persons. DESIGN: Randomized, double-blind, parallel-group study with a 13-week treatment period. SETTING: Multicenter study in Germany. PATIENTS: Obese patients with mild to moderate uncomplicated essential hypertension. INTERVENTION: Patients were treated with valsartan at a maximal dose of 160 mg/day or with atenolol at a maximal dose of 100 mg/day. Hydrochlorothiazide at doses of 12.5-25 mg was added in patients with blood pressure > 140/90 mmHg on monotherapy. MAIN OUTCOME MEASURES: Blood pressure, lipid and glucose metabolism, and highly sensitive C-reactive protein (hsCRP) were monitored. RESULTS: Sixty-seven patients were randomized to valsartan and 65 patients to atenolol. With valsartan, systolic blood pressure (SBP) decreased from 160.8 +/- 8.9 to 140.5 +/- 13.3 mmHg and diastolic blood pressure (DBP) from 96.1 +/- 7.0 to 85.1 +/- 8.1 mmHg by the end of the study. With atenolol, SBP decreased from 159.3 +/- 6.8 to 139.8 +/- 14.5 mmHg and DBP from 95.0 +/- 6.8 to 83.5 +/- 7.5 mmHg (P = 0.91 for SBP and P = 0.34 for DBP between interventions). Body weight did not change with either treatment. We did not see a significant difference in the response of lipid levels or hsCRP between interventions. To assess the cumulative effect of each intervention on glucose metabolism over the trial duration, we calculated individual areas under the curve for homeostasis model assessment for insulin resistance (HOMA-IR) over time. The resulting area under the curve was significantly smaller with valsartan compared with atenolol (P = 0.02). CONCLUSIONS: Beta-adrenoreceptor blockers and AT1-receptor blockers, particularly in combination with low-dose diuretics, effectively lower blood pressure in obese hypertensives. However, metabolic responses differ between both treatment strategies, with beneficial effects of AT1-receptor blockers. AT1-receptor blockers are a good choice in obese hypertensives, given the profoundly increased diabetes risk in this population.     

2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach to the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.     

Effect of endoscopic sphincterotomy on gall bladder bile lithogenicity and motility

Background—Endoscopic sphincterotomyhas been shown to inhibit stone formation in the gall bladder ofexperimental animals.
Aims—To investigate the alterations in bilecomposition and gall bladder motility after endoscopic sphincterotomy.
Patients—A study was performed of gall bladderbile composition and gall bladder motility in patients with gallstonedisease ((n = 20; age 40-60 years, median age 55 years: seven men),with gall bladder calculi (n = 12) and with diseased gall bladder(chronic inflammation) without gall bladder calculi (n = 8)), who hadreceived endoscopic sphincterotomy for common bile duct stones. Age and sex matched disease controls comprised 20 patients with gallstone disease but without stones and an intact sphincter of Oddi (with gallbladder calculi (n = 10) and diseased gall bladder without gall bladdercalculi (n =10)).
Methods—Gall bladder motility was assessed byultrasound. Duodenal bile collected by nasoduodenal tube afterstimulation of gall bladder by intravenous ceruletid infusion wasanalysed for cholesterol, phospholipid, and bile acidconcentrations, cholesterol saturation index, and nucleation time.
Results—There was a significant reduction in mean(SEM) fasting volume (12.5 (1.7) ml v 26.4 (2.5) ml;p<0.001) and mean (SEM) residual volume (4.34 (0.9) ml v14.7 (0.98) ml; p<0.001), and increase in mean (SEM) ejection fraction(65.7 (4.2)% v 43.6 (5.52)%; p<0.001) and mean (SEM)rate constant of gall bladder emptying (−0.031/min v−0.020/min; p<0.01) in patients who had been subjected to endoscopicsphincterotomy. Median nucleation time was significantly longer (17 days v 6 days; p<0.006) in treated patients. There was areduction in total mean (SEM) lipid concentrations (6.73(0.32) g/dlv 7.72 (0.84) g/dl; p<0.05), cholesterol (5.6 (1.5) mmol/l v 10.3 (2.23) mmol/l; p<0.001) and CSI (0.72 (0.15) v 1.32(0.31); p<0.001). There was no significantchange in mean (SEM) phospholipid (25.6 (3.5) mmol/l v23.4 (6.28) mmol/l) and bile acid (93.7 (7.31) mmol/l v105.07 (16.6) mmol/l) concentrations.
Conclusions—After endoscopic sphincterotomy therewas enhanced contractility of the gall bladder, accompanied by aprolongation of nucleation time and reduction in cholesterol saturation index.

Keywords:gall bladder emptying; gall bladder contractility; nucleation time; cholesterol saturation index; gallstones; endoscopicpapillotomy

     

Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials

IL-17 has a role in inflammation in RA, and its levels in joints correlate with disease severity. Multiple RCTs have been performed to study effects of anti-IL-17 agents. The objective of this study was to perform a systematic review and meta-analysis to analyze the efficacy and safety of anti-IL-17 agents in the management of RA. This work is based on a systematic review of studies retrieved by a sensitive search strategy in PubMed, EMBASE and Cochrane CENTRAL from inception through 9/7/15. Study selection criteria were the following: adult patients (age ≥ 18 years) with RAs, random selection of patients for anti-IL-17 therapy and treatment response compared to placebo. We performed systematic literature review per PRISMA guideline and two investigators independently selected seven randomized clinical trials (RCTs) for meta-analysis. We used random effect model calculating odds ratio (OR) and 95 % confidence interval (CI) to measure the efficacy with ACR20/50/70 responses and the safety with adverse events. Seven studies with total of 1226 patients including 905 in anti-IL-17 group and 321 in placebo were included in the meta-analysis. Anti-IL-17 was effective in achieving ACR20 and ACR50 compared to placebo (OR 2.47, 95 % CI 1.29–4.72, P = 0.006, I ² 77 % and OR 2.94, 95 % CI 1.37–6.28, P = 0.005, I ² 64 %, respectively). Data analysis for ACR70 showed a favorable trend toward anti-IL-17 (OR 2.62, 95 % CI 1–6.89, P = 0.05, I ² 15 %). Subgroup analysis of ACR20 for individual anti-IL-17 agents showed that ixekizumab was more effective than placebo, while secukinumab showed a trend toward achieving the ACR20 response. However, brodalumab was not effective compared to placebo. Safety analysis did not show increased risk of any or serious adverse effects by anti-IL-17 compared to placebo (OR 1.23, 95 % CI 0.94–1.61, P = 0.13, I ² = 0 % and OR 1.28, 95 % CI 0.57–2.88, P = 0.55, I ² = 0 %, respectively). This meta-analysis concludes that anti-IL-17 is effective in the treatment of RA without increased risk of any or serious adverse effects; however, the results are limited by significant heterogeneity and small duration of studies.     

Cytokines,apoptosis and cachexia: the potential for TNF antagonism

The cachexia syndrome is characterised by progressive weight loss and depletion of lean body mass and has long been recognised as a poor prognostic sign. Whilst the clinical features of the wasting process are readily apparent, its pathogenesis is complex and poorly understood. There is increasing evidence that the immune system, in particular inflammatory cytokines, may play an important role in the development of cachexia. The cytokine considered to be the most relevant to this process is tumor necrosis factor alpha (TNF), although other mediators such as interleukin (IL) 1, IL-6 and interferon gamma have also been implicated. Apoptosis represents a potential pathway by which wasting can occur in chronic diseases. Cytokines and their corresponding receptors are known to be important regulators of cell death. Apoptosis has been demonstrated in the skeletal muscle of patients with chronic heart failure (CHF) and is thought to be partly responsible for the significant impairment of functional work capacity associated with this condition. An understanding of the mechanisms that regulate muscle protein breakdown is essential for the development of strategies for treating or even preventing muscle cachexia in patients. It is the aim of this article to review the role of inflammatory cytokines, particularly TNF, in the pathogenesis of wasting and also the potential for anti-cytokine therapy. Although this review will concentrate predominantly on the syndrome of CHF, other chronic illnesses such as liver disease, cancer, and sepsis will also be discussed.     

Pathogenesis of acute infection in rhesus macaques with a lymphocyte-tropic strain of simian immunodeficiency virus.

The simian immunodeficiency virus, SIVmac, causes disease affecting multiple organ systems in macaques similar to human immunodeficiency virus infection in humans. Molecularly cloned SIVmac with a strong lymphocyte tropism was used in pathogenesis experiments to correlate viral cell tropism with disease. In 5 animals, exhaustive analyses on viruses from tissues and identification of infected precursor cells were done at multiple times during infection to ensure the virus had not mutated into a macrophage-tropic variant. Viral replication was measured by infectivity, infectious center assays, and in situ hybridization. Lymphocytes produced most virus in tissues, indicating the virus maintained its cell tropism in vivo. Lymphocytes in bone marrow were latently infected and those in the spleen and lymph nodes were productively infected. The virus failed to replicate in the brain after intracerebral inoculation. SIVmac that maintained a strong tropism for lymphocytes and a corresponding poor tropism for macrophages can cause persistent infection and AIDS but not other diseases such as primary pneumonia and encephalitis in rhesus macaques.     

4-Hydroxy TEMPO Attenuates Dichlorvos Induced Microglial Activation and Apoptosis

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