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Critically ill patients undergoing continuous renal replacement therapy (CRRT) have medical conditions requiring extensive pharmacotherapy. Continuous renal replacement therapy impacts drug disposition. Few data exist regarding drug dosing requirements with contemporary CRRT modalities and effluent rates. The practical limitations of pharmacokinetic studies requiring numerous plasma and effluent samples, and lack of generalizability of observations from specific CRRT prescriptions, highlight gaps in bedside assessment of CRRT drug elimination and individualized dosing needs. We employed a porcine model using transdermal fluorescence detection of the glomerular filtration rate fluorescent tracer agent MB-102, with the aim to assess the relationship between systemic exposure of MB-102 and meropenem during CRRT. Animals underwent bilateral nephrectomies and received intravenous bolus doses of MB-102 and meropenem. Once MB-102 equilibrated in the animal, CRRT was initiated. Continuous renal replacement therapy prescriptions comprised four combinations of blood pump (low versushigh) and effluent (low versushigh) flow rates. Changes in transdermal detected MB-102 clearance occurred immediately with a change in CRRT rates. Blood side meropenem clearance mirrored transdermal MB-102 clearance (r2: 0.95–0.97, pvalue all <0.001). We suggest transdermal MB-102 clearance provides real-time personalized assessment of drug elimination and could optimize prescription of drugs for critically ill patients requiring CRRT.

Transfer of B6 T cells to major histocompatibility complex (MHC) class I disparate bm1 × B6 F1 mice leads to the development of hepatic graft‐versus‐host disease (GVHD) characterized by an active hepatitis with portal and lobular inflammation as well as bile duct inflammation and venulitis. The present studies determined the role of tumor necrosis factor (TNF) in hepatic GVHD. B6 responder cells were cultured with irradiated MHC class I disparate bm1 or syngeneic spleen cells (SpC) in the presence or absence of TNF receptor inhibitor [TNFR‐immunoglobulin (Ig)]. Recipient bm1 × B6 F1 mice were irradiated (600 cGy) and reconstituted with 5 × 106T cell‐depleted B6 bone marrow cells and 1 × 107B6 SpC. Mice were injected with an adenovirus encoding TNFR‐Ig [TNF inhibitor‐encoding adenovirus (Adv‐TNFi)] or β‐galactosidase (Adv‐βgal). Severity of liver GVHD was assessed by a composite histopathological score consisting of the sum of scores for venulitis, lobular hepatitis, and bile duct inflammation. Addition of TNFR‐Ig reduced cell proliferation in mixed lymphocyte cultures using B6 responder SpC by 71% ± 12.8% and interferon‐γ responses by 78% ± 18%. GVHD‐induced “wasting disease” was reduced in Adv‐TNFi recipients [4.4%±5.2% weight loss (n=11)] compared with Adv‐βgal recipients [16.1%±7.6% weight loss (n=11; P=0.0004)] 9 days post‐transplant. Composite histopathological scores and individual venulitis scores were reduced with the addition of Adv‐TNFi. Hepatic CD8+ T cells in the recipients of Adv‐TNFi were reduced as compared with recipients of Adv‐βgal. In conclusion, Adv‐TNFi reduces MHC class I disparate alloproliferative responses and hepatic GVHD.

An unusual but well-documented presentation of minimal change disease is nephrotic proteinuria and acute renal failure. One pathophysiological mechanism proposed to explain this syndrome is nephrosarca, or severe oedema of the kidney. We describe a patient with minimal change disease who presented with heavy proteinuria and acute renal failure but had no evidence of renal interstitial oedema on biopsy. Aggressive fluid removal did not reverse the acute renal failure. Renal function slowly returned concomitant with resolution of the nephrotic syndrome following corticosteroid therapy. The time profile of the clinical events is not compatible with the nephrosarca hypothesis and suggests an alternative pathophysiological model for the diminished glomerular filtration rate seen in some cases of minimal change disease.

Collapsing glomerulopathy is a pathologic diagnosis characterized by obliteration of glomerular capillary lumina, seen most commonly as a primary glomerular disease in young black men. A secondary form with almost identical pathologic features is described in association with human immunodeficiency virus infection. The disease is characterized by heavy proteinuria with variable renal insufficiency at the onset followed by rapid progression to end-stage renal disease with no documented effective therapy. We describe a patient who presented with systemic manifestations, including fever, acute renal failure with massive proteinuria, and noncardiogenic pulmonary edema. Renal biopsy showed classic collapsing glomerulopathy. All known causes of noncardiogenic pulmonary edema were ruled out. The pulmonary syndrome resolved, but the renal disease progressed to end-stage renal disease. We propose consideration of collapsing glomerulopathy in the differential diagnosis of any patient presenting with a multisystem disease including acute renal failure and pulmonary edema. © 2002 by the National Kidney Foundation, Inc.

The induction of cyclooxygenase is an important event in the pathophysiology of acute lung injury. The purpose of this study was to examine the synergistic effects of various cyclooxygenase products (PGE2, PGI2, PGF2α) on thromboxane A2(TxA2)-mediated pulmonary microvascular dysfunction. The lungs of Sprague-Dawley rats were perfused ex vivo with Krebs-Henseleit buffer containing indomethacin and PGE2(5 × 10−8to 1 × 10−7M), PGF2α(7 × 10−9to 5 × 10−6M), or PGI2(5 × 10−8to 2 × 10−5M). The TxA2-receptor agonist U-46619 (7 × 10−8M) was then added to the perfusate, and then the capillary filtration coefficient (Kf), pulmonary arterial pressure (Ppa), and total pulmonary vascular resistance (Rt) were determined. The Kfof lungs perfused with U-46619 was twice that of lungs perfused with buffer alone (P= 0.05). The presence of PGE2, PGF2α, and PGI2within the perfusate of lungs exposed to U-46619 caused 118, 65, and 68% increases inKf, respectively, over that of lungs perfused with U-46619 alone (P< 0.03). The Rtof lungs perfused with PGE2+ U-46619 was ∼30% greater than that of lungs exposed to either U-46619 (P< 0.02) or PGE2(P< 0.01) alone. When paired measurements of Rttaken before and then 15 min after the addition of U-46619 were compared, PGI2was found to attenuate U-46619-induced increases in Rt(P< 0.01). These data suggest that PGE2, PGI2, and PGF2αpotentiate the effects of TxA2-receptor activation on pulmonary microvascular permeability.

Reports on the repowering project in Manchester Street Power Plant in Providence, Rhode Island. Increased power production from 132 MW to 489 MW; Advantages of repowering; Use of three combined cycle units; Reinforcement of aging structures; Soil and groundwater contaminant analysis; Absence of organized opposition.

Intestinal reperfusion (IR)-induced pulmonary edema has been related to endogenous pulmonary thromboxane A2(TxA2) release. This study examines the hypothesis that alveolar macrophages (aMs) activated during IR are an important cellular source of TxA2in this model. Anesthetized Sprague Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IR) or sham operation (Sham). aMs were isolated by bronchoalveolar lavage and incubated in Krebs buffer for 30 min, after which the supernatant was analyzed for TxB2(metabolite of TxA2) and prostaglandin E2. Other parameters of aM activation measured included lysosomal enzyme release (β-glucuronidase), superoxide (O2-) release, and procoagulant activity. aMs from animals sustaining IR generated more than twice as much TxA2and prostaglandin E2as did those isolated from controls (p< .05). Other evidence of aM activation included a nearly 100-fold increase in procoagulant activity, a 7-fold increase in β-glucuronidase release, and a 2.5-fold increase in O2release over that of controls (p< .05). These data suggest that TxA2is a major eicosanoid product of aMs during IR and that aMs may be an important cellular participant in IR-induced pulmonary microvascular injury, either directly by releasing O2-, lysosomal enzymes, and pro-coagulant factors, or indirectly by generating TxA2.

This study examines the hypothesis that neutrophils isolated from animals sustaining intestinal reperfusion (IIR) induce pulmonary microvascular dysfunction. Lungs were isolated from normal Sprague-Dawley rats and perfused with a physiologic buffer in vitro. Neutrophils (2 × 106) isolated from animals sustaining IIR (n 5) or sham operation (SHAM; n 6) were infused into the isolated lung model. A third group of lungs underwent in vitroperfusion without exposure to neutrophils (n 5). Lung injury was assessed by measuring wet to dry weight ratios and pulmonary artery pressure (PAP). Pulmonary ultrastructure was assessed by electron microscopy. The wetdry ratio of lungs from animals sustaining IIR was greater than that of lungs exposed to SHAM neutrophils (p.03) or perfusate alone (p.02). The PAP of lungs exposed to IIR neutrophils was nearly 10 times greater than that of lungs exposed to SHAM neutrophils (p.003) or buffer alone (p.006). Ultrastructural examination of lungs exposed to IIR neutrophils demonstrated interstitial edema with occasional focal disruptions in the alveolar capillary endothelial cell membrane whereas lungs exposed to SHAM neutrophils were normal. These experiments provide important in vitrocorrelation of prior in vivostudies suggesting that neutrophils are important pathogenic mediators of IIR-induced lung injury.

This study quantitates the physiologic forces governing the movement of fluid and protein into the lungs during intestinal reperfusion (IR) and describes the anatomic pattern of protein extravasation. Sprague–Dawley rats underwent IR after which pulmonary microvascular dysfunction was assessedin vivoby measuring the concentration of protein within the airways and by quantitating the extravasation of Evans blue dye (EBD). Pulmonary microvascular dysfunction was quantitatedin vitroby determining the capillary filtration coefficient(Kf), protein reflection coefficient (ς), and vascular resistance(Rt) using an isolated, perfused lung model. The morphologic pattern of protein extravasation into the lung was qualitatively assessed by fluorescence microscopy following the intravenous administration of fluorescent-labeled proteins of varying molecular weight. Sham-operated animals served as controls. The EBD content of lungs of IR animals was 48% greater than that of controls (P= 0.02). There was no difference in the protein concentration within the airways of these two groups. IR was associated with changes in pulmonary microvascular function favoring the movement of plasma fluid and protein into the interstitium(Kf= 0.02 ± 0.006 vs 0.005 ± 0.0005 g/min/mm Hg/100 g body wt; ς = 0.95 ± 0.02 vs 0.99 ± 0.005; andRt= 0.94 ± 0.08 vs 0.53 ± 0.04 mm Hg/ml/min/100 g body wt; IR vs SHAM, respectively,P< 0.05). Fluorescence microscopy demonstrated the focal extravasation of labeled proteins into the lungs of animals sustaining IR. These data suggest that both enhanced microvascular permeability and increased hydrostatic pressure contribute to the pulmonary edema associated with IR. Furthermore, the extravasation of protein is relatively focal in nature in contrast to the diffuse leak that characterizes more severe models of lung injury.

Rogers, ThomasE. (Louisiana State University, Baton Rouge), Richard J. Hidalgo, and George T. Dimopoullos. Immunology and serology of Anaplasma marginale. I. Fractionation of the complement-fixing antigen. J. Bacteriol. 88:81–86. 1964.—Studies were conducted to fractionate and purify the complement-fixation (CF) antigen of Anaplasma marginalein infected erythrocytes of cattle. Initial attempts were made to resolve the antigen from crude stromatal preparations by various chemical and physical methods. Fractionation procedures involving partial and total lipid extraction suggested that the CF antigen was lipoprotein in nature. Fluorocarbon deproteinization of stromatal antigens was also attempted. A method was developed for the preparation of a desirable AnaplasmaCF antigen which involved disintegration of infected erythrocytes by sonic vibration and separation of the antigen by differential centrifugation. Antigens prepared by this method were highly specific, colorless, did not exhibit anticomplementary activity, and possessed higher titers than standard Anaplasmaantigens. When density-gradient sedimentation was applied to sonic extracts of infected cells, it was demonstrated that the CF antigen could also be fractionated by this method.

A CF antigen for Anaplasma marginalewas prepared by differential centrifugation of the sonic lysate of infected bovine erythrocytes. Studies were conducted to determine the chemical and physical nature of the antigen. Qualitative biochemical tests and enzyme sensitivity studies indicated the antigen to be lipoprotein in nature. Electron microscopic observations showed that the preparation was not composed of Anaplasmabodies but of amorphous membranous material which probably constitutes the outer coating of the AB. Filtration studies were conducted and observations made on the effect of temperature on the antigen.

Fractionation of acute phase anti-Anaplasmasera and subsequent study of the fractions by CF showed that serologic activity was associated with the alpha- and beta-globulins of lower mobilities, and the gamma-globulins of highest mobility. Similar studies with convalescent sera showed a complete absence of CF activity in the alpha-globuliins. CF activity in the beta-globulin fractions was distributed essentially similar to that found in acute phase sera although the titers of the individual fractions were diminished. The CF activity in the gamma-globulins during the convalescent stages was associated with fractions of high and intermediate mobilities. It was confirmed that a relationship existed between the concentrations of globulin components and CF antibody titers.