Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis

Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis. Most forms of glomerulonephritis have a significant interstitial leukocytic infiltrate which is associated with disease progression. However, there is little data concerning the timing, initial location, and development of this interstitial component. Therefore, we have addressed these issues in a study of passive accelerated anti-GBM glomerulonephritis in the rat. In this model, interstitial leukocytic infiltration was an early event in the disease process with a significant infiltrate apparent at 12 hours after administration of nephrotoxic serum (NTS). This initial infiltrate was restricted to a perivascular sheath surrounding the hilar arterioles. The sheath infiltrate then spread to include the whole hilar area by day 1, the entire periglomerular area by day 3, and became widespread throughout the cortical tubulointerstitium by day 7. The early sheath infiltrate was composed of macrophages and T cells. Both cell types continued to increase as the infiltrate expanded, and a significant accumulation of activated cells (IL-2R+) was evident from day 7 onwards. There was a highly significant correlation between interstitial macrophage infiltration and renal function impairment, proteinuria, and histologic damage. Interstitial T cell infiltration correlated with proteinuria and histologic damage, while the appearance of immune-activated mononuclear cells (IL-2R+) exhibited a highly significant correlation with all disease parameters. This study demonstrates the importance of the glomerular hilar arteriolar region as a focus for mononuclear leucocytic migration and accumulation which not only affects the structure and function of the glomerulus but subsequently the entire tubulointerstitium

Plasma cholesterol esterase level is a determinant for an atherogenic lipoprotein profile in normolipidemic human subjects

AbstractPlasma cholesterol level is controlled by various factors. In the present study, high plasma activity of cholesterol esterase was found to correlate with plasma total cholesterol and low density lipoprotein (LDL) cholesterol levels in normolipidemic human subjects. However, the cholesterol esterase is not elevated in plasma of patients with familial hypercholesterolemia. These observations suggest that cholesterol esterase level is not determined by plasma cholesterol level, but elevated cholesterol esterase may be causative in increasing plasma cholesterol and LDL. Additional experiments further demonstrated that cholesterol esterase can convert the larger and less-atherogenic LDL to the smaller and more atherogenic LDL subspecies in vitro. These results suggest that plasma cholesterol esterase contributes to the formation and accumulation of atherogenic lipoproteins, and thus is a major risk factor for premature atherosclerosis in normal human subjects

Initial uptake, time to treatment, and real-world effectiveness of all-oral direct-acting antivirals for hepatitis C virus infection in the United States: A retrospective cohort analysis

BACKGROUND: Data on initiation and utilization of direct-acting antiviral therapies for hepatitis C virus infection in the United States are limited. This study evaluated treatment initiation, time to treatment, and real-world effectiveness of direct-acting antiviral therapy in individuals with hepatitis C virus infection treated during the first 2 years of availability of all-oral direct-acting antiviral therapies. METHODS: A retrospective cohort analysis was undertaken using electronic medical records and chart review abstraction of hepatitis C virus-infected individuals aged >18 years diagnosed with chronic hepatitis C virus infection between January 1, 2014, and December 31, 2015 from the Indiana University Health database. RESULTS: Eight hundred thirty people initiated direct-acting antiviral therapy during the 2-year observation window. The estimated incidence of treatment initiation was 8.8%±0.34% at the end of year 1 and 15.0%±0.5% at the end of year 2. Median time to initiating therapy was 300 days. Using a Cox regression analysis, positive predictors of treatment initiation included age (hazard ratio, 1.008), prior hepatitis C virus treatment (1.74), cirrhosis (2.64), and history of liver transplant (1.5). History of drug abuse (0.43), high baseline alanine aminotransferase levels (0.79), hepatitis B virus infection (0.41), and self-pay (0.39) were negatively associated with treatment initiation. In the evaluable population (n = 423), 83.9% (95% confidence interval, 80.1-87.3%) of people achieved sustained virologic response. CONCLUSION: In the early years of the direct-acting antiviral era, <10% of people diagnosed with chronic hepatitis C virus infection received direct-acting antiviral treatment; median time to treatment initiation was 300 days. Future analyses should evaluate time to treatment initiation among those with less advanced fibrosis

The independent association between parathyroid hormone levels and hyperuricemia: a national population study

Introduction: Increased frequencies of hyperuricemia and gout have been associated with primary hyperparathyroidism, and recent clinical trials of parathyroid hormone (PTH) have reported hyperuricemic adverse events. We evaluated the potential population impact of PTH on serum uric acid (SUA) levels by using a nationally representative sample of United States adults. Methods: By using data from 8,316 participants aged 18 years and older in the National Health and Nutrition Examination Survey 2003 to 2006, we examined the relation between serum PTH and SUA levels with weighted linear regression. Additionally, we examined the relation with hyperuricemia by using weighted logistic regression. Results: SUA levels increased with increasing serum PTH concentration. After adjusting for age, sex, dietary factors, glomerular filtration rate (GFR), and other potentially related biomarkers (calcium, phosphorus, alkaline-phosphatase, 25-hydroxyvitamin D), the SUA level differences from the bottom (referent) to top quintiles of serum PTH levels were 0, 8, 13, 14, and 19 μM (95% CI, 12 to 26; P for trend, < 0.001). These estimates were larger among renally impaired individuals (multivariate SUA difference between the extreme quintiles of PTH, 26 versus 15 μM among those with GFR ≥ 60 versus < 60 ml/min per 1.73 m2, respectively) (P for interaction = 0.004). The odds of hyperuricemia by various definitions increased with increasing PTH levels as well (multivariate P values for trend, < 0.05). Conclusions: These nationally representative data indicate that serum PTH levels are independently associated with serum uric acid levels and the frequency of hyperuricemia at the population level

Effect Of Combined Aerobic And Resistance Training On HPA Axis Reactivity In HIV+ Women Undergoing Treatment For Substance Abuse

Substance abuse and infection with human immunodeficiency virus (HIV) are chronic stressors that affect hypothalamic-pituitary-adrenal (HPA) axis function. The purpose of this study was to investigate the effect of combined aerobic and resistance training on HPA axis reactivity in women with HIV undergoing treatment for substance abuse. Sixteen women (mean ± SD; 41 ± 9 years, 164 ± 6 cm, 78.1 ± 17.1 kg, 36 ± 10 % body fat) infected with HIV and enrolled in an intensive 60-day in-patient substance addiction/abuse treatment program were recruited shortly after admission to the treatment facility. Participants were assigned to one of two groups using randomization: (1) supervised combined aerobic and resistance exercise sessions 3 times per week (EX) for six weeks or (2) no exercise training (Control) for six weeks. Before (PRE) and after (POST) the 6-week period participants completed a 10-min public speaking task (Trier Social Stress Test). Saliva samples were obtained before (baseline), immediately after, and every 10 min for 50 min after the task. Saliva samples were analyzed for cortisol. HPA axis reactivity was determined as the difference between the highest values after the test minus the baseline value. HPA axis reactivity did not differ between groups at PRE (EX: 1.9 ± 2.0 nmol•L-1; Control: 1.1 ± 2.7 nmol•L-1) or POST (EX: 1.7 ± 2.1 nmol•L-1; Control: 0.0 ± 1.3 nmol•L-1). Similarly no differences were found between PRE and POST although the reactivity for the Control group appeared to be reduced at POST. HIV+ women in early recovery from substance abuse appear to display blunted HPA axis reactivity. A combined aerobic and resistance training intervention did not affect this reactivity; although, the exercise intervention might have prevented a further decline in reactivity

Shear stress regulation of miR-93 and miR-484 maturation through nucleolin.

Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease

R-PEP-27, a Potent Renin Inhibitor, Decreases Plasma Angiotensin II and Blood Pressure in Normal Volunteers

The hemodynamic and humoral effects of the specific human renin inhibitor R-PEP-27 were studied in six normal human subjects on low and high sodium intake diets. An intravenous infusion of R-PEP-27 (0.5 to 16 μg/min/kg body wt) reduced blood pressure in a dose-dependent fashion; the mean arterial blood pressure at the end of the infusion fell from 128 ± 4/83 ± 4 to 119 ± 3/71 ± 3 mm Hg (mean ± SEM) (P < .01) during the low sodium intake diet. R-PEP-27 had no effect on blood pressure during the high sodium intake diet. R-PEP-27 significantly reduced plasma angiotensin II and aldosterone concentrations. The temporal response to R-PEP-27 suggests that it is a shortlived although highly potent competitive inhibitor of renin; this peptide is a valuable and specific physiologic probe of the renin-angiotensin system. Am J Hypertens 1994;7:295-30

De novo glomerular osteopontin expression in rat crescentic glomerulonephritis

De novo glomerular osteopontin expression in rat crescentic glomerulonephritis. Osteopontin (OPN) is a secreted acidic glycoprotein that has potent monocyte chemoattractant and adhesive properties. Up-regulation of tubular OPN expression is thought to promote interstitial macrophage infiltration in experimental nephritis; however, the role of OPN in glomerular lesions, particularly crescent formation, is unknown. The present study used Northern blotting, in situ hybridization and immunohistochemistry to examine OPN expression in a rat model of accelerated anti-GBM glomerulonephritis. Osteopontin mRNA and protein is expressed by some parietal epithelial cells, thick ascending limbs of Henle and medullary tubules and collecting ducts in normal rat kidney. De novo OPN mRNA and protein expression was evident in glomerular visceral and parietal epithelial cells in anti-GBM glomerulonephritis. Glomerular OPN expression preceded and correlated with macrophage infiltration in the development of hypercellularity, focal and segmental lesions and, notably, crescent formation. There was marked up-regulation of OPN expression by tubular epithelial cells that also preceded and correlated with interstitial macrophage (r = 0.93, P < 0.001) and T-cell infiltration (r = 0.85, P < 0.001). Both glomerular and tubular OPN expression correlated significantly with proteinuria (P < 0.001) and a reduction in creatinine clearance (P < 0.01). In addition, double immunohistochemistry showed co-expression of osteopontin and one of its ligands, CD44, in intrinsic renal cells. CD44 and OPN expression by parietal epithelial cells was evident in crescent formation, while virtually all OPN-positive tubules expressed CD44. Infiltrating macrophages and T-cells were CD44-positive, but only a small proportion of T-cells and few macrophages showed OPN expression. Interestingly, strong OPN mRNA and protein expression was seen in macrophage multinucleated giant cells. In summary, this study suggests that OPN promotes macrophage and T-cell infiltration in the development of renal lesions in rat anti-GBM glomerulonephritis, including glomerular crescent and multinucleated giant cell formation

The Low Redshift Lyman Alpha Forest in Cold Dark Matter Cosmologies

We study the physical origin of the low-redshift Lyman alpha forest in hydrodynamic simulations of four CDM cosmologies. Our main conclusions are insensitive to the cosmological model but depend on our assumption that the UV background declines at low redshift. We find that the expansion of the universe drives rapid evolution of dN/dz (the number of absorbers per unit z) at z > 1.7, but that at lower redshift the fading of the UV background counters the influence of expansion, leading to slow evolution. At every redshift, weaker lines come primarily from moderate fluctuations of the diffuse, unshocked IGM, and stronger lines originate in shocked or radiatively cooled gas of higher overdensity. However, the neutral hydrogen column density associated with structures of fixed overdensity drops as the universe expands, so an absorber at z = 0 is dynamically analogous to an absorber with neutral hydrogen column density 10 to 50 times higher at z = 2-3. We find no clear distinction between lines arising in "galaxy halos" and lines arising in larger scale structures; however, galaxies tend to lie near the dense regions of the IGM that produce strong Lyman alpha lines. The simulations provide a unified physical picture that accounts for the most distinctive observed properties of the low redshift Lyman alpha forest: (1) a sharp transition in the evolution of dN/dz at z ~ 1.7, (2) stronger evolution for absorbers of higher equivalent width, (3) a correlation of increasing Lyman alpha equivalent width with decreasing galaxy impact parameter, and (4) a tendency for stronger lines to arise in close proximity to galaxies while weaker lines trace more diffuse large scale structure. (Abridged)Comment: 57 pages, 18 figures, submitted to Ap