Trauma history and depression predict incomplete adherence to antiretroviral therapies in a low income country.

As antiretroviral therapy (ART) for HIV becomes increasingly available in low and middle income countries (LMICs), understanding reasons for lack of adherence is critical to stemming the tide of infections and improving health. Understanding the effect of psychosocial experiences and mental health symptomatology on ART adherence can help maximize the benefit of expanded ART programs by indicating types of services, which could be offered in combination with HIV care. The Coping with HIV/AIDS in Tanzania (CHAT) study is a longitudinal cohort study in the Kilimanjaro Region that included randomly selected HIV-infected (HIV+) participants from two local hospital-based HIV clinics and four free-standing voluntary HIV counselling and testing sites. Baseline data were collected in 2008 and 2009; this paper used data from 36 month follow-up interviews (N = 468). Regression analyses were used to predict factors associated with incomplete self-reported adherence to ART. INCOMPLETE ART ADHERENCE WAS SIGNIFICANTLY MORE LIKELY TO BE REPORTED AMONGST PARTICIPANTS WHO EXPERIENCED A GREATER NUMBER OF CHILDHOOD TRAUMATIC EVENTS: sexual abuse prior to puberty and the death in childhood of an immediate family member not from suicide or homicide were significantly more likely in the non-adherent group and other negative childhood events trended toward being more likely. Those with incomplete adherence had higher depressive symptom severity and post-traumatic stress disorder (PTSD). In multivariable analyses, childhood trauma, depression, and financial sacrifice remained associated with incomplete adherence.\ud This is the first study to examine the effect of childhood trauma, depression and PTSD on HIV medication adherence in a low income country facing a significant burden of HIV. Allocating spending on HIV/AIDS toward integrating mental health services with HIV care is essential to the creation of systems that enhance medication adherence and maximize the potential of expanded antiretroviral access to improve health and reduce new infections

Effects of Adrenomedullin on Human Myocyte Contractile Function and β-Adrenergic Response

Background: Adrenomedullin has been demonstrated to cause systemic vasodilation, and increased plasma adrenomedullin levels have been observed in cardiovascular disease states such as heart failure. While adrenomedullin receptors have been localized to the myocardium, the effects of adrenomedullin on human myocyte contractility remained unknown. Methods and Results: Left ventricular myocytes were isolated from myocardial biopsies of patients (n = 16) undergoing elective coronary artery bypass surgery with normal left ventricular ejection fractions (51 ± 1%). A total of 233 left ventricular myocytes were studied by videomicroscopy. Myocyte shortening velocity (μm/s) was measured at baseline and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The change in myocyte shortening velocity with increasing concentrations of adrenomedullin was computed. At all concentrations, adrenomedullin reduced myocyte shortening velocity from baseline values (P \u3c 0.05). Next, the potential interaction of adrenomedullin with the β-adrenergic receptor system was examined using 25 nM isoproterenol. The β-adrenergic receptor-mediated increase in the myocyte shortening velocity was blunted with adrenomedullin (29 ± 7 vs 63 ± 13 μm/s, P \u3c 0.05). Conclusions: These unique findings demonstrate that adrenomedullin reduced contractility in isolated human left ventricular myocytes and exhibited a negative interaction with the β-adrenergic receptor system. Past studies have shown that adrenomedullin induces nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism. Thus, while adrenomedullin causes systemic vasodilation, this peptide can also exert a negative contractile effect in human left ventricular myocytes

Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice

Recent studies have been directed at modulating the heart failure process through inhibition of activated matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency alters the course of postinfarction chamber remodeling and induced chronic myocardial infarction (MI) in wild-type (WT) and TIMP-1(-/-) mice. Left ventricular (LV) pressure-volume loops obtained from WT and TIMP-1(-/-) mice demonstrated that LV end-diastolic volume [52 +/- 4 (WT) vs. 71 +/- 6 (TIMP-1(-/-)) microl] and LV end-diastolic pressure [9.0 +/- 1.2 (WT) vs. 12.7 +/- 1.4 (TIMP-1(-/-)) mmHg] were significantly increased in the TIMP-1(-/-) mice 2 wk after MI. LV contractility was reduced to a similar degree in the WT and TIMP-1(-/-) groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-1(-/-) mice, indicating that the hypertrophic response was more pronounced. The observed significant loss of fibrillar collagen in the TIMP-1(-/-) controls may have been an important contributory factor for the observed LV alterations in the TIMP-1(-/-) mice after MI. These findings demonstrate that TIMP-1 deficiency amplifies adverse LV remodeling after MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-

Circulation Activity Metalloproteinase Reperfusion: Relation to Interstitial Membrane Type-1 Matrix Trafficking of the Membrane Type-1 Matrix Metalloproteinase in Ischemia and Trafficking of the Membrane Type-1 Matrix Metalloproteinase in Ischemia and Rep

Background-The matrix metalloproteinases (MMPs) contribute to regional remodeling after prolonged periods of ischemia and reperfusion (I/R), but specific MMP types activated during this process remain poorly understood. A novel class, the membrane-type MMPs (MT-MMPs), has been identified in the myocardium, but activity of these MMP types has not been assessed in vivo, particularly during I/R. Methods and Results-Pigs (30 kg, nϭ8) were instrumented with microdialysis catheters to measure MT1-MMP activity in both ischemic and nonischemic (remote) myocardium. A validated MT1-MMP fluorogenic substrate was infused through the microdialysis system, and changes in fluorescence were reflective of MT1-MMP activity at steady state, during ischemia (90 minutes), and during reperfusion (120 minutes). At peak ischemia, MT1-MMP activity was increased by Ͼ40% in the ischemic region, with no change in the remote region, which persisted with reperfusion (PϽ0.05). After I/R, MT1-MMP abundance was increased by Ͼ50% (PϽ0.05). Differential centrifugation revealed that the endosomal fraction (which contains subcellular organelles) within the ischemic myocardium was associated with a Ͼ135% increase in MT1-MMP (PϽ0.05). Furthermore, in an isolated left ventricular myocyte model of I/R, hypoxia (simulated ischemia) induced a Ͼ70% increase in MT1-MMP abundance in myocytes, and confocal microscopy revealed MT1-MMP internalization during this time period and reemergence to the membrane with reperfusion. Conclusions-These unique results demonstrate that a specific MMP type, MT1-MMP, is increased in abundance and activity with I/R and is likely attributed, at least in part, to changes in intracellular trafficking