Y1 receptor knockout increases nociception and prevents the anti-allodynic actions of NPY.

OBJECTIVE: Recent pharmacologic studies in our laboratory have suggested that the spinal neuropeptide Y (NPY) Y1 receptor contributes to pain inhibition and to the analgesic effects of NPY. To rule out off-target effects, the present study used Y1-receptor-deficient (-/-) mice to further explore the contribution of Y1 receptors to pain modulation. METHODS AND RESULTS: Y1(-/-) mice exhibited reduced latency in the hotplate test of acute pain and a longer-lasting heat allodynia in the complete Freund's adjuvant (CFA) model of inflammatory pain. Y1 deletion did not change CFA-induced inflammation. Upon targeting the spinal NPY systems with intrathecal drug delivery, NPY reduced tactile and heat allodynia in the CFA model and the partial sciatic nerve ligation model of neuropathic pain. Importantly, we show for the first time that NPY does not exert these anti-allodynic effects in Y1(-/-) mice. Furthermore, in nerve-injured CD1 mice, concomitant injection of the potent Y1 antagonist BIBO3304 prevented the anti-allodynic actions of NPY. Neither NPY nor BIBO3304 altered performance on the Rotorod test, arguing against an indirect effect of motor function. CONCLUSION: The Y1 receptor contributes to pain inhibition and to the analgesic effects of NPY.

Effect on renal function of tenofovir co-administered with either efavirenz or boosted lopinavir or boosted atazanavir: the Swiss HIV Cohort Study

Reduced re'nal function has been reported with tenofovir disoproxil fumarate (TDF). It is not clear whether TDF co-administered with a boosted protease inhibitor (PI) leads to a greater decline in renal function than TDF co-administered with a non-nucleoside reverse transcriptase inhibitor (NNRTI).Methods: We selected ail antiretroviral therapy-naive patients in the Swiss HIV Cohort Study (SHCS) with calibrated or corrected serum creatinine measurements starting antiretroviral therapy with TDF and either efavirenz (EFV) or the ritonavir-boosted PIs, lopinavir (LPV/r) or atazanavir (ATV/r). As a measure of renal function, we used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate the glomerular filtration rate (eGFR). We calculated the difference in eGFR over time between two therapies using a marginal model for repeated measures. In weighted analyses, observations were weighted by the product of their point of treatment and censoring weights to adjust for differences both in the sort of patients starting each therapy and in the sort of patients remaining on each therapy over time.Results: By March 2011, 940 patients with at least one creatinine measurement on a first therapy with either TDF and EFV (n=484), TDF and LPVlr (n=269) or TDF and ATV/r (n=187) had been followed for a median of 1. 7, 1.2 and 1.3 years, respectively. Table 1 shows the difference in average estimated GFR (eGFR) over time since starting cART for two marginal models. The first model was not adjusted for potential confounders; the second mode! used weights to adjust for confounders. The results suggest a greater decline in renal function during the first 6 months if TDF is used with a PI rather than with an NNRTI, but no further difference between these therapies after the first 6 months. TDF and ATV/r may lead to a greater decline in the first 6 months than TDF and LPVlr.Conclusions: TDF co-administered with a boosted PI leads to a greater de cline in renal function over the first 6 months of therapy than TDF co-administered with an NNRTI; this decline may be worse with ATV/r than with LPV/r.

Regional coronary endothelial function is closely related to local early coronary atherosclerosis in patients with mild coronary artery disease: pilot study.

BACKGROUND: Coronary endothelial function is abnormal in patients with established coronary artery disease and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the noninvasive assessment of both anatomic and functional (endothelial function) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endothelial function is related to measures of early atherosclerosis such as increased coronary wall thickness. METHODS AND RESULTS: Seventeen arteries in 14 healthy adults and 17 arteries in 14 patients with nonobstructive coronary artery disease were studied. To measure endothelial function, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor, and changes in coronary cross-sectional area and flow were measured. Black blood imaging was performed to quantify coronary wall thickness and indices of arterial remodeling. The mean stress-induced change in cross-sectional area was significantly higher in healthy adults (13.5%±12.8%, mean±SD, n=17) than in those with mildly diseased arteries (-2.2%±6.8%, P<0.0001, n=17). Mean coronary wall thickness was lower in healthy subjects (0.9±0.2 mm) than in patients with coronary artery disease (1.4±0.3 mm, P<0.0001). In contrast to healthy subjects, stress-induced changes in cross-sectional area, a measure of coronary endothelial function, correlated inversely with coronary wall thickness in patients with coronary artery disease (r=-0.73, P=0.0008). CONCLUSIONS: There is an inverse relationship between coronary endothelial function and local coronary wall thickness in patients with coronary artery disease but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease.