Understanding the elevated suicide risk of female soldiers during deployments.

BACKGROUND: The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) has found that the proportional elevation in the US Army enlisted soldier suicide rate during deployment (compared with the never-deployed or previously deployed) is significantly higher among women than men, raising the possibility of gender differences in the adverse psychological effects of deployment. METHOD: Person-month survival models based on a consolidated administrative database for active duty enlisted Regular Army soldiers in 2004-2009 (n = 975,057) were used to characterize the gender × deployment interaction predicting suicide. Four explanatory hypotheses were explored involving the proportion of females in each soldier's occupation, the proportion of same-gender soldiers in each soldier's unit, whether the soldier reported sexual assault victimization in the previous 12 months, and the soldier's pre-deployment history of treated mental/behavioral disorders. RESULTS: The suicide rate of currently deployed women (14.0/100,000 person-years) was 3.1-3.5 times the rates of other (i.e. never-deployed/previously deployed) women. The suicide rate of currently deployed men (22.6/100,000 person-years) was 0.9-1.2 times the rates of other men. The adjusted (for time trends, sociodemographics, and Army career variables) female:male odds ratio comparing the suicide rates of currently deployed v. other women v. men was 2.8 (95% confidence interval 1.1-6.8), became 2.4 after excluding soldiers with Direct Combat Arms occupations, and remained elevated (in the range 1.9-2.8) after adjusting for the hypothesized explanatory variables. CONCLUSIONS: These results are valuable in excluding otherwise plausible hypotheses for the elevated suicide rate of deployed women and point to the importance of expanding future research on the psychological challenges of deployment for women.

Occupational differences in US Army suicide rates.

BACKGROUND: Civilian suicide rates vary by occupation in ways related to occupational stress exposure. Comparable military research finds suicide rates elevated in combat arms occupations. However, no research has evaluated variation in this pattern by deployment history, the indicator of occupation stress widely considered responsible for the recent rise in the military suicide rate. METHOD: The joint associations of Army occupation and deployment history in predicting suicides were analysed in an administrative dataset for the 729 337 male enlisted Regular Army soldiers in the US Army between 2004 and 2009. RESULTS: There were 496 suicides over the study period (22.4/100 000 person-years). Only two occupational categories, both in combat arms, had significantly elevated suicide rates: infantrymen (37.2/100 000 person-years) and combat engineers (38.2/100 000 person-years). However, the suicide rates in these two categories were significantly lower when currently deployed (30.6/100 000 person-years) than never deployed or previously deployed (41.2-39.1/100 000 person-years), whereas the suicide rate of other soldiers was significantly higher when currently deployed and previously deployed (20.2-22.4/100 000 person-years) than never deployed (14.5/100 000 person-years), resulting in the adjusted suicide rate of infantrymen and combat engineers being most elevated when never deployed [odds ratio (OR) 2.9, 95% confidence interval (CI) 2.1-4.1], less so when previously deployed (OR 1.6, 95% CI 1.1-2.1), and not at all when currently deployed (OR 1.2, 95% CI 0.8-1.8). Adjustment for a differential 'healthy warrior effect' cannot explain this variation in the relative suicide rates of never-deployed infantrymen and combat engineers by deployment status. CONCLUSIONS: Efforts are needed to elucidate the causal mechanisms underlying this interaction to guide preventive interventions for soldiers at high suicide risk.

Sociodemographic and career history predictors of suicide mortality in the United States Army 2004-2009.

BACKGROUND: The US Army suicide rate has increased sharply in recent years. Identifying significant predictors of Army suicides in Army and Department of Defense (DoD) administrative records might help focus prevention efforts and guide intervention content. Previous studies of administrative data, although documenting significant predictors, were based on limited samples and models. A career history perspective is used here to develop more textured models. METHOD: The analysis was carried out as part of the Historical Administrative Data Study (HADS) of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). De-identified data were combined across numerous Army and DoD administrative data systems for all Regular Army soldiers on active duty in 2004-2009. Multivariate associations of sociodemographics and Army career variables with suicide were examined in subgroups defined by time in service, rank and deployment history. RESULTS: Several novel results were found that could have intervention implications. The most notable of these were significantly elevated suicide rates (69.6-80.0 suicides per 100 000 person-years compared with 18.5 suicides per 100 000 person-years in the total Army) among enlisted soldiers deployed either during their first year of service or with less than expected (based on time in service) junior enlisted rank; a substantially greater rise in suicide among women than men during deployment; and a protective effect of marriage against suicide only during deployment. CONCLUSIONS: A career history approach produces several actionable insights missed in less textured analyses of administrative data predictors. Expansion of analyses to a richer set of predictors might help refine understanding of intervention implications.

Association between Cognitive Function and Clustered Cardiovascular Risk of Metabolic Syndrome in Older Adults at Risk of Cognitive Decline.

OBJECTIVES: Metabolic syndrome (MetS) represents a cluster of obesity and insulin resistance-related comorbidities. Abdominal obesity, hypertension, elevated triglyceride and glucose levels are components of MetS and may have a negative effect on cognitive function, but few cognitive studies have examined the combined risk severity. We sought to determine which specific cognitive abilities were associated with MetS in older adults at risk of cognitive decline. DESIGN: Cross-sectional study. PARTICIPANTS: 108 AIBL Active participants with memory complaints and at least one cardiovascular risk factor. MEASUREMENTS: Cardiovascular parameters and blood tests were obtained to assess metabolic syndrome criteria. The factors of MetS were standardized to obtain continuous z-scores. A battery of neuropsychological tests was used to evaluate cognitive function. RESULTS: Higher MetS z-scores were associated with poorer global cognition using ADAS-cog (adjusted standardized beta=0.26, SE 0.11, p<0.05) and higher Trail Making B scores (adjusted beta=0.23, SE 0.11, p<0.05). Higher MetS risk was related to lower cognitive performance. CONCLUSION: Combined risk due to multiple risk factors in MetS was related to lower global cognitive performance and executive function. A higher MetS risk burden may point to opportunities for cognitive testing in older adults as individuals may experience cognitive changes.

Review article: the evidence that vancomycin is a therapeutic option for primary sclerosing cholangitis.

BACKGROUND AND AIMS: PSC is an autoimmune biliary inflammatory disorder that is often associated with inflammatory bowel disease (IBD), with 50%-75% of patients with PSC having coexisting IBD, most commonly ulcerative colitis. Currently, no medical therapies have been shown to improve the disease course or slow its progression. However, ongoing research has resulted in a growing interest in the use of antibiotics for treatment of PSC, of which vancomycin is the most studied. In this review, we summarise the current evidence on the use of vancomycin in PSC and comment on future research areas of interest. METHODS: A comprehensive PUBMED and EMBASE literature search for articles on vancomycin, PSC, therapeutic options and microbiome was performed. RESULTS: Two randomised clinical trials, three case series and two case reports were included in the study. These include uncontrolled data from at least 98 patients that include promising improvements in biochemistry and imaging. Optimal dosing regimens are unclear. CONCLUSION: Vancomycin is one of the most studied antibiotics used in the treatment of PSC with promising results. There is not currently sufficient evidence to support treatment recommendations. Further research is needed to establish if vancomycin is a PSC treatment.

PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis.

PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3Kδi. Here we characterize the molecular mechanisms responsible for PI3Kδi-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3Kδi-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (Eµ-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3Kδi imparted significant therapeutic responses in Eµ-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim-/- Eµ-Tcl1 Tg leukemias demonstrated resistance to PI3Kδi-induced apoptosis were refractory to PI3Kδi in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3Kδi, both alone and in combination therapy regimes.

BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma.

Genetic recombination during B-cell development regularly results in the generation of autoreactive, potentially pathogenic B-cell receptors (BCRs). Consequently, multiple mechanisms link inappropriate BCR specificity to clonal deletion. Similar pathways remain in malignant B cells, offering the potential for targeting BCR signaling. Recently, small molecule inhibitors have realized this potential and, therefore, a deeper understanding of BCR-induced signaling networks in malignant cells is vital. The BH3-only protein Bim has a key role in BCR-induced apoptosis, but it has long been proposed that additional BH3-only proteins also contribute, although conclusive proof has been lacking. Here, we comprehensively characterized the mechanism of BCR-induced apoptosis in Eµ-Myc murine lymphoma cells. We demonstrate the upregulation of Bim, Bik, and Noxa during BCR signaling in vitro and that intrinsic apoptosis has a prominent role in anti-BCR antibody therapy in vivo. Furthermore, lymphomas deficient in these individual BH3-only proteins display significant protection from BCR-induced cell death, whereas combined loss of Noxa and Bim offers enhanced protection in comparison with loss of Bim alone. Some but not all of these effects were reversed upon inhibition of Syk or MEK. These observations indicate that BCR signaling elicits maximal cell death through upregulation of multiple BH3-only proteins; namely Bim, Bik, and Noxa.

Identification of serotonin from rabbit upper stomach as a stimulant of in vitro gallbladder contraction.

Using an in vitro rabbit gallbladder bioassay, the distribution and identification of bioactive substances in rabbit gastrointestinal tract were investigated. Comparison of the bioactivities of tissue extracts before and after cholecystokinin was removed by affinity chromatography demonstrated that the distributions of cholecystokinin and non-cholecystokinin substances were different. While cholecystokinin bioactivity per g of tissue was highest in the duodenum, non-cholecystokinin bioactivity was greatest in the upper stomach. The biochemical properties of the non-cholecystokinin substance in the upper stomach could not be distinguished from those of serotonin. These included molecular weights of 176, identical ultraviolet spectra, similar nuclear magnetic resonance spectra, and co-chromatography in HPLC. By weight, serotonin had 1/6th of the bioactivity of cholecystokinin octapeptide. We conclude that the principal gallbladder-contracting substance in rabbit upper stomach is serotonin.

Liver transplantation in Langerhans' cell histiocytosis (histiocytosis X).

Two children with biopsy-proven LCH underwent successful hepatic transplantation for end-stage liver disease. These patients were thought not to have active LCH disease at the time of transplantation, although one had developed a new osteolytic lesion a few months before the operation and the other had suspicious osteolytic lesions at the time of transplantation. The histologic examination of the excised liver showed features consistent with primary sclerosing cholangitis. The two patients had an excellent recovery with no evidence of progression of LCH or recurrence of the underlying disease in the hepatic allograft at 1 and 3 years after organ transplantation.

Exercise and weight control in sedentary overweight men: effects on clinic and ambulatory blood pressure.

OBJECTIVE: To examine whether restriction of caloric intake and exercise of vigorous intensity can independently and additively influence clinic and ambulatory blood pressures in sedentary overweight men. DESIGN: Sixty subjects aged 20-50 years were randomly allocated either to continue their normal caloric intake or to restrict it by 4186-6279 kl/day, with 15% provided by protein, 30% by fat and 55% by carbohydrate, for 16 weeks. Within each of these groups subjects were further randomly allocated either to a control light intensity programme of exercise or to a vigorous intensity programme of exercise for 30 min three times a week. The light exercise group performed stationary cycling against no resistance, flexibility exercises and slow walking. The vigorous intensity group cycled on an ergometer at 60-70% of maximum their workload. RESULTS: Fifty-one subjects completed the study. Their maximal oxygen uptake was increased by approximately 24% with vigorous exercise but did not change with light exercise. Caloric intake restriction led to a significant loss of body mass of 9.5 kg (95% confidence interval 7.6-11.3), whereas vigorous exercise had no effect. Restriction of caloric intake reduced supine clinic systolic and diastolic blood pressures significantly by 5.6 (2.3-8.9) and 2.4 mmHg (0.4-4.2), respectively. Relative to the control light exercise group, exercise of vigorous intensity exercise had no significant effect on clinic blood pressure. In contrast, time series analysis revealed that both caloric intake restriction and vigorous exercise were associated with lower daytime ambulatory systolic blood pressure, the reduction in systolic blood pressure being sustained throughout the 24 h period when vigorous exercise and caloric intake restriction were combined. CONCLUSION: Compared with the effects of caloric intake restriction, the effects of a vigorous exercise programme on blood pressure are inconsistent, there being no influence on clinic blood pressure but a reduction in daytime ambulatory blood pressure. However, when combined with caloric intake restriction, regular vigorous exercise exhibits a synergistic effect in reducing ambulatory blood pressure throughout a 24 h period.

The combined effects of aerobic exercise and alcohol restriction on blood pressure and serum lipids: a two-way factorial study in sedentary men.

OBJECTIVES: To determine whether vigorous exercise and alcohol restriction have additive and independent effects in reducing blood pressure in sedentary male alcohol drinkers. Also to assess whether 4 weeks of vigorous exercise could offset the fall in high-density lipoprotein cholesterol (HDL-cholesterol) usually observed after alcohol restriction. DESIGN: Seventy-five sedentary men were randomly assigned to drink low-alcohol beer or continue their normal drinking habits. Within these two groups subjects were further assigned either to a vigorous exercise programme of three 30-min sessions a week of cycling at 60-70% of maximum workload or to a control light-exercise programme. RESULTS: Seventy-two subjects completed the trial. Alcohol consumption fell by 85% in the low-alcohol group. Fitness increased by 10% following vigorous exercise, with a significant improvement in maximum oxygen uptake. After adjustment for weight loss, a significant effect of alcohol restriction in reducing both systolic and diastolic blood pressure was demonstrated. There was no effect of vigorous exercise on blood pressure. Serum total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B were not influenced by alcohol restriction or vigorous exercise. However, alcohol restriction significantly reduced triglyceride, HDL-cholesterol, its subfractions HDL2-cholesterol and HDL3-cholesterol, and its major apolipoproteins apo A-I and apo A-II. These reductions were unaffected by moderate exercise. CONCLUSIONS: This study provides further evidence that alcohol restriction results in reductions in blood pressure in men who are regular alcohol drinkers. However, a simultaneous increase in fitness did not lead to lower blood pressures than those achieved with alcohol restriction alone, and was unable to offset alcohol-related falls in HDL-cholesterol, its subfractions and its major apolipoproteins.

Long-term effects of exercise on blood pressure and lipids in healthy women aged 40-65 years: The Sedentary Women Exercise Adherence Trial (SWEAT).

OBJECTIVES: To evaluate the long-term effects of regular moderate or vigorous intensity exercise on blood pressure and blood lipids in previously sedentary older women. DESIGN: Subjects were randomly assigned to either a supervised centre-based (CB) or a minimally supervised home-based (HB) exercise program, initially for 6 months. Within each program, subjects were further randomized to exercise either at moderate (40-55% heart rate reserve, HRres) or vigorous intensity (65-80% HRres). After 6 months, all groups continued a HB moderate or vigorous exercise program for another 12 months. METHODS: Healthy, sedentary women (aged 40-65 years) (n = 126) were recruited from the community. Subjects exercised three times per week for 30 min. They were evaluated at baseline, 6, 12 and 18 months. RESULTS: There was a significant fall of 2.81 mmHg in systolic blood pressure (P = 0.049) and 2.70 mmHg in diastolic blood pressure (P = 0.004) after correction for age and baseline values with moderate exercise, but not with vigorous-intensity exercise. When this analysis was repeated with the change in body mass included, the results were unchanged. After correction for potential confounding factors, there was a significant fall in total cholesterol and low density lipoprotein cholesterol with vigorous but not moderate exercise at 6 months (P < 0.05) but not at 18 months. CONCLUSIONS: In this largely normotensive population of older women, a moderate, but not vigorous exercise program, achieved sustained falls in resting systolic and diastolic blood pressure over 18 months. The study demonstrates that, in older women, moderate intensity exercise is well accepted, sustainable long-term and has the health benefit of reduced blood pressure.

Cholic acid synthesis is reduced in pediatric liver recipients during graft dysfunction due to ischemic injury and allograft rejection.

BACKGROUND: Bile acids are synthesized and secreted by the liver. During liver failure and hepatic dysfunction, a marked reduction of bile acid synthesis has been shown. The purpose of this study was to determine whether the biliary bile acid pattern was affected by preservation injury and rejection and whether it was a reliable marker for graft function in pediatric liver recipients after liver transplantation. METHODS: We prospectively measured the biliary bile acid pattern in 126 serial bile samples obtained from 15 consecutive pediatric liver recipients by reversed phase high pressure liquid chromatography and correlated our results with clinical findings: preservation injury, no rejection, rejection, or infection. RESULTS: There was a significant change of the bile acid pattern during the first 3 days after transplant. Total biliary bile acids, cholic acid (CA), and CA/chenodeoxycholic acid (CDCA) ratio increased in 12 of 15 patients with mild preservation injury. These changes of the bile acid pattern were markedly delayed in patients with severe preservation injury. During 16 rejection episodes, total biliary bile acid, CA, and CA/CDCA ratio decreased significantly, but returned to normal after successful treatment of rejection. Bacterial infection, observed in nine children, and cyclosporine toxicity, observed in three children, seemed to have no affect on the biliary bile acids. CONCLUSIONS: Liver cell damage as a result of preservation injury or rejection leads to a reduction of biliary CA, resulting in a decrease of total biliary bile acids and the CA/CDCA ratio in pediatric liver recipients. This might be caused by a diminished secretion of bile acids and by a decreased synthesis of bile acids.

Factors affecting survival after orthotopic liver transplantation in infants.

The technical and medical management of small infants requiring orthotopic liver transplantation remains a challenge. The present study examined 117 orthotopic liver transplantations performed in 101 infants from <1 to 23 months of age between March 1988 and February 1995 to determine factors that influence patient and graft outcome. Factors analyzed included etiology of liver disease, recipient and donor age and weight, United Network for Organ Sharing (UNOS) status, retransplantation, ABO-compatibility, full-size (FS) versus reduced-size grafts, vascular thrombosis (VT), including hepatic artery and portal vein (PVT), and the presence of lymphoproliferative disease (LPD). UNOS status 1, fulminant hepatic failure, and the development of Epstein-Barr virus-associated LPD were each associated with 10-20% lower patient and graft survival rates. Of 101 infants, 11 (11%) developed LPD with an associated 36% mortality. VT occurred in 10 (9 hepatic artery and 1 portal vein) of 117 orthotopic liver transplantations (9%), all less than 1 year of age, and was associated with significantly poorer 1-year (50% vs. 85% no VT, P<0.01) and 5-year patient survival rates (50% vs. 83% no VT, P<0.01). One-year graft survival rates for FS grafts in recipients <12 months versus 12-23 months were 67% vs. 94% (P<0.01); the patient survival rate was also significantly lower in FS graft recipients <12 months (76% vs. 100%, P<0.05). Recipients <5 months of age had the worst survival rates: 1-year and 5-year patient survival rates were 65% and 46% for recipients 0-4 months (n=17) versus 82% and 82% for recipients 5-11 months (n=56), and 93% and 93% for recipients age 12-23 months (n=28; P<0.05). In summary, factors associated with reduced survival rates include recipient age <5 months, recipient age <12 months who received FS grafts, development of VT and donor weight <6 kg. There was a trend for UNOS status 1, fulminant hepatic failure, and presence of LPD to be associated with reduced survival rates.

Oral tacrolimus (FK506) induction therapy in pediatric orthotopic liver transplantation.

We have adopted the use of an oral tacrolimus induction protocol in pediatric liver transplantation since the commercial release of tacrolimus in 1994. In this study we analyzed the efficacy of oral tacrolimus induction therapy in 17 consecutive transplants (15 patients) performed between 6/94 and 2/95 and 4 additional patients who were retransplanted between 11/93-5/94 and received compassionate oral tacrolimus induction. Sixteen transplants were treated with oral tacrolimus induction only; 5 transplants, oral tacrolimus + ATGAM/OKT3 induction. The protocol consisted of 0.2 mg/kg of tacrolimus orally on the first postoperative day with a corticosteroid taper. Oral tacrolimus was started at day 1-8 in the 5 patients receiving ATGAM/OKT3 induction. Dosages were adjusted over time to maintain a whole-blood trough level of 12-15 ng/ml at 0-1 month, 10-12 ng/ml at 1-3 months, and 5-10 ng/ml after 3 months. The incidence of acute rejection was 50% (8/16) in children on oral tacrolimus induction alone and 80% (4/5) in the tacrolimus + ATGAM/OKT3 group. Epstein-Barr virus infection occurred in 6 of 19 children (32%), with no child developing lymphoproliferative disorder. No adverse effect on renal function was noted. Serum fasting glucose was stable over time while a trend was noted in decreasing serum cholesterol levels at 6 months. Antihypertensive medication was required in 4 of 19 children (21%) posttransplantation. Corticosteroids were withdrawn in 11% (2/19) of patients. Actuarial 1-year patient and graft survivals were 95% and 86%, respectively. The use of oral tacrolimus induction therapy was associated with excellent survival and a low incidence of complications.

Continuous venovenous hemofiltration with dialysis in combination with total hepatectomy and portocaval shunting. Bridge to liver transplantation.

Children who experience acute liver failure following liver transplantation will have multiple organ failure and a high rate of mortality unless emergency retransplantation can be performed. Transplant hepatectomy with portocaval shunting has been described as a bridge to transplantation in the most severe cases, as well as in patients with fulminant hepatic failure at high risk for mortality who have not undergone liver transplantation. Patients with multiple organ failure who have undergone hepatectomy require renal replacement therapy. Continuous hemofiltration may be used in patients with fulminant hepatic failure to facilitate fluid removal and circulatory and metabolic balance. We used continuous venovenous hemofiltration with dialysis following hepatectomy with portocaval shunting in a patient who remained anhepatic for 66 hr in order to achieve circulatory and metabolic homeostasis as well as stable neurologic function prior to successful retransplantation.

An increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation.

The incidence of Epstein-Barr virus (EBV) infection and lymphoproliferative disorder (LPD) was determined in a pediatric liver transplant population consisting of 51 children treated with FK506 and 91 treated with cyclosporine. The incidence of symptomatic EBV infection was 21.9% (23 of 105 cases) in children < 5 yr old and 10.8% (4 of 37 cases) in children 5 to 17 yr old as compared with 2.7% (9 of 323 cases) in adults (P < 0.0001). In the under 5 yr old group on cyclosporine, the incidences of EBV infection and LPD were 9 of 68 (13.2%) and 2 of 68 children, (2.9%), respectively. In contrast, in children under 5 yr old group on FK506, the incidences of EBV infection and LPD in the FK506 group were 14 of 37 (37.8%) and 7 of 37 children (18.9%), respectively. The difference between these two groups was statistically significant (P < 0.02). There were no cases of LPD in the 5-17 yr-old children on either cyclosporine (n = 23) or FK506 (n = 14). The incidence of EBV infections in the 5 to 17 yr age group, 17.4% on cyclosporine and 0% on FK506, was less than for the younger children on FK506 (37.8%). A total of 39% (9 of 23) of children under 5 yr old who had symptomatic EBV infections developed LPD, and 44% (4 of 9) with LPD died. The higher incidence of EBV infections and LPD in the younger children treated with FK506 was probably related to a greater intensity of immunosuppression for patients on FK506 than those on cyclosporine.

Orthotopic liver transplantation in patients with cystic fibrosis.

An 11-year-old boy who had cystic fibrosis underwent an orthotopic liver transplantation. His immediate postoperative course was not unusually complicated when compared with other liver transplant recipients. Transplantation did not correct abnormalities in the sweat test or the respiratory disease. Cholestasis due to obstruction of the recipient duct with tenacious bile was cleared by instilling N-acetylcysteine into the duct. On the 48th day after the transplantation, he died of an intraventricular and intracerebral hemorrhage caused by an Aspergillus brain abscess. We conclude that certain patients with cystic fibrosis may be appropriate candidates for liver transplantation, but their pre- and post-operative management may need to differ from other liver transplant recipients.

Epstein-Barr virus lymphoproliferative disorders after liver transplantation.

Post-transplant lymphoproliferative disorders (PTLD) represent a spectrum of histological and immunological abnormalities, ranging from benign polyclonal B-cell hyperplasia to monoclonal malignant lymphoma. The important role of Epstein-Barr virus (EBV) in PTLD in liver transplant patients, particularly in pediatric recipients, is reviewed. Understanding the risks of EBV infection, the clinical presentations and diagnosis of PTLD, and its pathophysiology are crucial to the management of these disorders. Current treatment methods have resulted in better outcomes of these disorders, which in the past were uniformly fatal.

Oral tolerance in experimental autoimmune encephalomyelitis.

In work performed by a number of laboratories, it has become quite clear that the oral administration of autoantigens exerts a profoundly suppressive effect on the development and long-term clinical course of autoimmune disease. Specific peptide sequences derived from the autoantigens are similarly suppressive. An interesting sidelight to emerge from specificity studies is that oral administration of a self-protein or peptide sequence (i.e., rat MBP peptide administered to a rat) is markedly less tolerogenic than oral administration of a non-self or even closely related sequence (guinea pig MBP peptide administered to a rat). The dose of oral antigen is now known to play a critical role in determination of the mechanism of oral tolerance, with low doses of antigen causing active suppression with concomitant release of TGFbeta1. Studies outlined here suggest that oral administration of higher antigen doses (e.g., 20 mg MBP to rats or mice) results in deletion of specific antigen-reactive T lymphocytes. This conclusion stems from the fact that injections of IL-2 could not reverse high-dose tolerance while reversing low-dose oral tolerance. Moreover, feeding MBP to MBP-TCR transgenic mice caused trafficking of transgenic cells to the intestine followed by a profound depletion of transgene-positive cells and reduction in proliferative function in all peripheral lymphoid organs. Oral tolerance has proven to be of therapeutic benefit in other animal models of autoimmune disease as well, including uveitis, collagen-induced arthritis, adjuvant arthritis, thyroiditis, myasthenia gravis, and diabetes. Initial human trials in multiple sclerosis, rheumatoid arthritis, and uveitis show promising results.