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

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

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

Measurement of associated Z plus charm production in proton-proton collisions at root s=8TeV

A study of the associated production of a Z boson and a charm quark jet (Z + c), and a comparison to production with a b quark jet (Z + b), in pp collisions at a centre-of-mass energy of 8 TeV are presented. The analysis uses a data sample corresponding to an integrated luminosity of 19.7 fb(-1), collected with the CMS detector at the CERN LHC. The Z boson candidates are identified through their decays into pairs of electrons or muons. Jets originating from heavy flavour quarks are identified using semileptonic decays of c or b flavoured hadrons and hadronic decays of charm hadrons. The measurements are performed in the kinematic region with two leptons with pT(l) > 20 GeV, vertical bar eta(l)vertical bar 25 GeV and vertical bar eta(jet)vertical bar Z + c + X) B(Z -> l(+)l(-)) = 8.8 +/- 0.5 (stat)+/- 0.6 (syst) pb. The ratio of the Z+c and Z+b production cross sections is measured to be sigma(pp -> Z+c+X)/sigma (pp -> Z+b+X) = 2.0 +/- 0.2 (stat)+/- 0.2 (syst). The Z+c production cross section and the cross section ratio are also measured as a function of the transverse momentum of theZ boson and of the heavy flavour jet. The measurements are compared with theoretical predictions.Peer reviewe

Measurement of differential cross sections in the kinematic angular variable phi* for inclusive Z boson production in pp collisions at root s=8 TeV

Measurements of differential cross sections d sigma/d phi* and double-differential cross sections d(2)sigma/ld phi*d/y/ for inclusive Z boson production are presented using the dielectron and dimuon final states. The kinematic observable phi* correlates with the dilepton transverse momentum but has better resolution, and y is the dilepton rapidity. The analysis is based on data collected with the CMS experiment at a centre-of-mass energy of 8 TeV corresponding to an integrated luminosity of 19.7 fb(-1). The normalised cross section (1/sigma) d sigma/d phi*, within the fiducial kinematic region, is measured with a precision of better than 0.5% for phi* <1. The measurements are compared to theoretical predictions and they agree, typically, within few percent.Peer reviewe

Search for a singly produced third-generation scalar leptoquark decaying to a tau lepton and a bottom quark in proton-proton collisions at root s=13 TeV

A search is presented for a singly produced third-generation scalar leptoquark decaying to a tau lepton and a bottom quark. Associated production of a leptoquark and a tau lepton is considered, leading to a final state with a bottom quark and two tau leptons. The search uses proton-proton collision data at a center-of-mass energy of 13 TeV recorded with the CMS detector, corresponding to an integrated luminosity of 35.9 fb(-1). Upper limits are set at 95% confidence level on the production cross section of the third-generation scalar leptoquarks as a function of their mass. From a comparison of the results with the theoretical predictions, a third-generation scalar leptoquark decaying to a tau lepton and a bottom quark, assuming unit Yukawa coupling (lambda), is excluded for masses below 740 GeV. Limits are also set on lambda of the hypothesized leptoquark as a function of its mass. Above lambda = 1.4, this result provides the best upper limit on the mass of a third-generation scalar leptoquark decaying to a tau lepton and a bottom quark.Peer reviewe