Influence of low and high pressure baroreceptors on plasma renin activity in humans

The effects of low and high pressure baroreceptors on plasma renin activity (immunoassay) were evaluated using graded lower body suction (LBS) in six healthy men. LBS at -10 and -20 mmHg for 10 min decreased central venous pressure without changing arterial pressure and thereby presumably reduced low but not high pressure baroreceptor inhibition of renin release. LBS at these levels produced forearm vasoconstriction, but did not increase renin. LBS at -40 mmHG decreased central venous and arterial pulse pressure and thus reduced both low and high pressure baroreceptor inhibition. LBS at this level produced forearm vasoconstriction and tachycardia and increased renin. In summary, reduction in low pressure baroreceptor inhibition in humans did not increase renin in the presence of physiological tonic inhibition from high pressure baroreceptors. Increases in renin did not occur until there was combined reduction of high and low pressure baroreceptor inhibition on plasma renin activity

Endothelin stimulates PDGF secretion in cultured human mesangial cells

Endothelin stimulates PDGF secretion in cultured human mesangial cells. Endothelin, a 17-DKa peptide originally described as a potent vasoconstrictor, also stimulates the release of important regulators of glomerular hemodynamics such as atrial natriuretic factor and renin. In the present study we investigated the role of endothelin in the release of another potent vasoconstrictor and mitogen of human mesangial cells, the platelet-derived growth factor. Endothelin stimulated PDGF release at 12 hours and the effect was sustained for 36 hours. This effect was associated with the enhanced induction of mRNAs encoding PDGF A-and B-chain. Endothelin also induced mitogenesis in human mesangial cells which was accompanied by activation of phospholipase C with increased inositol phosphate turnover. These data suggest a mechanism by which endothelin may regulate mesangial cell function in disease states

A high-wavenumber boundary-element method for an acoustic scattering problem

In this paper we show stability and convergence for a novel Galerkin boundary element method approach to the impedance boundary value problem for the Helmholtz equation in a half-plane with piecewise constant boundary data. This problem models, for example, outdoor sound propagation over inhomogeneous flat terrain. To achieve a good approximation with a relatively low number of degrees of freedom we employ a graded mesh with smaller elements adjacent to discontinuities in impedance, and a special set of basis functions for the Galerkin method so that, on each element, the approximation space consists of polynomials (of degree $\nu$) multiplied by traces of plane waves on the boundary. In the case where the impedance is constant outside an interval $[a,b]$, which only requires the discretization of $[a,b]$, we show theoretically and experimentally that the $L_2$ error in computing the acoustic field on $[a,b]$ is ${\cal O}(\log^{\nu+3/2}|k(b-a)| M^{-(\nu+1)})$, where $M$ is the number of degrees of freedom and $k$ is the wavenumber. This indicates that the proposed method is especially commendable for large intervals or a high wavenumber. In a final section we sketch how the same methodology extends to more general scattering problems

Accuracy of Emergency Medical Services Dispatcher and Crew Diagnosis of Stroke in Clinical Practice.

BACKGROUND: Accurate recognition of stroke symptoms by Emergency Medical Services (EMS) is necessary for timely care of acute stroke patients. We assessed the accuracy of stroke diagnosis by EMS in clinical practice in a major US city. METHODS AND RESULTS: Philadelphia Fire Department data were merged with data from a single comprehensive stroke center to identify patients diagnosed with stroke or TIA from 9/2009 to 10/2012. Sensitivity and positive predictive value (PPV) were calculated. Multivariable logistic regression identified variables associated with correct EMS diagnosis. There were 709 total cases, with 400 having a discharge diagnosis of stroke or TIA. EMS crew sensitivity was 57.5% and PPV was 69.1%. EMS crew identified 80.2% of strokes with National Institutes of Health Stroke Scale (NIHSS) ≥5 and symptom durationmodel, correct EMS crew diagnosis was positively associated with NIHSS (NIHSS 5-9, OR 2.62, 95% CI 1.41-4.89; NIHSS ≥10, OR 4.56, 95% CI 2.29-9.09) and weakness (OR 2.28, 95% CI 1.35-3.85), and negatively associated with symptom duration \u3e270 min (OR 0.41, 95% CI 0.25-0.68). EMS dispatchers identified 90 stroke cases that the EMS crew missed. EMS dispatcher or crew identified stroke with sensitivity of 80% and PPV of 50.9%, and EMS dispatcher or crew identified 90.5% of patients with NIHSS ≥5 and symptom duration \u3c6 \u3eh. CONCLUSION: Prehospital diagnosis of stroke has limited sensitivity, resulting in a high proportion of missed stroke cases. Dispatchers identified many strokes that EMS crews did not. Incorporating EMS dispatcher impression into regional protocols may maximize the effectiveness of hospital destination selection and pre-notification

Angiotensin II and growth factors in the pathogenesis of diabetic nephropathy

Angiotensin II and growth factors in the pathogenesis of diabetic nephropathy. The renin-angiotensin system (RAS) and growth factors mediate structural and functional changes during the course of diabetic nephropathy (DN). Studies in humans and experimental models with DN suggest their involvement in the development and progression of DN. Activation of renal tissue RAS and increased expression of growth factors have been demonstrated at early stages of the disease. Angiotensin II and growth factors alter renal hemodynamics and exert trophic changes in renal cells that eventually result in fibrosis through direct mechanisms or through the release of other mediators. Their effects are likely modulated by metabolic changes including high glucose and free fatty acids. While blockade of the RAS ameliorates DN in humans, such evidence for blockade of growth factors is still lacking. It is likely that susceptibility to the development of DN and therapeutic efficacy are modulated by genetic polymorphisms in components of the RAS and growth factors including their receptors and other target molecules. Approaches to understand the intricate relationship between these systems and the mechanism(s) by which they alter capillary permeability and result in structural changes are areas of fruitful investigation

Shiga toxin 1 elicits diverse biologic responses in mesangial cells

Shiga toxin 1 elicits diverse biologic responses in mesangial cells.BackgroundShiga toxin 1 (Stx1) is a causative agent in hemolytic uremic syndrome (HUS). Its receptor, the glycosphingolipid globotriaosylceramide (Gb3), is expressed on cultured human endothelial and mesangial cells. Mesangial cell injury in HUS ranges from mild cellular edema to severe mesangiolysis and eventual glomerulosclerosis. We hypothesized that, in addition to endothelial cells, mesangial cells are targets of Stx1.MethodsHuman mesangial cells were exposed to Stx1. Protein synthesis was measured using [35S]-methionine/cysteine. Cell viability was measured as the lysosomal uptake of Neutral Red. Monocyte chemotactic peptide (MCP-1) mRNA and protein were analyzed by Northern blotting and ELISA.ResultsStx1 (0.25 to 2500ng/ml) resulted in a dose-dependent inhibition of protein synthesis. This effect of Stx1 was potentiated by preincubation of the cells with interleukin-1α (IL-1α; 2ng/ml) or tumor necrosis-α (TNF-α; 500 U/ml). Stx1 had little effect on mesangial cell viability during the first 24hours of exposure to Stx1. However, prolonged incubation with Stx1 for 48 and 72hours resulted in a 68% and 80% decrease in cell-viability, respectively. Stx1 elicited a dose and time dependent increase in the levels of MCP-1 mRNA, an effect that was potentiated by preincubation with IL-1α.ConclusionThese data indicate that mesangial cells are susceptible to the effects of Stx1 in vitro. Stx1 exerts a spectrum of biologic effects on mesangial cells ranging from activation of chemokine genes to a lethal toxic injury. Immunoinflammatory cytokines potentiate the effects of Stx1. Thus, glomerular pathology in HUS may also result from a direct effect of Stx1 on mesangial cells

Tuberin haploinsufficiency is associated with the loss of OGG1 in rat kidney tumors

<p>Abstract</p> <p>Background</p> <p>Tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, <it>TSC-1 </it>or <it>TSC-2</it>. <it>TSC-2 </it>gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors. Loss of heterozygosity (LOH) at the <it>TSC2 </it>locus has been detected in <it>TSC</it>-associated renal cell carcinoma (RCC) and in RCC in the Eker rat. Tuberin downregulates the DNA repair enzyme 8-oxoguanine DNA-glycosylase (OGG1) with important functional consequences, compromising the ability of cells to repair damaged DNA resulting in the accumulation of the mutagenic oxidized DNA, 8-oxo-dG. Loss of function mutations of OGG1 also occurs in human kidney clear cell carcinoma and may contribute to tumorgenesis. We investigated the distribution of protein expression and the activity of OGG1 and 8-oxo-dG and correlated it with the expression of tuberin in kidneys of wild type and Eker rats and tumor from Eker rat.</p> <p>Results</p> <p>Tuberin expression, OGG1 protein expression and activity were higher in kidney cortex than in medulla or papilla in both wild type and Eker rats. On the other hand, 8-oxo-dG levels were highest in the medulla, which expressed the lowest levels of OGG1. The basal levels of 8-oxo-dG were also higher in both cortex and medulla of Eker rats compared to wild type rats.</p> <p>In kidney tumors from Eker rats, the loss of the second <it>TSC2 </it>allele is associated with loss of OGG1 expression. Immunostaining of kidney tissue shows localization of tuberin and OGG1 mainly in the cortex.</p> <p>Conclusion</p> <p>These results demonstrate that OGG1 localizes with tuberin preferentially in kidney cortex. Loss of tuberin is accompanied by the loss of OGG1 contributing to tumorgenesis. In addition, the predominant expression of OGG1 in the cortex and its decreased expression and activity in the Eker rat may account for the predominant cortical localization of renal cell carcinoma.</p

A Survey of Expert Opinion Regarding Rotator Cuff Repair.

Many patients with rotator cuff tears have questions for their surgeons regarding the surgical procedure, perioperative management, restrictions, therapy, and ability to work after a rotator cuff repair. The purpose of our study was to determine common clinical practices among experts regarding rotator cuff repair and to assist them in counseling patients. We surveyed 372 members of the American Shoulder and Elbow Surgeons (ASES) and the Association of Clinical Elbow and Shoulder Surgeons (ACESS); 111 members (29.8%) completed all or part of the survey, and 92.8% of the respondents answered every question. A consensus response (\u3e50% agreement) was achieved on 49% (24 of 49) of the questions. Variability in responses likely reflects the fact that clinical practices have evolved over time based on clinical experience

Computational evidence for an early, amplified systemic inflammation program in polytrauma patients with severe extremity injuries

Extremity and soft tissue injuries contribute significantly to inflammation and adverse in-hospital outcomes for trauma survivors; accordingly, we examined the complex association between clinical outcomes inflammatory responses in this setting using in silico tools. Two stringently propensity-matched, moderately/severely injured (Injury Severity Score > 16) patient sub-cohorts of ~30 patients each were derived retrospectively from a cohort of 472 blunt trauma survivors and segregated based on their degree of extremity injury severity (above or below 3 on the Abbreviated Injury Scale). Serial blood samples were analyzed for 31 plasma inflammatory mediators. In addition to standard statistical analyses, Dynamic Network Analysis (DyNA) and Principal Component Analysis (PCA) were used to model systemic inflammation following trauma. Patients in the severe extremity injury sub-cohort experienced longer intensive care unit length of stay (LOS), total LOS, and days on a mechanical ventilator, with higher Marshall Multiple Organ Dysfunction (MOD) Scores over the first 7 days post-injury as compared to the mild/moderate extremity injury sub-cohort. The higher severity cohort had statistically significant elevated lactate, base deficit, and creatine phosphokinase on first blood draw, along with significant changes in multiple circulating inflammatory mediators. DyNA pointed to a sustained role for type 17 immunity in both sub-cohorts, along with IFN-γ in the severe extremity injury group. DyNA network complexity increased over 7 days post-injury in the severe injury group, while generally decreasing over this same time period in the mild/moderate injury group. PCA suggested a more robust activation of multiple pathways in the severe extremity injury group as compared to the mild/moderate injury group. These studies thus point to the possibility of self-sustaining inflammation following severe extremity injury vs. resolving inflammation following less severe extremity injury