C5b-9 increases albumin permeability of isolated glomeruli in vitro

C5b-9 increases albumin permeability of isolated glomeruli in vitro. Deposition of antibody and activation of the complement cascade are important in both naturally occurring glomerulonephritis and in experimental models including passive Heymann nephritis. We studied the effect of antibody and complement on albumin permeability of isolated glomeruli to determine the role of the terminal complement components (C5-C9) in mediating the proteinuria in nephritis. Isolated glomeruli were treated with anti-Fx1a (Heymann antibody) and then incubated them with pooled human serum, serum in which complement had been inactivated by heat, or serum deficient in C6 or C7. The albumin reflection coefficient (σalbumin) was calculated from the volumetric response of glomeruli to transcapillary oncotic gradients produced by albumin or high molecular weight neutral dextran (252 kD). Convectional permeability to albumin (Palbumin) was calculated as 1-σalbumin. Albumin permeability of control glomeruli was not different from 0. Albumin permeability was not altered by antibody alone but was increased to 0.65 ± 0.04 when antibody treated glomeruli were incubated for 10 minutes with pooled serum as a source of complement. Heat treatment of serum to inactivate complement prevented the increase in permeability. Incubation for 10 minutes with serum without antibody pretreatment caused a lesser increase in permeability of isolated glomeruli (0.18 ± 0.06). Serum deficient in either C6 or C7 did not cause an increase in albumin permeability of antibody pre-treated glomeruli, but incubation with a combination of these sera (now containing the complete cascade) increased permeability to the same extent as did pooled normal serum (0.58 ± 0.04). We conclude that activation of the terminal complement components is required for the increase in glomerular macromolecular permeability caused by anti-Fx1a and that terminal complement activation is sufficient to alter the permeability independent of complement hemodynamic events or contribution by circulating cells

Ultrafiltration coefficient and glomerular capillary resistance in a model of immune complex glomerulonephritis

Ultrafiltration coefficient and glomerular capillary resistance in a model of immune complex glomerulonephritis. Decreased ultrafiltration coefficient, LpA or Kf, was documented previously in micropuncture studies of glomerulonephritis in rats. Observations were made immediately following an injection of antiglomerular basement membrane (anti-GBM) antibody, later in the course of glomerulonephritis, and during the chronic phase of Heymann nephritis. To gain further insight into the basis of reduced glomerular filtration rate in immune-complex glomerulonephritis, we studied the anatomic, physiologic, and rheologic properties of isolated glomeruli from female Buffalo rats with nephritis which developed during infection withTrypanosoma rhodesiense. Immune-complex mediated glomerulonephritis was present 2 weeks after inoculation and progressed throughout the 4 weeks of study. Renal insufficiency occurred, with serum creatinine concentrations rising to 5 to 10 times control values by week 4. Mesangial hypercellularity, mesangial electron dense deposits, and endothelial cell swelling were observed. Increased numbers of mononuclear cells were present within the glomerulus. Total glomerular water volume was greater in nephritic than in normal animals. Increased cell volume accounted for most of the volume increment. When filtration into the capillaries was induced in vitro by imposing an oncotic gradient of 6.5mm Hg or greater across the capillary wall, rapid and uniform erythrocyte movement occurred within the capillaries of control glomeruli and erythrocytes were ejected into the medium. In contrast, a transcapillary gradient of 30 to 40mm Hg was required to produce erythrocyte movement in glomeruli from nephritic animals studied 4 weeks after inoculation. The ultrafiltration coefficient of nephritic glomeruli was estimated in vitro and was not different from that of control glomeruli (5.81 ± 0.35 vs. 6.21 ± 0.49 nl/minmm Hg). An impairment of capillary perfusion may be responsible for the decreased rate of glomerular filtration observed in this model of glomerulonephritis.Evaluation in vitro du coefficient d'ultrafiltration et de la résistance capillaire glomérulaire dans un modèle de glomérulonéphrite des comples immuns. La diminution du coefficient d'ultrafiltration, LpA ou Kf, a été établie précédement au cours de travaux utilisant les microponctions chez des rats atteints de glomérulonéphrite, immédiatement après l'injection d'anti-corps anti-membrane basale glomérulaire (anti-GBM) et, ultérieurement, au cours de l'évolution de glomérulonéphrite et durant la phase chronique de la néphrite de Heymann. Afin d'obtenir plus d'informations sur les fondements de la diminution du débit de filtration glomérulaire au cours de la néphrite des complexes immuns, nous avons étudié les propriétés anatomiques, physiologiques, et biologiques des glomérules isolés de rats femelles de la souche Buffalo atteints de néphrite développée au cours de l'infection parTrypanosoma rhodesiense. Une glomérulonéphrite des complexes immuns existait deux semaines après l'inoculation et évoluait pendant les 4 semaines de l'étude. Il existait une insuffisance rénale et la créatinine sérique atteignait des valeurs 5 à 10 fois plus grandes que les contrôles à la 4 semaine. L'hypercellularité mésangiale, sous la forme de dépôts denses mésangiaux en microscopie électronique, et le gonflement des cellules endothéliales ont été observés. Le nombre des cellules mononucléés du glomérule était augmenté. Le volume total d'eau du glomérule était plus grand chez les animaux atteints de néphrite que chez les contrôles. L'augmentation du volume cellulaire rendait compte de la plus grande partie de l'augmentation de volume. Quand la filtration dans les capillaires a été declenchée par l'imposition d'un gradient oncotique de 6,5mm Hg ou plus à travers la paroi capillaire, un mouvement rapide et uniforme des érythrocytes est apparu et les érythrocytes ont été éjectés dans le milieu. Par contre, pour les glomérules provenant d'animaux néphritiques, étudiés quatre semaines après l'inoculation, un gradient de 30 à 40mm Hg était nécessaire pour produire un mouvement des érythrocytes. Le coefficient d'ultrafiltration des glomérules d'animaux néphritiques a été évalué in vitro et n'est pas différent de celui des animaux contrôles (5,81 ± 0,35 vs. 6,21 ± 0,49 nl/minmm Hg). L'altération de la perfusion capillaire est responsable de la diminution du débit de filtration glomérulaire observée dans ce modèle de glomérulonéphrite

Perspectives on Astrophysics Based on Atomic, Molecular, and Optical (AMO) Techniques

About two generations ago, a large part of AMO science was dominated by experimental high energy collision studies and perturbative theoretical methods. Since then, AMO science has undergone a transition and is now dominated by quantum, ultracold, and ultrafast studies. But in the process, the field has passed over the complexity that lies between these two extremes. Most of the Universe resides in this intermediate region. We put forward that the next frontier for AMO science is to explore the AMO complexity that describes most of the Cosmos.Comment: White paper submission to the Decadal Assessment and Outlook Report on Atomic, Molecular, and Optical (AMO) Science (AMO 2020

Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design

Abstract Background The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. Methods/Design The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. Discussion This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases Trial Registration ClinicalTrials.gov, NCT0081425

Follow-up of phase I trial of adalimumab and rosiglitazone in FSGS: III. Report of the FONT study group

Abstract Background Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Methods 21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m2 -- received adalimumab (n = 10), 24 mg/m2 every 14 days or rosiglitazone (n = 11), 3 mg/m2 per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. Results 19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). Conclusion Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments

Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group

Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end stage kidney disease. Antifibrotic agents, such as tumor necrosis factor α (TNF-α) antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis