Effects of Renal Denervation on Insulin Sensitivity and Inflammatory Markers in Nondiabetic Patients with Treatment-Resistant Hypertension

Increased sympathetic activity is important in the pathogenesis of hypertension and insulin resistance. Afferent signaling from the kidneys elevates the central sympathetic drive. We investigated the effect of catheter-based renal sympathetic denervation (RDN) on glucose metabolism, inflammatory markers, and blood pressure in nondiabetic patients with treatment-resistant hypertension. Eight subjects were included in an open-labelled study. Each patient was studied before and 6 months after RDN. Endogenous glucose production was assessed by a 3-3H glucose tracer, insulin sensitivity was examined by hyperinsulinemic euglycemic clamp, hormones and inflammatory markers were analyzed, and blood pressure was measured by office blood pressure readings and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity (M-value) increased nonsignificantly from 2.68 ± 0.28 to 3.07 ± 0.41 (p=0.12). A significant inverse correlation between the increase in M-value and BMI 6 months after RDN (p=0.03) was found, suggesting beneficial effects on leaner subjects. Blood pressure decreased significantly, but there were no changes in hormones, inflammatory markers, or endogenous glucose production. Our results indicate that RDN may improve insulin sensitivity in some patients with treatment-resistant hypertension, albeit confirmation of these indications of beneficial effects on leaner subjects awaits the outcome of larger randomized controlled studies

Clinical outcomes after treatment of multiple lesions with zotarolimus-eluting versus sirolimus-eluting coronary stents (a SORT OUT III substudy)

<p>Abstract</p> <p>Background</p> <p>Data on clinical outcomes among patients treated with the zotarolimus-eluting Endeavor™ stent versus the sirolimus-eluting Cypher™ stent favor the sirolimus-eluting stent. However, a separate comparison of clinical outcome among patients treated for multiple lesions with these stents is lacking. We performed this comparison within the SORT OUT III trial data set.</p> <p>Methods</p> <p>Among 2332 patients randomized in SORT OUT III, 695 were treated for multiple lesions with zotarolimus-eluting (n = 350) or sirolimus-eluting (n = 345) stents and followed for 18 months. Major adverse cardiac events (MACE); composite of cardiac death, myocardial infarction, or target vessel revascularization (TVR); was the primary endpoint.</p> <p>Results</p> <p>Zotarolimus-eluting compared to sirolimus-eluting stent treatment was associated with increased MACE rate (13.2% vs. 2.6%; hazard ratio 5.29 with 95% confidence interval: 2.59-10.8). All secondary endpoints; all cause death, cardiac death, myocardial infarction, TVR, target lesion revascularization, in-stent restenosis, and definite stent thrombosis; were observed more frequently among zotarolimus-eluting stent treated patients. For all endpoints, hazard ratios were 1.6 to 4.6 times higher than in the overall results of the SORT OUT III trial.</p> <p>Conclusions</p> <p>We observed better clinical outcomes among patients treated for multiple lesions with the sirolimus-eluting stent compared to those treated with the zotarolimus-eluting stent.</p

The impact of liraglutide on diabetes-related foot ulceration and associated complications in patients with type 2 diabetes at high risk for cardiovascular events: Results from the LEADER trial

OBJECTIVE: Diabetes-related foot ulcers (DFUs) and their sequelae result in large patient and societal burdens. Long-term data determining the efficacy of individual glucose-lowering agents on DFUs are lacking. Using existing data from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, we conducted post hoc analyses assessing the impact of liraglutide versus placebo in people with type 2 diabetes and at high risk of cardiovascular (CV) events on the incidence of DFUs and their sequelae. RESEARCH DESIGN AND METHODS: The LEADER trial (NCT01179048) was a randomized, double-blind, multicenter, CV outcomes trial assessing liraglutide (1.8 mg/day) versus placebo, in addition to standard of care, for up to 5 years. Information on DFUs was collected systematically during the trial, and DFU complications were assessed post hoc through reviewing case narratives. RESULTS: During a median of 3.8 years' follow-up, similar proportions of patients reported at least one episode of DFU in the liraglutide and placebo groups (3.8% [176/4,668] versus 4.1% [191/4,672], respectively; hazard ratio [HR] 0.92 [95% CI 0.75, 1.13; P = 0.41]). Analysis of DFU-related complications demonstrated a significant reduction in amputations with liraglutide versus placebo (HR 0.65 [95% CI 0.45, 0.95; P = 0.03]). However, no differences were found for foot infections, involvement of underlying structures, or peripheral revascularization in the main analysis. CONCLUSIONS: Treatment with liraglutide in patients with type 2 diabetes and at high risk of CV events in the LEADER trial did not increase the risk of DFU events and was associated with a significantly lower risk of DFU-related amputations compared with placebo. This association, possibly due to chance, needs further investigation

Genetic Analysis of the Capsular Biosynthetic Locus from All 90 Pneumococcal Serotypes

Several major invasive bacterial pathogens are encapsulated. Expression of a polysaccharide capsule is essential for survival in the blood, and thus for virulence, but also is a target for host antibodies and the basis for effective vaccines. Encapsulated species typically exhibit antigenic variation and express one of a number of immunochemically distinct capsular polysaccharides that define serotypes. We provide the sequences of the capsular biosynthetic genes of all 90 serotypes of Streptococcus pneumoniae and relate these to the known polysaccharide structures and patterns of immunological reactivity of typing sera, thereby providing the most complete understanding of the genetics and origins of bacterial polysaccharide diversity, laying the foundations for molecular serotyping. This is the first time, to our knowledge, that a complete repertoire of capsular biosynthetic genes has been available, enabling a holistic analysis of a bacterial polysaccharide biosynthesis system. Remarkably, the total size of alternative coding DNA at this one locus exceeds 1.8 Mbp, almost equivalent to the entire S. pneumoniae chromosomal complement

The Freedoms and Capabilities of Farm Animals: How Can Organic Husbandry Fulfill Them?

Organic farming promotes animal husbandry practices that consider the welfare of the animals on the farm. The concept of animal welfare and the standards that should encompass this concept have in many cases been largely generalised in practice, which leaves relevant aspects of animal freedom or capabilities insufficiently addressed. This chapter puts forth the prospect that the capabilities approach offers an appropriate practical platform by which to improve welfare in farm animals by meeting a wider range of their natural needs and abilities. The capabilities approach coupled with effective health planning could foster organic husbandry towards a more acceptable production system for farmers and consumers alike

Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis

Colonic epithelial ion transport is not affected in patients with diverticulosis

<p>Abstract</p> <p>Background</p> <p>Colonic diverticular disease is a bothersome condition with an unresolved pathogenesis. It is unknown whether a neuroepithelial dysfunction is present. The aim of the study was two-fold; (1) to investigate colonic epithelial ion transport in patients with diverticulosis and (2) to adapt a miniaturized Modified Ussing Air-Suction (MUAS) chamber for colonic endoscopic biopsies.</p> <p>Methods</p> <p>Biopsies were obtained from the sigmoid part of the colon. 86 patients were included. All patients were referred for colonoscopy on suspicion of neoplasia and they were without pathological findings at colonoscopy (controls) except for diverticulosis in 22 (D-patients). Biopsies were mounted in MUAS chambers with an exposed area of 5 mm². Electrical responses to various stimulators and inhibitors of ion transport were investigated together with histological examination. The MUAS chamber was easy to use and reproducible data were obtained.</p> <p>Results</p> <p>Median basal short circuit current (SCC) was 43.8 μA·cm^-2(0.8 – 199) for controls and 59.3 μA·cm^-2(3.0 – 177.2) for D-patients. Slope conductance was 77.0 mS·cm^-2(18.6 – 204.0) equal to 13 Ω·cm²for controls and 96.6 mS·cm^-2(8.4 – 191.4) equal to 10.3 Ω·cm²for D-patients. Stimulation with serotonin, theophylline, forskolin and carbachol induced increases in SCC in a range of 4.9 – 18.6 μA·cm^-2, while inhibition with indomethacin, bumetanide, ouabain and amiloride decreased SCC in a range of 6.5 – 27.4 μA·cm^-2, and all with no significant differences between controls and D-patients. Histological examinations showed intact epithelium and lamina propria before and after mounting for both types of patients.</p> <p>Conclusion</p> <p>We conclude that epithelial ion transport is not significantly altered in patients with diverticulosis and that the MUAS chamber can be adapted for studies of human colonic endoscopic biopsies.</p

Addressing preference heterogeneity in public health policy by combining Cluster Analysis and Multi-Criteria Decision Analysis: Proof of Method.

The use of subgroups based on biological-clinical and socio-demographic variables to deal with population heterogeneity is well-established in public policy. The use of subgroups based on preferences is rare, except when religion based, and controversial. If it were decided to treat subgroup preferences as valid determinants of public policy, a transparent analytical procedure is needed. In this proof of method study we show how public preferences could be incorporated into policy decisions in a way that respects both the multi-criterial nature of those decisions, and the heterogeneity of the population in relation to the importance assigned to relevant criteria. It involves combining Cluster Analysis (CA), to generate the subgroup sets of preferences, with Multi-Criteria Decision Analysis (MCDA), to provide the policy framework into which the clustered preferences are entered. We employ three techniques of CA to demonstrate that not only do different techniques produce different clusters, but that choosing among techniques (as well as developing the MCDA structure) is an important task to be undertaken in implementing the approach outlined in any specific policy context. Data for the illustrative, not substantive, application are from a Randomized Controlled Trial of online decision aids for Australian men aged 40-69 years considering Prostate-specific Antigen testing for prostate cancer. We show that such analyses can provide policy-makers with insights into the criterion-specific needs of different subgroups. Implementing CA and MCDA in combination to assist in the development of policies on important health and community issues such as drug coverage, reimbursement, and screening programs, poses major challenges -conceptual, methodological, ethical-political, and practical - but most are exposed by the techniques, not created by them