Search

Biology: Pathways for Induction and the Nature of Macrophage Procoagulant Activity (R.J. Fingerote and G.A. Levy). The Role of Cytokines in Induction of Macrophage Procoagulant Activity (C.L. Geczy). Monocyte/Macrophage-Endothelial Cell Interactions (E.H. Cole and P.A. Marsden). Role of Procoagulant Activity in Disease: The Role of Macrophage Procoagulants in Infection (G.F. Brisseau, P.Y.C. Cheung, and O.D. Rotstein). Procoagulant Activity in Gastroenterology (A.J. Wakefield, M. Hudson, and L. More). The Role of Procoagulant Activity in Fulminant Viral Hepatitis (S.W. Chung, C.-Y. Li, J. Leibowitz, and G.A. Levy). Procoagulant Activity in Diseases of the Kidney (S. Holdsworth and P. Tipping). Role of Procoagulant Activity in Neoplastic Disease (R.L. Edwards and F.R. Rickles). Role of Procoagulant Activity PCA in Allograft Rejection (P. Kim, I. Koh, and Z. Cohen). Procoagulant Activity and Lung Disease (H.A. Chapman, J.S. Munger, and D.A. Waltz). Index.

Unlike the United States, the potential to increase organ donation in Canada may be sufficient to meet the need for transplantation. However, there has been no national coordinated effort to increase organ donation. Strategies that do not involve payment for organs, such as investment in health care resources to support deceased donor organ donation and introduction of a remuneration framework for the work of deceased organ donation, should be prioritized for implementation. Financial incentives that may be permitted under existing legislation and that pose little risk to existing donation sources should be advanced, including the following: payment of funeral expenses for potential donors who register their decision on organ donation during life (irrespective of the decision to donate or actual organ donation) and removal of disincentives for directed and paired exchange living donation, such as payment of wages, payment for pain and suffering related to the donor surgery, and payment of directed living kidney donors for participation in Canada's paired exchange program. In contrast, it would be premature to contemplate a regulated system of organ sales that would require a paradigm shift in the current approach to organ donation and legislative change to implement.

Hypercalcemia, occurring in up to 25% of patients within 12 months following renal transplantation, and persistent hyperparathyroidism were evaluated following renal transplantation, by retrospective chart review of 1000 adult patients transplanted between January 1, 2003 and January 31, 2008 with at least six months follow-up. Serum calcium, parathyroid hormone, and phosphate levels were recorded at 12, 24, 36, and 48 months. Average follow-up was 766 (535) d (mean (SD); median 668 d). Majority were first transplants (85%); deceased donor 57%. Point prevalence of hypercalcemia (serum Ca(2+) > 2.6 mM) was 16.6% at month 12, 13.6% at month 24, 9.5% at month 36, and 10.1% at month 48. Point prevalence of serum parathyroid hormone (PTH) > 10 pM was 47.6% at month 12, 51.1% at month 24, 43.4% at month 36, and 39.3% at month 48. Estimated glomerular filtration rate (GFR) was maintained throughout and was not different between patients with or without hypercalcemia or elevated PTH. Cinacalcet was prescribed in 12% of patients with hypercalcemia and persistent hyperparathyroidism; parathyroidectomy was performed in 112/1000 patients, 15 post-transplant. Persistent hyperparathyroidism, often accompanied by hypercalcemia, is common following successful renal transplantation, but the lack of clear management suggests the need for further study and development of evidence-based guidelines.

Approximately one-third of kidney transplant candidates have medically acceptable living donors, but are unable to receive transplants due to donor–recipient incompatibilities. Kidney paired donation (KPD) is a strategy that matches incompatible pairs in order to find compatible matches, thus increasing living donor transplantation. The concept was first conceived in 1986. Since then, significant strides have been made. However, the technique remains underutilized. This article describes the current advances, types of paired donation programmes, registries, worldwide experience, outcomes, barriers, and limitations.

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49 ± 18 mL/min/1.73 m(2) . In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m(2) higher eGFR at levels below 45 mL/min/1.73 m(2) was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m(2) . In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.

)wasdevelopedafteradirectivefromtheWorldHealthAssemblyin2004(resolution57.18),whichurgedmemberstates:“totakemeasurestoprotectthepoorestand vulnerable groups from transplant tourism and the saleof tissues and organs, including attention to the wider prob-lemofinternationaltraffickinginhumantissuesandorgans”(

Delayed graft function (DGF) associates with an increased risk for graft failure, but its link with death with graft function (DWGF) is unknown. We used the US Renal Data System to assemble a cohort of all first, adult, deceased-donor kidney transplant recipients from January 1, 1998, through December 31, 2004. In total, 11,542 (23%) of 50,246 recipients required at least one dialysis session in the first week after transplantation. Compared with patients without DGF, patients with DGF were significantly more likely to die with a functioning graft (relative hazard 1.83 [95% confidence interval 1.73 to 1.93] and 1.53 [95% CI 1.45 to 1.63] for unadjusted and fully adjusted models, respectively). The risk for DWGF was slightly higher among women with DGF than among men. There was no significant heterogeneity among other subgroups, and the results were robust to sensitivity analyses. Acute rejection within the first year attenuated the DGF–DWGF association. Cardiovascular and infectious deaths were slightly more prevalent in the DGF group, but the relative hazards of cause-specific death were similar between DWGF and deaths during total follow-up. In summary, DGF associates with an increased risk for DWGF; the mechanisms underlying the negative impact of DGF require further study.

Background. There is a paucity of population-level data on the long-term outcomes of kidney transplants from deceased donors with a history of diabetes mellitus (DM). Methods. We examined the association of donor DM with graft and patient survival in 66,654 deceased donor kidney transplant recipients (KTR) from January 1, 1994, to December 31, 2003, in the United States. KTR receiving kidneys from DM versus non-DM donors were compared in the total study population and in a 1:1 propensity score-matched cohort. Results. A total of 2302 KTR received kidneys from DM donors over the study period. Older and female recipients, increased donor age, longer cold ischemia time, and transplants after 2000 were associated with a greater odds of receiving a DM donor. After propensity score matching, Cox proportional hazards models revealed hazard ratios of 1.11 (95% CI: 1.02-1.22), 1.17 (95% CI: 1.04-1.33), and 1.06 (95% CI: 0.94-1.18) for graft failure, death-censored graft failure, and patient mortality, respectively. No significant effect measure modification was seen across various patient subgroups. Longer duration of donor DM was generally associated with an increased risk of adverse outcomes. The results were robust to several sensitivity analyses. Conclusions. The long-term graft survival of KTR with DM donors is significantly inferior to non-DM donors, but the absolute difference is small. DM donors do not adversely impact patient survival. This suggests that DM donors may be effectively used to expand the donor pool, but evidence-based guidelines on the appropriate selection of these donors are needed.

As offshore drilling plans increase drill pipe sizes and push into deeper water, emergency accumulator systems for BOP control are also being pushed to maximum performance conditions. Recently some systems have failed subsea deadman/autoshear testing despite shore calculations that predicted they should work. Changing the accumulator precharge led to success in each case, but at the expense of costly stack pulls. This paper explores the causes of these failures and provides a new strategy to help prevent similar avoidable downtime events. Optimization of subsea BOP lower stack deadman/autoshear accumulators should include consideration of temperature and pressure uncertainties that are inherent in the process of setting precharge pressure. For each well application, calculations typically compute an optimum precharge which provides the maximum usable fluid for the emergency function sequence. For single function sequences, this theoretically produces a subsea condition in which all of the fluid in the accumulators is usable. Precharge pressures below this optimum will provide more fluid, but the usable portion of this fluid gradually diminishes as precharge pressure is reduced. Precharge pressures above the optimum rapidly diminish the total amount of fluid (and thus usable fluid) in the accumulators. The usable volume penalty is therefore much higher for precharging above optimum than for precharging below optimum. As systems are pushed to maximum performance conditions, the margin between an optimum condition and a failing condition can be within normally accepted tolerances. If temperature and pressure uncertainties involved in setting the precharge according to plan are considered, the most practical precharge plan will target slightly below the mathematical optimum. This will balance the asymmetric effects of uncertainties in the precharge settings. Correct calibration of the precharge pressure gauge and correct adjustments of precharge pressure for ambient temperature are both critical for reduction of precharge condition uncertainties. Adjustment of precharge to a specified plan is inherently difficult in practice for several reasons; therefore training of rig personnel and awareness of the effects of precharge condition uncertainty by planners on shore can prevent costly downtime. In multi-function emergency sequences, accumulator precharge pressures are typically optimized to balance the needs of all functions. The same thought process described for single function sequences can be applied to multi-function sequences to keep the band of precharge uncertainty within the operating limits for all functions in the sequence.

Statins have anti-inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new-onset diabetes mellitus in renal transplant recipients. The records of all previously non-diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow-up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New-onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose > or =7.0 mmol/L or 2-h postprandial glucose > or =11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time-dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New-onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109-0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127-0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003-1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003-1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023-1.480]) and age > or =45 years (p = 0.01, HR 2.226[1.162-4.261]) were associated with increased diabetes. Statin use is associated with reduced new-onset diabetes development after renal transplantation.

Background. Genotypes of the renin-angiotensin system have been implicated in essential hypertension and in progression of native kidney diseases, but gene effects on progression in chronic renal allograft dysfunction are unclear. Methods. To examine gene effects on long-term renal allograft function, we conducted a prospective cohort study of 210 nondiabetic renal allograft recipients younger than 36 years of age who underwent transplantation between 1980 and 1993 and were followed up through 1999. All grafts survived more than 1 year and all subjects received cyclosporine-based immunosuppression. DNA was analyzed by polymerase chain reaction for the angiotensin-converting enzyme insertion/deletion and angiotensinogen (AGT) M235T polymorphisms. Linear regression multivariate modeling of the slope of the inverse creatinine-versus-time, survival analyses for time-to-sustained doubling of baseline serum creatinine, time-to-graft loss, and a composite endpoint including patient death were performed. Results. Mean follow-up time was 8.4±3 years. Genotype frequencies for each marker system did not deviate significantly from the Hardy-Weinberg equilibrium. The slope of the inverse creatinine-versus-time for AGT 235T/T and M/T was significantly increased compared with M/M (P

Background. Survival in pig-to-baboon kidney xenotransplantation is currently limited by acute humoral xenograft rejection (AHXR). We hypothesized that the administration of rabbit antithymocyte serum (RATS) would delay or prevent AHXR as compared with a cyclophosphamide (CyP)-based immunosuppressiv

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral) therapy, and that CsA exposure early post-transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration-controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough-level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time-concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12-h dosage interval (AUC[0-12]) (p = 0.0068), AUC over the first 4 h of the 12-h dosage interval (AUC[0-4]) (p = 0.0014) or 2h post-dose (C2) CsA level (p = 0.0027). Day 3 dose- and weight-corrected C2 values (EMIT equivalent) separated patients into low (200 microg/L/mg/kg dose), intermediate (200-350 microg/L/mg/kg dose) and high absorber categories (350 microg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500 microg/L by day 3 post-transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using C0 levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single-point C2 concentrations which accurately predict individual AUC[0-4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose- and weight-corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (C0) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.

Recent data suggest that optimal cyclosporine (CsA) exposure early post-transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration-controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral. An international, prospective, multicenter study examined the feasibility, accuracy, precision and clinical utility of cyclosporine microemulsion (Neoral) absorption profiling in de novo renal transplant recipients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression. The nested pharmacokinetic study reported here was conducted in 4 study centers in which full (11-point) pharmacokinetic profiles were performed on days 3, 7, 14 and 84 post-transplant to examine absorption profile and absorption efficiency, and to determine optimal sparse-sampling pharmacokinetic methods to predict Neoral exposure. Twenty-four patients had complete 12-h pharmacokinetic (PK) data on all 4 sampling days. Area under the time-concentration curve (AUC) over the first 4 h of the 12-h dosage interval (AUC[0-4]) and AUC over the entire 12-h dosage interval (AUC[0-12]) reached 3803 +/- 1033 and 7462 +/- 2120 microg.h/L respectively, by day 3, remained stable throughout the first 2 weeks, and declined to 2310 +/- 698 and 4062 +/- 1158 microg.h/L by day 84 (p0.001). AUC[0-4], capturing the drug absorption phase, represented 52% of the AUC[0-12] values across the four PK study days (mean R20.90). Between-patient variability was highest for C0 and C1 (mean coefficient of variation [c.v.] 36-47%), and lower for C2 (mean c.v. 28%) and subsequent time-points during the dosing interval. Mean relative CsA absorption, measured by dose- and weight-adjusted AUC[0-4] and AUC[0-12], increased significantly over time. The dose- and weight-corrected AUC[0-4h] (DWC.AUC[0-4]) rose by over 100% (p0.001) from 753 +/- 202 at day 3 to 905 +/- 232 at day 7, 1080 +/- 330 at day 14 and 1521 +/- 316 by day 84, while the dose-and weight-corrected AUC[0-12h] (DWC.AUC[0-12]) rose by over 80% (p0.001) from 1477 +/- 390 microg.h/L/ mg/kg on day 3, to 1721 +/- 426 on day 7, 2086 +/- 478 on day 14 and 2690 +/- 602 on day 84 (p0.001). Relative CsA absorption varied over 5-fold between patients at day 3, but patients tended to remain within the same quartiles over time. Sparse-sample modeling identified optimum 3-point, 2-point and 1-point predictors for AUC[0-4] and AUC[0-12]. C2 was the most accurate and robust .1-point predictor for AUC[0-4] (mean R2: 0.80), while C3 was superior for AUC[0-12] (mean R2: 0.75). C0 was not a good predictor of either AUC[0-4] or AUC[0-12] (mean R2: 0.13 and 0.24, respectively).Absorption profiling defines the heterogeneity in CsA exposure and relative absorption post-transplant. A 2-h post-dose blood sample is the most consistent, accurate and robust single-point predictor of the absorption phase measured by AUC[0-4] and should replace trough level monitoring for accurate concentration-control of Neoral therapy in the clinical setting. The use of additional samples at 1 and 3h is more complex and costly, but increases prediction accuracy and may be valuable in selected patients with erratic absorption.

Background Establishment of a national kidney paired donation (KPD) program represents a unique achievement in Canada's provincially organized health care system. Methods Key factors enabling program implementation included consultation with international experts, formation of a unique organization with a mandate to facilitate interprovincial collaboration, and the volunteer efforts of members of the Canadian transplant community to overcome a variety of logistical barriers. Results As of December 2013, the program had facilitated 240 transplantations including 10% with Calculated panel reactive antibody (cPRA) ≥97%. Unique features of the Canadian KPD program include participation of n = 55 nondirected donors, performance of only donor specific antibody negative transplants, the requirement for donor travel, and nonuse of bridge donors. Conclusion The national KPD program has helped maintain the volume of living kidney donor transplants in Canada over the past 5 years and serves as a model of inter-provincial collaboration to improve the delivery of health care to Canadians.

Delayed graft function (DGF), most commonly defined as the need for dialysis in the first 7 days post-transplant, continues to be a common problem in the modern era of kidney transplantation. Multiple complex biochemical and structural changes occur at the cellular level as a result of ischemia and reperfusion injury of the allograft, which predispose recipients to DGF. Several transplant, donor, and recipient factors have been found to be associated with an increased risk of DGF. This chapter will provide an overview of these risk factors as well as a practical approach to the clinical evaluation of DGF. A number of preventive and therapeutic interventions such as the use of certain preservation solutions, pulsatile machine perfusion, vasodilatory drugs, and immunosuppressive agents have been extensively studied with variable results. These interventions, as well as the quality of the evidence supporting their use, will also be reviewed. Finally, this chapter will highlight the short- and long-term consequences of DGF, with a particular emphasis on the association between DGF, graft survival, and death with graft function.

Purpose: 1. To review current knowledge about patient and graft survival, complication rates, patient selection and management protocols in patients aged 60 years or more with a renal transplant. 2. To review the advantages and disadvantages of cadaveric organ retrieval from older donors. Data Sources: Evidence was obtained from published articles identified using a MEDLINE search from 1976 to 1996; expert opinion and citations from previous review articles. Results: Survival rates have improved with time and now range from 54 to 75% 5-year patient survival and 52–74% 5-year graft survival. The most common reason for graft loss is patient death as both acute and chronic rejection is less commonly seen in older patients. Censored graft survival (if death with a functioning graft is treated as censored data) is higher in elderly patients compared to younger ESRD patients. Based on cohort data from an administrative database a survival advantage is seen in older dialysis patients accepted for transplantation even after matching for comorbidity. Post-transplant morbidity is mainly attributable to infectious complications and an increased prevalence of malignancy. There is insufficient data about the most optimal immunosuppression regime and further research is required in this direction. The evidence currently supports the use of kidneys from older donors because of a relative lack of cadaveric organs from younger donors although a worse patient and graft outcome is recognized in the long term. Insuffient evidence exists to support a firm conclusion regarding age matching or targeting of older organs to special groups.

One thousand and eighteen patients who received first cadaveric renal transplants (age 18–80 yr) at the University of Toronto from 1981–1991 were reviewed in order to compare the results of patients older than 55 years of age (n=251) with the rest of the group (n=767). One- and 5-year graft survival were significantly lower in patients over 55 years of age compared to younger patients; 74% vs. 82% at one year and 49% vs. 75% at 5 years (p

Sixty-three patients with crescentic glomerulonephritis (cellular crescents in >50% of glomeruli) were considered for a prospective randomized trial comparing intravenous methylprednisolone, prednisone, and azathioprine with and without plasma exchange. Of 32 patients who fulfilled the inclusion criteria for this study, 16 were randomly assigned to receive drug therapy (control) and 16 to receive plasma exchange as well. The randomization was stratified for initial need of dialysis, and the presence of oliguria and sclerosis. Renal pathology was similar in the two groups of patients. There was no significant difference in the number of patients initially on dialysis who were able to discontinue it during the study (2/7 control v 3/4 plasma exchange), whereas no control but two plasma exchange-treated patients started dialysis during the study. Serum creatinine at randomization was similar in the two groups: 769 ± 486 µmol/L (8.7 + 5.5 mg/dL) in the control group versus 643 ± 275 µmol/L (7.3 ± 3.1 mg/dL) in the plasma exchange group. There was no significant difference between the two groups in mean serum creatinine, change in serum creatinine, change in reciprocal, or change in logarithm of serum creatinine at 1, 3, 6, or 12 months following randomization. Power calculation, assuming a 20% difference would be clinically relevant, was 0.94 at 12 months. There was significant morbidity in both groups; there were two deaths within 1 year of randomization, both of pulmonary infection and both in the plasma exchange group. We conclude that plasma exchange offers no additional therapeutic benefit to patients with idiopathic rapidly progressive glomerulonephritis (RPGN) who are not dialysis-dependent at presentation.

Patients with systemic lupus erythematosus (SLE), with or without end-stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE.Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5-6-year trial, and then invited to continue in a 2-year open-label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7-8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures.Fluvastatin reduced low-density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3-40%), from a mean +/- SD of 4.0 +/- 0.9 mmoles/liter to 2.8 +/- 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7-27.5%), from 6.4 +/- 0.9 mmoles/liter to 5.1 +/- 1.1 mmoles/liter. Compared with placebo-treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9-119.4], P = 0.064).Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.

A panel of 24 IgG2ak monoclonal antibodies was produced against murine hepatitis virus strain 3 (MHV-3)-induced procoagulant activity (PCA) from murine macrophages. The antibodies were specific and did not react in an enzyme-linked immunosorbent assay with purified MHV-3; lipopolysaccharide-induced PCA; crude mouse, human, or rabbit tissue factor, or unstimulated murine macrophages. Sixteen of 24 monoclonal antibodies inhibited functional PCA expression in a one-stage clotting assay. More detailed studies on one monoclonal antibody, 3D4.3, demonstrated that it inhibited prothrombin cleavage at concentrations of greater than or equal to 0.1 microgram/ml, and by Western blot this antibody reacted with proteins of a molecular mass of 140, 74, and 70 kDa on nonreduced gels and 74 and 70 kDa on reduced gels distinct from tissue factor known to have a molecular mass of 47 kDa. Induction of PCA was dependent on both host RNA and protein synthesis. Immunofluorescence studies showed specific binding to MHV-3-stimulated PCA-positive macrophage membranes. Both numbers of positive macrophages and intensity of staining correlated with multiplicity of infection. These monoclonal antibodies will be useful in isolation and characterization of the unique viral-induced PCA as well as in determining its biologic role in MHV infection and other diseases in which the prothrombinase has been implicated.

Background and objectives: Development of new therapeutic strategies to improve long-term transplant outcomes requires improved understanding of the mechanisms by which these complications limit long-term transplant survival. Design, setting, participants, & measurements: The association of acute rejection and new-onset diabetes was determined in the first posttransplantation year with the outcomes of transplant failure from any cause, death-censored graft loss, and death with a functioning graft in 27,707 adult recipients of first kidney-only transplants, with graft survival of at least 1 yr, performed between 1995 and 2002 in the United States. Results: In multivariate analyses, patients who developed acute rejection or new-onset diabetes had a similar risk for transplant failure from any cause, but the mechanisms of transplant failure were different: Acute rejection was associated with death-censored graft loss but only weakly associated with death with a functioning graft. In contrast new-onset diabetes was not associated with death-censored graft loss but was associated with an increased risk for death with a functioning graft. Conclusions: Acute rejection and new-onset diabetes have a similar impact on long-term transplant survival but lead to transplant failure through different mechanisms. The mechanisms by which new-onset diabetes leads to transplant failure should be prospectively studied. Targeted therapeutic strategies to minimize the impact of various early posttransplantation complications may lead to improved long-term outcomes.

Steroids are effective immunosuppressants in renal transplantation but are associated with significant adverse effects. As a result, there has been increased interest in protocols utilizing steroid minimization. Initial trials stopped steroids at approximately 3 months, when the highest risk phase for acute rejection was over. As two randomized trials using cyclosporine and mycophenolate mofetil without induction therapy showed an unacceptably high acute rejection rate, more recent interest has focused on the cessation of steroids very early, usually within the first week after transplantation. Most protocols have used antibody induction combined with calcineurin inhibitors and mycophenolic acid derivatives. Uncontrolled studies have shown a low rate of acute rejection, but the most recent randomized controlled trials have demonstrated an increased risk of acute rejection. These trials have not shown any consistent difference in short-term patient or graft survival. Cardiovascular risk factors do not appear to be consistently improved by early steroid withdrawal. Most trials lack sufficient follow-up (5 years or more) to assess the impact of the increased acute rejection rate seen with early steroid withdrawal on long-term outcomes. Thus, the use of such protocols remains investigational.

Cyclosporine metabolites (CM) were compared with cyclosporine for their in vitro and in vivo immunosuppressive, nephrotoxic, and hepatotoxic effects using (A) in vitro mixed lymphocyte induction of monocyte/macrophage procoagulant activity (PCA), an accurate marker of allograft rejection; (B) in vitro toxic effects on renal cells in culture; and (C) a unidirectional rejection model of rat small intestinal transplantation (SIT). CM were composed of OL1, OL17, OL18, and two additional peaks C and H, (peak C: mass = 1235, 15.3% of total CM, peak H: mass = 1205, 6.3% of total CM). In vitro, CM fully suppressed the one-way mixed lymphocyte culture-induced PCA from 52.5 +/- 8.2 mU/10(6) PBM to the basal level 22.3 +/- 6.6 mU/10(6) PBM (P less than 0.01), which was comparable to CsA (21.3 +/- 5.5 mU/10(6) PBM). Lewis rats that had received Lewis-Brown Norway F1 hybrid intestinal allografts when treated with CM, demonstrated near-normal histology with minimal signs of rejection as compared with the fulminant clinical and histological rejection observed in the control (untreated and Cremaphor/NaCl treated) animals. PCA was markedly elevated in the control animals, 278 +/- 172 (untreated) and 160 +/- 98 mU/10(6) PBM (Cremaphor/normal saline treated), whereas CsA-treated allogeneic transplants expressed only basal levels of PCA (14.0 +/- 4 mU/10(6) PBM) (P less than 0.01), associated with normal histology. CM-treated animals expressed PCA levels of 27.0 +/- 10 mU/10(6) PBM, which was significantly different from both control and CsA-treated animals (P less than 0.01). In contrast to CsA-treated animals, CM-treated allogeneic transplants demonstrated no apparent renal or hepatic toxicity, as measured by blood urea nitrogen (25.3 +/- 9.5 vs. 10.0 +/- 5.3 mg/dl), alkaline phosphatase (160.7 +/- 29.3 vs. 100.3 +/- 19.5 U/L), and aspartate transaminase (96.7 +/- 23.7 vs. 61.7 +/- 11.7 U/L) (P less than 0.01). Similarly, in contrast to CsA, CM had minimal or no toxicity in renal epithelial and mesangial cells in culture, as measured by minimal or no inhibition of DNA, RNA, and protein synthesis. These results suggest that CM have potent immunosuppressive properties with no apparent nephrotoxicity and hepatotoxicity in vitro and in vivo.

Summary Addition of interleukin-2 receptor antagonist (IL-2RA) induction to calcineurin inhibitor (CNI)-based regimens reduces biopsy-proven acute rejection by 30–40%. IL-2RA induction facilitates early withdrawal of steroids, and supports the safe use of reduced-exposure CNI or delayed CNI introduction. IL-2RAs and rabbit antithymocyte globulin (Thymoglobulin®) show comparable efficacy in patients at standard or low immunologic risk, but the adverse event profiles of lymphocyte-depleting agents are less favorable. IL-2RAs, uniquely, provide effective immunosuppression with similar tolerability to placebo.

Genotypes of the renin-angiotensin system have been implicated in essential hypertension and in progression of native kidney diseases, but gene effects on progression in chronic renal allograft dysfunction are unclear.To examine gene effects on long-term renal allograft function, we conducted a prospective cohort study of 210 nondiabetic renal allograft recipients younger than 36 years of age who underwent transplantation between 1980 and 1993 and were followed up through 1999. All grafts survived more than 1 year and all subjects received cyclosporine-based immunosuppression. DNA was analyzed by polymerase chain reaction for the angiotensin-converting enzyme insertion/deletion and angiotensinogen (AGT) M235T polymorphisms. Linear regression multivariate modeling of the slope of the inverse creatinine-versus-time, survival analyses for time-to-sustained doubling of baseline serum creatinine, time-to-graft loss, and a composite endpoint including patient death were performed.Mean follow-up time was 8.4+/-3 years. Genotype frequencies for each marker system did not deviate significantly from the Hardy-Weinberg equilibrium. The slope of the inverse creatinine-versus-time for AGT 235T/T and M/T was significantly increased compared with M/M (0.0001). The AGT 235T/T genotype was also associated with a shorter time-to-sustained doubling of serum creatinine ( =0.001). When subjects were divided into quartiles based on slope magnitude, the frequency of the AGT 235T/T genotype was overrepresented in the fastest progressing group compared with the slowest ( =0.001). The AGT 235T/T genotype was also associated with shorter time-to-graft loss ( =0.007) and the composite endpoint ( =0.001).The AGT 235 T allele independently influences long-term decline in renal allograft function.

Transplantation offers superior life expectancy and quality of life compared with dialysis in young patients with end-stage renal failure. However, the initial risks of mortality and morbidity are high. This study used a decision analysis model to evaluate the costs and benefits of kidney transplantation versus continued dialysis for older patients with renal failure. A decision analytic model comparing cadaveric renal transplantation to continued hemodialysis treatment was developed. The base case considered a theoretical cohort of patients aged 65 yr without known comorbidity or contraindications to transplantation who would have to wait 2 yr for a cadaveric transplant. Separate models were constructed for patients with diabetes or cardiovascular disease and for patients receiving an organ after a variety of wait-list times. Probability, utility, and survival data were obtained from published reports and renal registries. For 65-yr-old patients, quality-adjusted life expectancy increased by 1.1 quality-adjusted life years (QALY) at an incremental cost of $67,778 per QALY. Assuming a 2-yr wait-listed time, transplantation remained economically attractive for 70-yr-old patients (incremental cost effectiveness [ICE], $79,359 per QALY) but was less economically attractive for those over 75 yr of age (ICE, $99,553) or for 70-yr-olds with either cardiovascular disease or diabetes (ICE, $126,751 and $161,090 per QALY, respectively). The analytic results were sensitive only to the time spent waiting for the graft. The cost-effectiveness reduced such that the costs associated with one QALY were in excess of $100,000/yr when the probability of a complication was > or = 50% per 3-mo cycle and when the utility of transplantation fell below 0.62. If available within a timely period, transplantation may offer substantial clinical benefits to older patients at a reasonable financial cost. Prolonged waiting times dramatically decrease the clinical benefits and economic attractiveness of transplantation, suggesting that living donor transplantation may be of particular benefit in this population.

Survival in pig-to-baboon kidney xenotransplantation is currently limited by acute humoral xenograft rejection (AHXR). We hypothesized that the administration of rabbit antithymocyte serum (RATS) would delay or prevent AHXR as compared with a cyclophosphamide (CyP)-based immunosuppressive regimen.Nine baboons received life-supporting heterotopic single-kidney transplants from human decay accelerating factor transgenic pigs. Immunosuppression consisted of GAS (a galactosyl alpha-1,3-galactose analog), cyclosporine, and steroids. Group 1 (n=2) was also treated with CyP and a rapamycin derivative (RAD), group 2 (n=4) received RATS and RAD, and group 3 (n=3) received only RATS. Animals were maintained until death or sacrifice because of uncontrollable rejection or other complications. Graft histopathology was assessed at the study endpoint.Mean survival was 28+/-11.3 days, 23+/-2.5 days, and 20+/-2.5 days for groups 1, 2, and 3 (not significant). Graft rejection was the cause of death in both CyP-treated animals. One RATS-treated animal died of rejection; the others died of infections or bleeding. Two RATS-treated animals developed posttransplant lymphoproliferative disorder, and one died of cytomegalovirus pneumonitis. Histopathology revealed severe AHXR in group 1 kidneys, involving 100+/-0% of the tissue examined. In contrast, AHXR was reduced in groups 2 and 3, involving 21+/-14% and 18+/-28%, respectively, of the tissue examined (P0.01).Substitution of RATS for CyP was well tolerated and resulted in reduced severity of AHXR in this model. Complications seen in RATS-treated animals may be preventable through the use of standard prophylaxis for infections. Our data suggest that further studies are warranted to explore the use of antilymphocyte agents in xenotransplantation.

Background Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids. Methods Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts. Results At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149+/-58 micromol/L, compared with 158+/-102 micromol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density. Conclusions On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.

To develop a set of comprehensive, standardized, evidence-based guidelines for the use of antiviral therapy to prevent cytomegalovirus disease in adult patients having undergone renal transplantation.The use of medication, at the time of induction therapy or at the earliest sign of viremia. Treatments were evaluated by patient and donor serologic groups and the induction regimen used.The control of symptoms and features of cytomegalovirus disease over the first 6 mo to 1 yr after transplantation.Articles, compiled using a MEDLINE search from 1976 to July 1997, were reviewed by representatives of nephrology, microbiology, pharmacy, and epidemiology. Additional information was obtained from recent review articles and conference abstracts, and from experts in the field.The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examinations were used. High value was placed on studies with a randomized controlled design and blinded outcome observers. Study quality was classified as poor when cointervention was present (especially with regard to immunosuppressive regimens), when more than 20% of patients were lost to follow-up, and when intention to treat analysis was not performed. Recommendations were made with a graded system (grades A and B: Use of the intervention advised, based on high or fair quality evidence, respectively; grades D and E: Use of the intervention not advised, based on high or fair quality evidence, respectively: grade C: No recommendation made because of insufficient or conflicting evidence).(1) Seropositive recipient; donor seropositive or seronegative; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation). (2) Seronegative recipient; seropositive donor; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation) (3) Seronegative recipient; seropositive donor; conventional immunosuppression. Prophylaxis with antiviral therapy recommended (grade B recommendation). (4) Seronegative recipient; seronegative donor; any immunosuppressive regimen. No prophylaxis with antiviral therapy required (grade D/E recommendation). (5) Seropositive recipient: donor seropositive or seronegative; conventional immunosuppression. Prophylaxis left to the discrimination of the physician in charge (grade C recommendation).

It has long been recognized that members of the Jewish community generally do not sign organ donor cards or consent to the donation of the organs of their family members. In order to address this issue, the position of Jewish law on organ donation was examined and a sample of the Jewish population of Toronto was surveyed in an attempt to better understand the reasons for the observed reluctance to donate within this community. The results confirmed that the rate of signing organ donor cards was much lower in the Jewish community than in the general population, and although other reasons do exist, the major barrier to donation was a perception that Jewish law prohibits such action. The study of Jewish law revealed that organ donation is permitted and, in fact, encouraged by all branches of modern Judaism. Finally, in response to these results, a guide titled “Organ Donation: A Jewish Perspective” was compiled to help explain both the religious and medical aspects of organ donation for Jewish people and transplant personnel.

The strain-specific spectrum of liver disease following murine hepatitis virus type 3 (MHV-3) infection is dependent on inflammatory mediators released by macrophages. Production of nitric oxide (NO) by macrophages has been implicated in resistance to a number of viruses, including ectromelia virus, vaccinia virus, and herpes simplex virus type 1. This study was undertaken to define the role of NO in MHV-3 infection. Gamma interferon-induced production of NO inhibited growth of MHV-3 in a murine macrophage cell line (RAW 264.7). Viral inhibitory activity was reproduced by the NO donor S -nitroso- N -acetyl- dl -penicillamine (SNAP), whereas N -acetyl- dl -pencillamine (NAP), an inactive analog of SNAP, had no effect. Electron microscopy studies confirmed the inhibitory effects of NO on viral replication. Peritoneal macrophages isolated from A/J mice known to be resistant to MHV-3 produced a fivefold-higher level of NO and higher levels of mRNA transcripts of inducible NO synthase in response to gamma interferon than macrophages from susceptible BALB/cJ mice. SNAP inhibited growth of MHV-3 in macrophages from both strains of mice to similar degrees. In vivo inhibition of NO by N -monomethyl- l -arginine resulted in loss of resistance to MHV-3 in A/J mice. These results collectively demonstrate a defect in the production of NO in macrophages from susceptible BALB/cJ mice and define the importance of endogenous NO in resistance to MHV-3 infection in resistant A/J mice.

PURPOSE This retrospective review of all patients who developed Kaposi's sarcoma (KS) after solid organ transplantation at a single institution was undertaken to define the clinical presentation of this malignancy in the setting of iatrogenic immunodeficiency, and to determine the most appropriate treatment for patients in this clinical setting. MATERIALS AND METHODS The records of 2,099 patients who underwent heart, lung, liver, or kidney transplantation at The Toronto Hospital between January 1, 1981 and June 30, 1995, were reviewed. Twelve patients were identified who developed biopsy-proven KS in the posttransplantation period. Five patients who had disseminated KS who had not responded to either reduction or withdrawal of immunosuppression or to local radiotherapy were treated with combination chemotherapy consisting of doxorubicin 20 to 30 mg/m2, bleomycin 10 mg/m2, and vincristine 2 mg (ABV) administered intravenously every 3 weeks. RESULTS Eight of 12 patients were male and nine were of Italian origin. KS was limited to a localized area of the skin for only six patients, all after kidney transplantation. Visceral KS was present in three patients. Four of five patients responded to ABV chemotherapy (two complete and two partial remissions). The fifth patient responded to second-line etoposide and cisplatin. The median duration of response was in excess of 13 months (range, 8+ to 45+ months). Toxicity was limited to grade 1 neurotoxicity and grade 1 skin toxicity. CONCLUSION KS is an uncommon but recognized complication of solid organ transplantation. Combination chemotherapy is a safe and effective treatment for patients with disseminated or visceral KS that fails to respond to changes in immunosuppression.

Activation of the immune coagulation system has been implicated in the pathogenesis of liver injury following infection of inbred mice with murine hepatitis virus strain 3 (MHV-3). Following MHV-3 infection, macrophages isolated from MHV-3-susceptible and -semisusceptible inbred strains of mice express increased procoagulant activity (PCA), whereas macrophages from resistant strains express no increase in PCA over basal levels. The PCA induced by MHV-3 is a prothrombinase, encoded by the gene Fgl-2, which encodes a fibrinogen-like protein (musfiblp). In this study, MHV-3-resistant A/J mice treated with methylprednisolone prior to infection with MHV-3 developed elevated levels of alanine aminotransferase in serum and died within 10 days of infection, with histological findings of fulminant hepatitis. In vitro, macrophages isolated from A/J mice and pretreated with methylprednisolone produced a marked increase in functional PCA following infection with MHV-3. The PCA was shown to be a prothrombinase by its ability to cleave 125I-prothrombin. Northern blot analysis of RNA transcripts from these macrophages demonstrated increased transcription of the Fgl-2 gene relative to that in macrophages which had not been pretreated with methylprednisolone prior to MHV-3 infection. Methylprednisolone pretreatment of MHV-3-infected macrophages stabilized the Fgl-2 mRNA. Thus, loss of resistance to MHV-3 secondary to methylprednisolone therapy is associated with increased transcription and stability of Fgl-2 mRNA resulting in expression of the Fgl-2 gene product, musfiblp. These results provide further insight into mechanisms of PCA regulation in response to MHV-3 infection in inbred strains of mice.

A solitary native kidney is generally considered to be an absolute contraindication to percutaneous biopsy. However, technical advances, such as real-time ultrasound guidance and automated core biopsy systems, provide an excellent safety profile with an extremely low risk of catastrophic complications and have caused some investigators to call for a reassessment of this contraindication. The overall results at our institution are reported. Of 544 consecutive native and allograft kidney biopsies conducted over 2.5 years, 482 were performed with an automated core biopsy system and 281 also used real-time ultrasound guidance. The overall complication rate was 5.3%. Transient gross hematuria was seen in 4.4% and hematoma was seen in 1.5%; no patient experienced loss of kidney function and there were no deaths. We recently have begun to perform percutaneous biopsy of solitary native kidneys in carefully selected patients. To date, nine such procedures have been attempted, with success in eight cases. One patient had transient gross hematuria; no other complications were noted. This encouraging preliminary experience suggests that otherwise uncomplicated adult patients with a solitary kidney might be considered for percutaneous biopsy. It now seems appropriate to prospectively evaluate percutaneous biopsy of solitary kidneys in a larger cohort of unselected patients.

The Space Telescope Imaging Spectrograph (STIS) uses two 1K by 1K photon counting array (PCA) detector systems. Design of the PCA detector systems is described in this paper. These detector systems are similar in many ways and are mechanical mirror images of each other but cover different UV wavelength bands. A top-down design methodology was used to produce the two detector systems that feature: manufacturability, serviceability to the component level, system-level replacement without optical realignment or calibration, and a high level of parts commonality for cost control. The design meets the Space Telescope's structural, thermal, and electromagnetic compatibility requirements as well as electro-static discharge compatibility requirements of MIL-STD-1686A.

1K by 1K UV Photon Counting Array (PCA) imaging detectors have been built for the Space Telescope Imaging Spectrometer (STIS) program by Ball Aerospace in Boulder, Colorado. The STIS detectors are the largest of this type everproduced. These detectors have unique electronic and electro-mechanical requirements. This paper discusses the STIS PCA detector (MAMA detector) charge amplifier and discriminator electronic and packaging requirements. Critical system parameters, including speed, noise, power consumption, and size are described. Cost drivers including fabrication methods, test methods, and production techniques are discussed. Additional cost reduction techniques suitable for ground-based systems will be suggested. System requirements and circuit performance are comparedto demonstrate that performance meets or exceeds all system requirements. 1. INTRODUCTION The STIS MAMA Detector electronics uses a proprietary analog application specific integrated circuit (ASIC) pair de-signed at Ball Aerospace in Boulder, Colorado. There are two types ofASICs: a charge amp and a dual voltage discriminator.The die were fabricated by Tektronix using their QC 6 process and packaged by Kyocera USA in ceramic, hermetic, J leadedpackages.1Surface mount technology was used to reduce size, fabrication cost, and facilitate repair. The use of surface mount parts,rather than through-hole mounted parts, greatly reduces the probability of damaging the multilayer boards during rework andincreases reliability.The only through-hole components used were select resistors. These parts were used in small numbers to eliminate theneed to stock a large selection of surface mount resistors since the leaded resistors were already in stock at Ball.

Murine hepatitis virus strain (MHV-3) produces a strain-dependent pattern of disease which has been used as a model for fulminant viral hepatitis. This study was undertaken to examine whether there was a correlation between macrophage activation and susceptibility or resistance to MHV-3 infection. Peritoneal macrophages were isolated from resistant A/J and susceptible BALB/cJ mice and, following stimulation with MHV-3 or lipopolysaccharide (LPS), analyzed for transcription of mRNA and production of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), mouse fibrinogen-like protein (musfiblp), tissue factor (TF), leukotriene B4, and prostaglandin E2 (PGE2). Macrophages from BALB/cJ mice produced greater amounts of IL-1, TNF-alpha, TGF-beta, leukotriene B4, and musfiblp following MHV-3 infection than macrophages from resistant A/J mice, whereas in response to LPS, equivalent amounts of IL-1, TNF-alpha, TGF-beta, and TF were produced by macrophages from both strains of mice. Levels of mRNA of IL-1, TNF-alpha, and musfiblp were greater and more persistent in BALB/cJ than in A/J macrophages, whereas the levels and kinetics of IL-1, TNF-alpha, and TF mRNA following LPS stimulation were identical in macrophages from both strains of mice. Levels of production of PGE2 by MHV-3-stimulated macrophages from resistant and susceptible mice were equivalent; however, the time course for induction of PGE2, differed, but the total quantity of PGE2 produced was insufficient to inhibit induction of musfiblp, a procoagulant known to correlate with development of fulminant hepatic necrosis in susceptible mice. These results demonstrate marked differences in production of inflammatory mediators to MHV-3 infection in macrophages from resistant A/J and susceptible BALB/cJ mice, which may explain the marked hepatic necrosis and fibrin deposition and account for the lethality of MHV-3 in susceptible mice.

Plasma procoagulant activity inducing factor (PIF) is a spontaneously occurring, potent inducer of macrophage procoagulant activity (PCA) in the male BXSB murine model of systemic lupus erythematosus. The physical characteristics of PCA induction by PIF, aggregated mouse IgG, and lipopolysaccharide (LPS) were compared. Both aggregated IgG and PIF-induced PCA were heat, acid and alkali sensitive. In contrast, LPS-induced PCA was heat resistant and only partially acid and alkali sensitive. Plasma containing PIF was fractionated on Sephacryl S-300. The PIF activity localized to the first protein peak, molecular weight 400,000 to 900,000 daltons. Analysis of peak 1 by an enzyme-linked immunosorbent assay showed the presence of IgM, IgA and IgG. This was confirmed by Western blot analysis using 125I-labelled goat anti-mouse IgM, IgA and IgG probes. The concentration of PIF increased with Sephacryl S-300 chromatography and was reduced by removal of IgG, but not IgA or IgM by affinity chromatography. Peak 1 did not contain DNA as revealed by ethidium bromide staining. Thus, IgG from the plasma of BXSB mice, a strain which develops lupus nephritis, stimulates macrophages to express PCA, accounting for PCA induction in the BXSB model of murine lupus.

Placental thrombosis is a prominent feature in patients with unexplained recurrent fetal loss. To determine whether induction of monocyte procoagulant activity might be a relevant mechanism for unexplained recurrent fetal loss, peripheral blood mononuclear cells isolated from normal healthy controls were cocultured with (a) sera from normal healthy controls (n = 16), (b) sera from habitual aborters (n = 41), and (c) lipopolysaccharide as a positive control. Sera from three patients were fractionated on Sephracryl S-300 and the inducing molecule(s) characterized. Sera from normal healthy controls failed to induce procoagulant activity above basal levels of 21 +/- 4.6 mU/10(5) peripheral blood mononuclear cells. Of the sera from 41 habitual aborters examined 26 (63%) induced procoagulant to a mean value of 410 +/- 48 mU/10(5) peripheral blood mononuclear cells (P0.01). Sera from 15 patients failed to augment procoagulant activity. The induction of procoagulant activity was maximal after 6 hr of incubation and was lymphocyte dependent. Fractionation of serum from the three patients on Sepharcryl S300 revealed the procoagulant activity (PCA)-inducing factor(s) to have a molecular weight of between 300,000 and 800,000 Da. The serum factor was found to be heat, alkaline, and acid sensitive. Both anti-IgM and anti-IgA immunoabsorbents reduced the PCA-inducing factor. We conclude that IgM and IgA from some patients with unexplained recurrent fetal loss are capable of inducing procoagulant activity and could contribute to the development of placental microthrombi and infarction, prominent features of this syndrome.

Murine hepatitis virus strain 3 (MHV) infection produces a strain dependent spectrum of disease1,2. Mice of the A and SJL strain are fully resistant to the effects of viral infection, whereas mice of semisusceptible strains (C3H/HeJ) develop acute hepatitis which progesses to varying degrees of chronic hepatitis. Mice of fully susceptible strains (Balb/cJ, C57BL/6J) die of fulminant hepatic failure. The resistance of the A strain mice cannot be explained by a lack of a cellular receptor for MHV as viral binding occurs on cells from these resistant mice3,4. Furthermore, restriction of viral replication does not explain resistance, as resistance occurs despite the presence of active viral replication in the resistant A strain. Bang and Warwick previously reported that differences in viral replication in cultures of macrophages reflects the relative susceptibility/resistance (S/R) to viral infections5. However, several laboratories have shown that MHV replicates in cultures of macrophages, endothelial cells and hepatocytes from both susceptible and resistant animals4,6–8although viral replication occurs to a lesser degree in cells derived from resistant animals6,9. Thus, absolute differences in viral replication do not account for the strain dependent S/R pattern seen in MHV infection.

A total 166 first cadaveric renal allograft recipients were randomly assigned to receive either rabbit antithymocyte serum (RATS) (n = 83) or OKT3 (n = 83) for 10 to 14 days after transplant as prophylaxis against rejection. Both groups were similar with respect to age, sex, donor age, diabetes, time on dialysis, panel-reactive antibody, HLA matching, and transfusion before transplantation. All patients were followed for 1 year after transplantation. A comparison of the rejection rates between the 2 groups of patients showed that patients receiving OKT3 had a rate of first rejection 1.87 times higher than those receiving RATS (95% confidence interval 1.18-2.8, P = 0.007). Twenty-five steroid-resistant rejections occurred in OKT3-treated patients as compared with 12 in the RATS-treated group (P < 0.05). There was no significant difference in early or late renal function between the 2 groups of patients. Actuarial 1-year graft survival for the RATS group was 78% and for the OKT3 group, 80.7% (P = NS). Actuarial 1-year patient survival was similar: 89.5% in the RATS group and 94.6% in the OKT3 group (P = NS). Total hospitalization time was 29.8 +/- 19.9 days for RATS vs. 39.5 +/- 22.1 days for those treated with OKT3 (P < 0.006). A number of infections were observed but there were no significant differences between the groups. We conclude that RATS provides better prophylaxis than OKT3 in first cadaveric renal transplants because it is associated with fewer rejection episodes, less hospitalization, and no additional morbidity or mortality.

The continuing effort to improve detectors for low light applications has resulted in the development of imaging photon counting detectors. One such device is the MAMA (Multi- Anode Microchannel Array) detector fabricated by Ball Aerospace. This paper provides a brief overview of the STIS (Space Telescope Imaging Spectrograph) MAMA detector and a detailed description of the analog signal processing electronics. The analog signal processing circuit is built using two unique Ball Aerospace and Communications Group (BACG) designed ASICs (application specific integrated circuits). Each MAMA detector analog signal processing channel uses a pair of the ASICs. The first is a charge to voltage amplifier and the second a voltage discriminator. The amplifier has lower noise and higher speed than previous BACG designs. Its first stage gain bandwidth is 10 GHz with an equivalent input noise voltage of about 1 nV per root hertz. It has a single ended input and differential output to drive the voltage discriminator. The voltage discriminator ASIC has differential input and single ended, CMOS compatible, output. The system has a 120 ns pulse pair resolution with 21 ns amplitude dependent timing uncertainty. Calculated false event rate, for prototype devices, is 1 count in 107 sec with 100 pF detector capacitance and a 20,000 electron threshold. Counting rates greater than 1 million per second per channel can be accommodated. Both ASICs have much lower power consumption than previous discrete designs. The ASIC process used allows the fabrication of extremely robust devices while reducing the total number of parts.© (1993) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The results of renal transplantation have improved remarkably over the past 10 years; one-year graft survival is in the range of 80–85% and one-year patient survival is around 95% [1]. As a consequence, the number of patients with end-stage renal failure wanting a renal transplant has increased substantially, but unfortunately cadaveric organ donation is on a plateau. As a result, the list of patients waiting and the waiting time for cadaveric organs have increased substantially. The average waiting time for an adult kidney in the City of Toronto is now about 24 months [2]. As cadaveric kidneys become even more precious, many have expressed concern that the organs be reserved for those who can benefit most. After his recent review, Kjellstrand suggested that, more than any other variable, age influences the likelihood of being transplanted; older patients are far less likely to received a transplant in the United States and a number of other developed countries [3]. These considerations, and the patient’s wish to understand therapeutic options, have lead many groups to examine the results of renal transplantation in older individuals. While, in general, such patients should receive therapy for end-stage renal failure, many fear that transplantation would be associated with a higher mortality. In fact, the reverse is true: in older patients in both the European and Canadian series, the death rate is substantially less for transplanted patients compared to those on dialysis [4, 5]. On the other hand, these statistics must be interpreted with caution because patients with serious extrarenal disease are less likely to be offered transplants, more likely to remain on dialysis, and more likely to die.