Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Aims Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. Methods and results It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. Conclusions These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.Fil: Kelley, Eric E.. University of Pittsburgh; Estados UnidosFil: Baust, Jeff. University of Pittsburgh; Estados UnidosFil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Golin Bisello, Franca. University of Pittsburgh; Estados UnidosFil: Devlin, Jason E.. University of Pittsburgh; Estados UnidosFil: Croix, Claudette M. St.. University of Pittsburgh; Estados UnidosFil: Watkins, Simon C.. University of Pittsburgh; Estados UnidosFil: Gor, Sonia. University of Pittsburgh; Estados UnidosFil: Cantu Medellin, Nadiezhda. University of Pittsburgh; Estados UnidosFil: Weidert, Eric R.. University of Pittsburgh; Estados UnidosFil: Frisbee,Jefferson C.. University of Virginia; Estados UnidosFil: Gladwin, Mark T.. University of Pittsburgh; Estados UnidosFil: Champion, Hunter C.. University of Pittsburgh; Estados UnidosFil: Freeman, Bruce A.. University of Pittsburgh; Estados UnidosFil: Khoo, Nicholas K.H.. University of Pittsburgh; Estados Unido

Oncology providers' perspectives on endocrine therapy prescribing and management.

Adjuvant endocrine therapy (ET) can reduce the risk of recurrence among females with hormone receptor-positive breast cancer. Overall, initiation and adherence to ET are suboptimal, though reasons are not well described. The study's objective was to better understand ET decision making, prescribing, and patient management from oncology providers' perspectives. Using purposive sampling, we recruited oncology providers who saw five or more breast cancer patients per week (n=20). We conducted 30-45-minute telephone interviews, using a semistructured guide to elicit perspectives on ET use. We used thematic content analysis to systematically identify categories of meaning and double-coded transcripts using Atlas.ti. Providers recommend ET to all eligible patients except those with contraindications or other risk factors. Providers base their ET prescribing decisions on the patient's menopausal status, side effects, and comorbidities. ET is typically discussed multiple times: at the onset of breast cancer treatment and in more detail after other treatment completion. Providers felt that the associated recurrence risk reduction is the most compelling argument for patients during ET decision making. While providers rarely perceived noninitiation as a problem, nonadherence was prevalent, often due to unresolvable side effects. From the clinicians' perspectives, side effects from ET are the dominant factor in nonadherence. Efforts to improve adherence should focus on strategies to minimize side effects and ensure clinicians and patients are well informed regarding optimal side effect management. This finding has important implications for novel endocrine regimens that offer improved outcomes through longer duration or more intensive therapy

An Adiabatic Theorem without a Gap Condition

The basic adiabatic theorems of classical and quantum mechanics are over-viewed and an adiabatic theorem in quantum mechanics without a gap condition is described.Comment: Talk at QMath 7, Prague, 1998. 10 pages, 7 figure

On a Linear Program for Minimum-Weight Triangulation

Minimum-weight triangulation (MWT) is NP-hard. It has a polynomial-time constant-factor approximation algorithm, and a variety of effective polynomial- time heuristics that, for many instances, can find the exact MWT. Linear programs (LPs) for MWT are well-studied, but previously no connection was known between any LP and any approximation algorithm or heuristic for MWT. Here we show the first such connections: for an LP formulation due to Dantzig et al. (1985): (i) the integrality gap is bounded by a constant; (ii) given any instance, if the aforementioned heuristics find the MWT, then so does the LP.Comment: To appear in SICOMP. Extended abstract appeared in SODA 201

Underuse of Surveillance Colonoscopy in Patients at Increased Risk of Colorectal Cancer

Colorectal cancer incidence and mortality have declined over the past two decades, and much of this improvement is attributed to increased use of screening. Approximately 25% of patients who undergo screening colonoscopy have premalignant adenomas that require removal and follow-up colonoscopy. However, there are few studies of the use of surveillance colonoscopy in increased risk patients with previous adenomas

Medical providers and harm reduction views on pre-exposure prophylaxis for hiv prevention among people who inject drugs

Despite high pre-exposure prophylaxis (PrEP) acceptability among people who inject drugs (PWID) and PrEP providers, PrEP uptake is low and little is known about how to promote PrEP among PWID. This qualitative study with providers in North Carolina explored views on PrEP delivery approaches for PWID. Interviewers conducted semistructured interviews with 10 PrEP providers and 10 harm reduction (HR) providers. Interviews were transcribed and analyzed. Many participants expressed acceptability for providing PrEP referrals at syringe exchange sites, stationing PrEP providers at syringe exchange sites to provide PrEP prescriptions, and providing standing orders for PrEP at syringe exchange sites. Barriers were identified, including low PrEP awareness and limited resources. Many advocated for co-location of HR and PrEP services and scaled-up outreach services. PrEP providers emphasized maintenance of clinical requirements, while HR providers emphasized flexibility when treating PWID. Promoting PrEP uptake and adherence among PWID likely requires integration of HR and PrEP services

“You're in a World of Chaos”: Experiences Accessing HIV Care and Adhering to Medications After Incarceration

Most HIV-infected inmates leave prison with a suppressed viral load; many, however, become disconnected from care and non-adherent to medications during reentry to community life. In this secondary data analysis of focus groups (N = 6) and in-depth interviews (N = 9) with 46 formerly incarcerated HIV-infected people during reentry, we used an inductive analytic approach to explore the interplay between individual, interpersonal, community, and structural factors and HIV management. Participants described barriers and facilitators to care engagement and adherence at each of these 4 levels, as well as a milieu of HIV and incarceration-related stigma and discrimination. The constellation of barriers and facilitators created competing demands and a sense of chaos in participants’ lives, which led them to address reentry-related basic needs (e.g., housing, food) before health care needs. Interventions that simultaneously address multiple levels, including augmenting employment and housing opportunities, enhancing social support, and reducing stigma, are needed

Quantum Conductance in Semimetallic Bismuth Nanocontacts

Electronic transport properties of bismuth nanocontacts are analyzed by means of a low temperature scanning tunneling microscope. The subquantum steps observed in the conductance versus elongation curves give evidence of atomic rearrangements in the contact. The underlying quantum nature of the conductance reveals itself through peaks in the conductance histograms. The shape of the conductance curves at 77 K is well described by a simple gliding mechanism for the contact evolution during elongation. The strikingly different behaviour at 4 K suggests a charge carrier transition from light to heavy ones as the contact cross section becomes sufficiently small.Comment: 5 pages including 4 figures. Accepted for publication in Phys. Rev. Let

Feasibility Analysis of an Evidence-Based Positive Prevention Intervention for Youth Living With HIV/AIDS in Kinshasa, Democratic Republic of the Congo

We evaluated the feasibility of a Positive Prevention intervention adapted for youth living with HIV/AIDS (YLWH) ages 15–24 in Kinshasa, Democratic Republic of the Congo. We conducted in-depth interviews and focus group discussions with intervention facilitators and YLWH participants on the following four areas of a feasibility framework: acceptability, implementation, adaptation, and limited-efficacy. The adapted intervention was suitable, satisfying, and attractive to program facilitators and participants and able to be implemented effectively. It performed well with a new population and showed preliminary efficacy. However, we identified certain aspects of the intervention that must be addressed prior to wider implementation such as: (1) including more content on navigating marriage while living with HIV and disclosure; (2) adjusting intervention timing and session length; and (3) simplifying the more complicated content. An adapted evidence-based intervention was found to be feasible and lessons learned can be applied to YLWH in other low-resource settings

Randomized Controlled Pilot Study of Antiretrovirals and a Behavioral Intervention for Persons with Acute HIV Infection: Opportunity for Interrupting Transmission

Background. Persons with acute HIV infection (AHI) have heightened transmission risk. We evaluated potential transmission reduction using behavioral and biomedical interventions in a randomized controlled pilot study in Malawi. Methods. Persons were randomized 1:2:2 to standard counseling (SC), 5-session behavioral intervention (BI), or behavioral intervention plus 12 weeks of antiretrovirals (ARVs; BIA). All were followed for 26-52 weeks and, regardless of arm, referred for treatment according to Malawi-ARV guidelines. Participants were asked to refer partners for testing. Results. Among 46 persons (9 SC, 18 BI, 19 BIA), the average age was 28; 61% were male. The median viral load (VL) was 5.9 log copies/mL at enrollment. 67% (10/15) of BIA participants were suppressed (<1000 copies/mL) at week 12 vs 25% BI and 50% SC (P = .07). Although the mean number of reported condomless sexual acts in the past week decreased from baseline across all arms (1.5 vs 0.3 acts), 36% experienced incident sexually transmitted infection by 52 weeks (12% SC, 28% BI, 18% BIA). Forty-one percent (19/46) of participants referred partners (44% SC, 44% BI, 37% BIA); 15 of the partners were HIV-infected. Conclusions. Diagnosis of AHI facilitates behavioral and biomedical risk reduction strategies during a high-transmission period that begins years before people are typically identified and started on ARVs. Sexually transmitted infection incidence in this cohort suggests ongoing risk behaviors, reinforcing the importance of early intervention with ARVs to reduce transmission. Early diagnosis coupled with standard AHI counseling and early ARV referral quickly suppresses viremia, may effectively change behavior, and could have tremendous public health benefit in reducing onward transmission