Optic neuritis in Hong Kong: a 1-year follow-up study.

To investigate the etiology and prevalence of optic neuritis in a Chinese population. This was a single centre prospective cohort study. Consecutive patients with either a first or recurrent attack of optic neuritis from November 2010 to December 2011 were recruited from a district hospital in Hong Kong Special Administrative Region, China. All patients underwent serology testing for NMO (neuromyelitis optica) IgG; oligoclonal bands from lumbar puncture; computer tomography and contrast magnetic resonance imaging (MRI) of the brain and orbit as well as visual field; and optical coherence tomography testing. Patients were followed up for 1 year after the initial attack. 30 optic neuritis subjects were recruited. 73.3 % (22/30) remain as clinical isolated syndrome (CIS) after 1-year follow-up. 10 % (3/30) patients developed multiple sclerosis. 10 % (3/30) were diagnosed with NMO and 6.7 % (2/30) with NMO-spectrum disorder. The majority of acute unilateral optic neuritis in Chinese was CIS in origin although a fraction does progress to develop MS or NMO-related disorders. Clinicians should be aware of the associations and offer appropriate systemic workups.

Longitudinal Changes in Retinal Nerve Fibre Layer Thickness after an Isolated Unilateral Retrobulbar Optic Neuritis: 1-Year Results.

The objective of this study was to investigate the longitudinal changes in retinal nerve fibre layer (RNFL) thickness 1 year after an episode of unilateral acute optic neuritis. This prospective cohort study recruited consecutive patients with a first episode of isolated, unilateral acute optic neuritis from October 2010 to June 2013. RNFL thickness of the attack and normal fellow eyes was measured by optical coherence tomography on presentation and 3, 6, and 12 months post attack in both the treatment and non-treatment groups. The treatment group consisted of subjects that opted for systemic steroids to hasten recovery time. In 20 subjects, 11 received systemic steroids and 9 were treated conservatively. The baseline RNFL thickness was similar in the attack and fellow eyes (p ≥ 0.4). Progressive RNFL thinning was seen in the attack eye over the 12-month period, with significant differences for baseline versus 3 months; baseline versus 12 months; and 3 versus 12 months (all p < 0.0001). At 12 months, the attack eye had a thinner average RNFL than the fellow eye (100.9 ± 6.1 versus 107.3 ± 5.5 µm; p = 0.002). The 12-month RNFL was similar between the treatment and non-treatment groups (p ≥ 0.6). A single episode of optic neuritis triggered an accelerated, progressive RNFL thinning up to 6 months post attack. Initial treatment with systemic steroids did not seem to alter the degree of RNFL loss at 12 months.

Prospective study on retinal nerve fibre layer thickness changes in isolated unilateral retrobulbar optic neuritis.

PURPOSE: To investigate the retinal nerve fibre layer (RNFL) thickness after unilateral acute optic neuritis using optical coherence tomography (OCT). PATIENTS AND METHODS: This prospective cohort study recruited consecutive patients with a first episode of isolated, unilateral acute optic neuritis. RNFL thickness and visual acuity (VA) of the attack and normal fellow eye were measured at presentation and 3 months in both the treatment and nontreatment groups. RESULTS: 11 subjects received systemic steroids and 9 were treated conservatively. The baseline RNFL thickness was similar in the attack and fellow eye (P ≥ 0.4). At 3 months, the attack eye had a thinner temporal (P = 0.02) and average (P = 0.05) RNFL compared to the fellow eye. At 3 months, the attack eye had significant RNFL thinning in the 4 quadrants and average thickness (P ≤ 0.0002) compared to baseline. The RNFL thickness between the treatment and nontreatment groups was similar at baseline and 3 months (P ≥ 0.1). Treatment offered better VA at 3 months (0.1 ± 0.2 versus 0.3 ± 0.2 LogMAR, P = 0.04). CONCLUSION: Generalized RNFL thinning occurred at 3 months after a first episode of acute optic neuritis most significantly in the temporal quadrant and average thickness. Visual improvement with treatment was independent of RNFL thickness.

Acute ischaemic stroke during short-term travel to high altitude.

This is a case report of a young healthy adult who had acute cerebral infarcts after a short-term visit to high-altitude area. He developed acute onset of right-sided limb weakness and right hemianopia a few hours after arrival at an altitude of 3600 m by train. He was initially treated for high-altitude cerebral oedema but later computed tomography and magnetic resonance imaging confirmed ischaemic infarcts in the medial left occipital lobe and left thalamus. Subsequent investigations, including laboratory tests and imaging including an echocardiogram, revealed no culpable predisposing factors.

The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation--a single-centre experience.

OBJECTIVE: To describe the natural history of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) after liver transplant, the predictors of PSC and IBD recurrence, and the interaction of these disease processes. METHODS: Data regarding patients who received liver transplants for PSC at the University of Alberta Hospital (Edmonton, Alberta) from 1989 to 2006 were retrospectively reviewed. Recurrent PSC (rPSC) was defined by the Mayo Clinic criteria. Cox proportional hazards modelling and Kaplan-Meier statistics were used. RESULTS: Fifty-nine patients were studied, with a median follow-up of 68 months. A total of 71.2% of patients were diagnosed with IBD pretransplant. Clinical IBD severity post-transplant compared with severity pretransplant was unchanged in 67%, worse in 26.5% and improved in 6.1% of patients. Twenty-five per cent of patients developed rPSC posttransplant. The occurrence of at least one episode of acute cellular rejection (hazard ratio 5.7; 95% CI 1.3 to 25.8) and cytomegalovirus mismatch (hazard ratio 4.2; 95% CI 1.1 to 15.4) were found to be significant predictors of rPSC. Although not statistically significant, there was no rPSC in patients without pre- or post-transplant IBD, and in only one patient with a colectomy. Actuarial patient survival rates at one, five and 10 years posttransplant were 97%, 86% and 79%, respectively. Although a significant proportion of patients experienced worsening IBD post-transplantation, the presence or severity of IBD did not influence rPSC or patient survival. CONCLUSION: Acute cellular rejection and cytomegalovirus mismatch were both identified as independent predictors of rPSC. The impact of steroids and the ideal immunosuppressive regimen for the control of both IBD and PSC post-transplant requires further examination in prospective studies.

A shorter duration of pre-transplant abstinence predicts problem drinking after liver transplantation.

OBJECTIVES: Liver transplantation for alcoholic liver disease (ALD) can be complicated by abusive or "problem" drinking (PD) after transplant. There are limited data for evaluating the effect of pre-transplant abstinence on post-transplant PD. Few existing studies have included a substantial number of patients with co-existing causes of hepatic dysfunction, and the effect of PD on survival in recent European studies has been controversial. We hypothesized that a longer duration of pre-transplant abstinence would lead to less PD after transplantation. Accordingly, the objectives of this study are to analyze a North American cohort of patients with ALD with or without a secondary diagnosis of liver disease to estimate (i) the incidence of PD and its predictors, as well as (ii) the effect of PD on patient survival. METHODS: We conducted a retrospective review of all patients transplanted for ALD surviving for more than 3 months after transplant. PD was defined as either any drinking (AD) to the point of intoxication or drinking above the toxic threshold (>20 g/day in women and >40 g/day in men) on at least two separate occasions. We used Cox's proportional hazards regression to estimate risk ratios and Kaplan-Meier curves with log-rank analysis to compare survival. RESULTS: Of 213 eligible transplant patients, 42 were excluded. Of the 171 remaining patients, 78% were male; mean age was 52 years. Overall 53% of patients had co-existing causes of liver dysfunction. The mean follow-up was 64.8 months. The median pre-transplant abstinence was 19 months. In all patients, the risk of AD was 24% and PD 13%. Pre-transplant abstinence duration was the only independent predictor of PD after transplant. For every 1-month increment in pre-transplant abstinence, there was a 5% decrease in the adjusted relapse rate. There was no survival difference noted between problem drinkers and non-drinkers. CONCLUSIONS: The risk of PD decreased with increasing pre-transplant abstinence. Our data support pre-transplant abstinence as an important predictor of post-transplant recidivism; however, the optimal period of abstinence remains unclear. Patients with <18 months of abstinence may benefit from more intensive follow-up and rehabilitation after transplant.

The effect of 1 month of therapy with midodrine, octreotide-LAR and albumin in refractory ascites: a pilot study.

BACKGROUND: The pathogenesis of refractory ascites (RA) is linked to splanchnic vasodilation. We hypothesized that a combination of midodrine, octreotide long-acting release (LAR) and albumin would result in increased natriuresis, better control of ascites and an improvement in renal function in patients with RA+/-Type 2 hepatorenal syndrome. METHODS: A prospective pilot study in patients with RA as defined by the International Ascites Club. Consecutive patients received an intramuscular injection of octreotide-LAR, 50 g of albumin three times per week and midodrine titrated to increase the systolic blood pressure for 1 month. RESULTS: Ten patients with RA were enrolled and eight with complete data to 1 month post-treatment were included in the analysis. There was no change in renal function but there was a trend towards a reduction in the volume of ascites removed by paracentesis (P=0.08) and a significant reduction in the plasma renin (P=0.01) and aldosterone concentrations (P=0.01). Interestingly, there was a transient worsening in the model for end-stage liver disease (MELD) score (P=0.01). The deterioration in MELD was completely reversible after discontinuation of therapy. CONCLUSIONS: To our knowledge, this is the first study of prolonged midodrine, octreotide and albumin therapy in RA. We observed a significant reduction in the plasma renin and aldosterone concentrations and a trend towards a reduction in the volume of ascites removed by paracentesis without an effect on renal function. The beneficial effects are at the expense of a reversible deterioration in the MELD score. Large controlled trials are needed before this therapy can be routinely recommended.

Effects of probiotic therapy on portal pressure in patients with cirrhosis: a pilot study.

BACKGROUND: Recent literature has supported the role of bacterial translocation as a mediator of splanchnic vasodilatation and portal hypertension. The objective of this study was to determine whether the probiotic VSL#3 would reduce portal pressure in patients with cirrhosis. METHODS: Eight patients with compensated or very early decompensated cirrhosis and hepatic venous pressure gradient (HVPG) >10 mmHg, received 2 months of VSL#3 (3600 billion bacteria daily). The HVPG, intestinal permeability, endotoxin, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, renin and aldosterone were measured at baseline and study end. RESULTS: There was no change in the HVPG or intestinal permeability from baseline to study end but there was a trend to reduction in plasma endotoxin (P=0.09), a mild but significant increase in serum TNF-alpha (P=0.02) and a significant reduction in plasma aldosterone (P=0.03). CONCLUSIONS: Within the limitations of small sample size, there does not appear to be a benefit of probiotic therapy for portal pressure reduction in patients with compensated or early decompensated cirrhosis. The reductions in endotoxin and aldosterone suggest possible beneficial effects of probiotics for this patient population. The clinical significance of the small but unexpected increase in TNF-alpha is unclear. Future studies are planned in patients with decompensated cirrhosis.

De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects.

BACKGROUND: We report long-term outcomes and side effects after transplantation for hepatocellular carcinoma (HCC) using de novo, sirolimus-based immunosuppression (IS). METHODS: A total of 70 patients with HCC (mean age: 54.4+/-7 years, female/male: 12/58) were transplanted and included in the study. Immunosuppression included de novo sirolimus, low-dose calcineurin inhibitor for 6 to 12 months, with short-course (3 months) or no steroids. RESULTS: After 49 months-median follow-up, eight patients have experienced an HCC recurrence, 2 of 34 when Milan criteria were respected (6%) and 6 of 36 when beyond Milan criteria (17%). One- and 4-year tumor-free survivals were 85 and 73%, when Milan criteria were respected and 82% and 75% when they were not, respectively. (P=0.9). After recurrence, mean survival was 23+/-28 months. Half (35 of 70) of the patients experienced a rejection. Incisional hernia (24 of 70, 34%), wound infection (12 of 70, 17%), anemia (39 of 70, 56%), leucopenia (39 of 70, 56%), high triglyceride (43 of 70, 61%), and cholesterol (28 of 70, 40%) levels and mouth ulcers (20 of 70, 29%) were among the most frequent complications. No hepatic artery thrombosis was observed. CONCLUSIONS: These data suggest that de novo sirolimus-based immunosuppression is associated with satisfactory outcomes after transplantation, even in selected patients beyond Milan criteria. The protocol has proven safe, with an acceptable side-effect profile. This study supports the conduct of larger randomized trials investigating sirolimus after transplantation for HCC.

Enhancement of T helper type 1 immune responses against hepatitis B virus core antigen by PLGA nanoparticle vaccine delivery.

Currently, there is a need for therapeutic vaccines that are effective in inducing robust T helper type 1 (Th1) immune responses capable of mediating viral clearance in chronic hepatitis B infection. Hepatitis B therapeutic vaccines were designed and formulated by loading the hepatitis B core antigen (HBcAg) into poly(D,L-lactic-acid-co-glycolic acid) (PLGA) nanoparticles with or without monophospholipid A (MPLA), a Th1-favoring immunomodulator. These particles were around 300 nm in diameter, spherical in shape and had approximately 50% HBcAg encapsulation efficiency. A single immunization with a vaccine formulation containing (MPLA+HBcAg) coformulated in PLGA nanoparticles induced a stronger Th1 cellular immune response with a predominant interferon-gamma (IFN-gamma) profile than those induced by HBcAg alone, free (HBcAg+MPLA) simple mixture or HBcAg-loaded nanoparticles in a murine model. More importantly, the level of HBcAg-specific IFN-gamma production could be increased further significantly by a booster immunization with the (HBcAg+MPLA)-loaded nanoparticles. In summary, these results demonstrated that codelivery of HBcAg and MPLA in PLGA nanoparticles promoted HBcAg-specific Th1 immune responses with IFN-gamma production. These findings suggest that appropriate design of the vaccine formulation and careful planning of the immunization schedule are important in the successful development of effective HBV therapeutic vaccines.

Mechanisms of ocular toxicity using the in vitro bovine lens and sodium dodecyl sulfate as a chemical model.

Previous work using the in vitro bovine lens as a model has shown a correlation between toxicity and lens optical function and showed much higher sensitivity in detecting irritancy of several surfactants at much lower concentrations than the Draize score. In the current study, cultured bovine lenses were used to study the effects of the surfactant sodium dodecyl sulfate (SDS) on lens optical properties and mitochondrial integrity. Bovine lenses were exposed to SDS (0.1 to 0.00625%) for 30 min and cultured for 24 h. Compared to controls (n = 17), loss of sharp focus was evident immediately following exposure to 0.1% SDS (n = 14, p < 0.0001). At 24 h loss of sharp focus became evident in all groups. Loss of lens transparency, significant increase in lens wet weight, and axial length were seen 24 h postexposure in lenses treated with 0.1 to 0.025% SDS. Confocal analysis 24 h postexposure showed SDS concentration-dependent decrease in number and length of the mitochondria in lens epithelial and superficial cortical fiber cells. The results of this study show a correlation between lens optical properties and metabolic function and together provide a sensitive in vitro model of ocular chemical toxicity. Results of confocal analysis suggest that the mitochondrial integrity of the superficial cortical fiber cells is most sensitive to damage caused by SDS. The results further suggest that recovery of lens metabolic function is necessary for the recovery of lens optical properties.

Hepatology and the Canadian gastroenterologist: interest, attitudes and patterns of practice: results of a national survey from the Canadian Association of Gastroenterology.

BACKGROUND: Hepatology has emerged as a subspecialty distinct from gastroenterology. Despite this, there is no formal certification examination or accredited training program, and training remains combined with gastroenterology. AIM: To determine attitudes, perceptions and patterns of practice with respect to liver disease among Canadian gastroenterologists. METHODS: A survey questionnaire was distributed to clinician gastroenterologists who are members of the Canadian Association of Gastroenterology. The responses of subgroups of respondents were compared by univariate and multivariate statistical techniques. RESULTS: Hepatologists constituted 20 of 201 respondents, the rest identifying themselves as gastroenterologists. Among gastroenterologists, liver disease constituted 10% of in- and out-patient practice. Despite this, 85% of gastroenterologists maintain an interest in hepatology, 49% perform liver biopsies, 60% treat hepatitis C, and 54% treat hepatitis B. In all of these areas, university-based gastroenterologists were consistently less likely than community-based gastroenterologists to maintain an interest and practice in hepatology, a finding that remained statistically significant on multivariate analysis. With regard to hepatology training, 90% of hepatologists and 94% of gastroenterologists felt that hepatology training should remain combined with gastroenterology, although 55% of hepatologists felt that current training was adequate compared with 79% of gastroenterologists, who were satisfied with the status quo. CONCLUSIONS: Hepatology remains relevant and important to Canadian gastroenterologists, especially those who have community-based practices. Canadian gastroenterologists and hepatologists are not in favour of separating hepatology training from existing gastroenterology training programs, although hepatologists feel that the current level of training is suboptimal.

Alkaline biosolids and EDTA for phytoremediation of an acidic loamy soil spiked with cadmium.

A greenhouse experiment was conducted to investigate the growth of Brassica juncea and Cd phytoextraction in a mimicked Cd contaminated acidic loamy soil amended with alkaline biosolids, prepared from sewage sludge and coal fly ash, in the presence and absence of EDTA at 2 mmol kg(-1). The acidic loamy soil was spiked with 0, 5, 20, 50 and 100 mg Cd kg(-1) in the form of CdCO(3) and then amended with 4% alkaline biosolids (w/w). Alkaline biosolids and 0.12% CaCO(3) amendments resulted in a higher biomass than unamended soil spiked with 20 mg kg(-1) Cd where plants did not survive and of the two amendments, alkaline biosolids amendment had higher plant dry weight yield and phytoextraction of Cd. Adding 2 mmol kg(-1) EDTA to alkaline biosolids amended soil significantly increased the solubility of Cd ions by 9- to 29-fold, but plant Cd accumulation decreased by a factor of 24-48%. The results indicate that alkaline biosolids amendment is an effective approach for assisting growth of B. juncea and phytoextraction of Cd from the contaminated acidic loamy soil, but further application of chelating agents did not enhance the phytoextraction efficiency of Cd.

Chronic hepatitis C in Western Canada: a survey of practice patterns among gastroenterologists in Alberta and British Columbia.

OBJECTIVE: To survey gastroenterologists in British Columbia and Alberta with regard to awareness of chronic hepatitis C virus (HCV) management and practice patterns among physicians who treat and do not treat HCV-infected patients. METHODS: An anonymous two-page mail survey was distributed to actively practicing adult gastroenterologists in British Columbia and Alberta. Among physicians who treated HCV patients, respondents answered assessment of fibrosis pretreatment, measurement of rapid virological response, prescription of protease inhibitors (PIs), barriers to using these agents and referral patterns. For those who did not treat HCV, referral of patients for treatment and to whom was assessed. RESULTS: Seventy-seven of 166 individuals completed the survey (46% response rate). Most (49%) practiced in academic or large community (42%) settings. Chronic liver disease comprised <25% of individual practice in 71%. Forty-eight (62%) treated HCV and two-thirds prescribed a PI. Barriers to prescription included unfamiliarity (six of 16), lack of allied health (five of 16) and few suitable patients (seven of 16). Pretreatment liver biopsy was performed by 33% (16 of 48) and 69% (33 of 48) used noninvasive measures. Rapid virological response was measured in 83% (40 of 48). Referral patterns changed in 46% (22 of 48) of physicians who treated HCV. All respondents who did not treat HCV referred patients for consideration, with 90% (26 of 29) made to hepatologists. CONCLUSIONS: Chronic liver disease comprised <25% of practice in the majority of surveyed respondents. Among those who treated HCV, one-third have not prescribed a PI. Barriers to prescription and referral pattern changes are noted by those currently treating patients with HCV infection.

Prostate contouring variation: can it be fixed?

PURPOSE: To assess whether an education program on CT and MRI prostate anatomy would reduce inter- and intraobserver prostate contouring variation among experienced radiation oncologists. METHODS AND MATERIALS: Three patient CT and MRI datasets were selected. Five radiation oncologists contoured the prostate for each patient on CT first, then MRI, and again between 2 and 4 weeks later. Three education sessions were then conducted. The same contouring process was then repeated with the same datasets and oncologists. The observer variation was assessed according to changes in the ratio of the encompassing volume to intersecting volume (volume ratio [VR]), across sets of target volumes. RESULTS: For interobserver variation, there was a 15% reduction in mean VR with CT, from 2.74 to 2.33, and a 40% reduction in mean VR with MRI, from 2.38 to 1.41 after education. A similar trend was found for intraobserver variation, with a mean VR reduction for CT and MRI of 9% (from 1.51 to 1.38) and 16% (from 1.37 to 1.15), respectively. CONCLUSION: A well-structured education program has reduced both inter- and intraobserver prostate contouring variations. The impact was greater on MRI than on CT. With the ongoing incorporation of new technologies into routine practice, education programs for target contouring should be incorporated as part of the continuing medical education of radiation oncologists.

Half-life of the duck hepatitis B virus covalently closed circular DNA pool in vivo following inhibition of viral replication.

Covalently closed circular DNA (cccDNA) is a crucial intermediate in the replication of hepadnaviruses. We inhibited the replication of duck hepatitis B virus in congenitally infected ducks with a combination of lamivudine and a dideoxyguanosine prodrug. Inhibition of viral replication should prevent renewal of the cccDNA pool, and its decay was measured in liver biopsy samples collected over a 5-month period. In three ducks, the cccDNA pools declined exponentially, with half-lives ranging from 35 to 57 days. In two others, the pools declined exponentially for about 70 days but then stabilized at about 6 copies/diploid genome. The selection of drug-resistant virus mutants is an unlikely explanation for this unexpected stabilization of cccDNA levels. Liver sections stained for the cell division marker PCNA showed that animals in which cccDNA loss was continuous had significantly greater numbers of PCNA-positive nuclei than did those animals in which cccDNA levels had plateaued.

Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma.

An increasing number of patients with hepatocellular carcinoma (HCC) are undergoing evaluation for listing for liver transplantation. Criteria for selection require ongoing review for suitability. A consecutive series of 40 patients with HCC within the standard Milan criteria (single tumors n = 19 < 5 cm, or up to 3 tumors < 3 cm) and beyond (Extended Criteria; single tumors n = 21 < 7.5 cm, multiple tumors < 5 cm) underwent liver transplant with a sirolimus-based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitors and steroids. At 44.3 +/- 19.3 months (mean +/- standard deviation) follow-up, 1- and 4-year survivals (Kaplan-Meier) are 94.1 +/- 5.7% and 87.4 +/- 9.3%, in the Milan group, respectively, and 90.5 +/- 6.4% and 82.9 +/- 9.3% in the Extended Criteria group, respectively. Five patients died during follow-up, only 1 from recurrent HCC. Five tumor recurrences have occurred at median 17 (mean 22 +/- 17) months posttransplant, 1 in the Milan group and 4 in the Extended Criteria group. Median survival in the patients with recurrent tumor is 42 months (mean 45 +/- 25), and the median postrecurrence survival is 15.5 months (mean 23 +/- 16). The rate of patients who were alive and free of tumor at 1 and 4 years is 94.1 +/- 5.7% and 81.1 +/- 9.9%, respectively, in the Milan group and is 90.5 +/- 6.4% and 76.8 +/- 10.5%, respectively, in the Extended Criteria group. Five patients had sirolimus discontinued for toxicity, while 24 of 35 surviving patients have sirolimus monotherapy immunosuppression. In conclusion, the Milan criteria for liver transplantation in the presence of HCC can be carefully extended without compromising outcomes. This sirolimus based immunosuppression protocol appears to have beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity.

Late acute rejection after liver transplantation: the Western Canada experience.

Acute rejection usually occurs within 3 months posttransplantation. Most centers reduce immunosuppression over 6 to 12 months to minimize opportunistic infection, malignancy, and drug toxicity. Pretransplant disease and low immunosuppression have been reported in association with late acute rejection (LAR). The objective of this study was to determine the incidence, predictive factors, and outcomes of LAR via retrospective review of adult liver transplant recipients in Western Canada from 1989 to 2000. LAR was defined as biopsy-proven acute rejection occurring more than 180 days posttransplantation. Patient characteristics, immunosuppression, and outcome were determined. Both a univariate and multiple logistic regression analysis were performed. LAR occurred in 97 (23%) of 415 patients more than 180 days posttransplantation. Median follow-up was 402 days (range, 180 to 3137 days); 79% of LAR episodes were graded mild. At the time of LAR, 33% were on a steroid taper. A total of 73% of LAR episodes were treated with pulse intravenous steroids, and 5% were steroid-resistant. In the univariate analysis, patients undergoing transplantation for viral etiologies and older age were associated with less LAR. Immunosuppression was significant in a multiple logistic regression model, but not with a proportional hazards model. On multivariate analysis, only patients undergoing transplantation for viral etiologies remained resistant to LAR (hazard ratio, 0.52; range, 0.34 to 0.93, P = .02). There was a trend toward increased chronic rejection in patients who developed LAR (P = .04). LAR is common and occurs after more than 1 year posttransplantation. Patients undergoing transplantation for viral etiologies seem to have a lower risk of LAR. There may be an increased risk of chronic rejection in those developing LAR.

Structure-based design of nonpeptide inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1).

A novel class of reversible inhibitors of Interleukin-1beta-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure-activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.