Visions for the 20th International Epidemiological Association's World Congress of Epidemiology (WCE 2014).

During August 17th-21st, 2014, the University of Alaska Anchorage, along with other local, state, and federal agencies throughout Alaska, will host the 20(th) International Epidemiological Association's (IEA) World Congress of Epidemiology (WCE 2014). The theme for this Congress is "Global Epidemiology in a Changing Environment: The Circumpolar Perspective." The changing environment includes the full range of environments that shape population health and health inequities from the physical to the social and economic. Our circumpolar perspective on these environments includes views on how political systems, work, immigration, Indigenous status, and gender relations and sexuality affect the global world and the health of its people. Suggestions and insights from the 3(rd) North American Congress of Epidemiology (2011) and the first-ever joint regional workshop co-organized by the IEA North American Region and the IEA Latin American and Caribbean Region held at the 19(th) IEA World Congress of Epidemiology (2011) have helped direct the focus for WCE 2014. Since the Arctic regions are feeling the effects of climate change first, we believe focusing on the emerging data on the health impacts of climate change throughout the world will be an important topic for this Congress. This will include a broad range of more traditional epidemiology areas such as infectious disease epidemiology, environmental epidemiology, health disparities, and surveillance and emergency preparedness. Addressing health inequities and promoting health equity is likewise a key concern of the Congress. This Congress will also host presentations on injury epidemiology, occupational health, infectious diseases, chronic diseases, maternal and child health, surveillance and field epidemiology, mental health, violence (from self-directed, e.g., suicide, to interpersonal to structural), psychoactive substance use (including tobacco), and measures of subjective health. Attention will be given to epidemiology's theoretical frameworks and emphasizing knowledge translation, from epidemiology to health systems, to policy, and to the broader public. We also plan to offer many hands-on workshops including practical uses of epidemiology to improve health systems and reduce health inequities within and between countries; the manner in which epidemiology can inform public health practice; the understanding and use of the Dictionary of Epidemiology; and many others.

Efficacy of the non-adenosine analogue A1 adenosine receptor agonist (BR-4935) on cardiovascular function after cardiopulmonary bypass.

BACKGROUND: We tested the hypothesis that pharmacological preconditioning with a newly developed, potent non-adenosine analogue A1AdoR agonist (BR-4935) improves biventricular cardiac and endothelial function after cardiopulmonary bypass. METHODS: Twelve anesthetized dogs underwent cardiopulmonary bypass. Dogs were divided into two groups: group 1 (n = 6) received saline vehicle, group 2 (n = 6) received BR-4935 before cardiopulmonary bypass. Biventricular hemodynamic variables were measured using a combined pressure-volume conductance catheter. Coronary blood flow, ATP content, malondialdehyde and myeloperoxidase levels and vasodilatative responses to acetylcholine and sodium nitroprusside were also determined. RESULTS: Administration of the A1AdoR agonist led to a significantly better recovery of left and right ventricular systolic function after 60 minutes of reperfusion. Although the vasodilatative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary blood flow in the BR-4935 group. In addition, the ATP content was significantly higher in the same group. Furthermore, malondialdehyde and myeloperoxidase levels significantly decreased in the A1AdoR group. CONCLUSION: Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.

Lifelong socioeconomic trajectory and premature mortality (35-65 years) in France: findings from the GAZEL Cohort Study.

BACKGROUND: Studies conducted in the UK and Scandinavia show an inverse association between lifetime socioeconomic position and adult mortality. However, there are virtually no data from other countries and few investigations have examined non-cardiovascular mortality in men and women. METHODS: Lifelong socioeconomic trajectories (father's occupation, own occupation in young adulthood and in mid-life) and premature (< or = 65 years) mortality (all-cause, smoking-related cancer, diseases of the circulatory system and external causes) in the French GAZEL Cohort Study (14,972 men and 5,598 women, followed up between 1990 and 2004) were studied. Hazard ratios (HRs) were estimated using Cox's regression models adjusted for age, marital status, tobacco smoking, alcohol consumption, body mass index, and fruit and vegetable consumption. RESULTS: Men and women who experienced lifelong disadvantage or downward intergenerational mobility were at high risk of dying prematurely compared with those with a favourable trajectory (age-adjusted HRs for all-cause mortality: cumulative disadvantage: HR 1.61, 95% confidence interval (CI) 1.26 to 2.06 in men and HR 1.95, 95% CI 1.10 to 3.47 in women; downward mobility: HR 1.87, 95% CI 1.35 to 2.58 in men and HR 2.05, 95% CI 1.12 to 3.75 in women). Associations were strongest for mortality due to chronic diseases (smoking-related cancers and diseases of the circulatory system). These associations were partly explained by marital status, body mass index, alcohol consumption, cigarette smoking, and fruit and vegetable consumption. CONCLUSIONS: In France, where the leading cause of premature death is cancer, lifelong socioeconomic position is associated with the risk of dying before the age of 65 years. Adult factors seem more relevant than childhood socioeconomic circumstances.

Lifetime socioeconomic position in relation to onset of perimenopause.

STUDY OBJECTIVE: To assess the association between lifetime socioeconomic position and onset of perimenopause. DESIGN: Prospective cohort study. SETTING: Boston, Massachusetts. PARTICIPANTS: 603 premenopausal women aged 36-45 years at baseline who completed a cross sectional survey on childhood and adult socioeconomic position. MAIN OUTCOME MEASURES: Time to perimenopause, defined as time in months from baseline interview to a woman's report of (1) an absolute change of at least seven days in menstrual cycle length from baseline or subjective report of menstrual irregularity; (2) a change in menstrual flow amount or duration; or (3) cessation of periods for at least three months, whichever came first. MAIN RESULTS: Incidence of perimenopause was 1.75 times higher (95%CI 1.10 to 2.79) and median age at onset was 1.2 years younger (44.7 v 45.9 years) for women reporting childhood and adult economic distress compared with women reporting no lifetime economic distress. After adjustment for age, race/ethnicity, age at menarche, parity, oral contraceptive use, family history of early menopause, depression, smoking, and body mass index, the association weakened (incidence rate ratio (IRR)=1.59; 95%CI 0.97 to 2.61). Inverse associations were observed for most, but not all, measures of educational level. Measures of current household income were not associated with risk of perimenopause. CONCLUSIONS: This study suggests that adverse socioeconomic conditions across the lifespan, when measured in terms of economic hardship and low educational attainment, may be associated with an increased rate of entry into perimenopause.

Sequences in the 5' nontranslated region of hepatitis C virus required for RNA replication.

Sequences in the 5' and 3' termini of plus-strand RNA viruses harbor cis-acting elements important for efficient translation and replication. In case of the hepatitis C virus (HCV), a plus-strand RNA virus of the family Flaviviridae, a 341-nucleotide-long nontranslated region (NTR) is located at the 5' end of the genome. This sequence contains an internal ribosome entry site (IRES) that is located downstream of an about 40-nucleotide-long sequence of unknown function. By using our recently developed HCV replicon system, we mapped and characterized the sequences in the 5' NTR required for RNA replication. We show that deletions introduced into the 5' terminal 40 nucleotides abolished RNA replication but only moderately affected translation. By generating a series of replicons with HCV-poliovirus (PV) chimeric 5' NTRs, we could show that the first 125 nucleotides of the HCV genome are essential and sufficient for RNA replication. However, the efficiency could be tremendously increased upon the addition of the complete HCV 5' NTR. These data show that (i) sequences upstream of the HCV IRES are essential for RNA replication, (ii) the first 125 nucleotides of the HCV 5' NTR are sufficient for RNA replication, but such replicon molecules are severely impaired for multiplication, and (iii) high-level HCV replication requires sequences located within the IRES. These data provide the first identification of signals in the 5' NTR of HCV RNA essential for replication of this virus.

Ovarian function in late reproductive years in relation to lifetime experiences of abuse.

The objective of this study was to investigate the relation between violence victimization and levels of ovarian hormones during women's late reproductive years, as measured by serum levels of follicle-stimulating hormone and estradiol, which respectively rise and fall with onset of menopause. In March 1999, 732 women 36-45 years of age from the Harvard Study of Moods and Cycles cohort completed a survey of lifetime experiences of physical and sexual harm. Follicle-stimulating hormone and estradiol levels were measured during the menstrual period after entry into the cohort. Associations for violence and follicle-stimulating hormone and estradiol levels were estimated using crude and adjusted risk differences. Overall, women who experienced abuse during childhood or adolescence relative to never-abused women had a slight positive association of violence with high follicle-stimulating hormone. However, a positive association with high follicle-stimulating hormone was not observed among women whose first abuse occurred during adulthood. Age stratification indicated modification of the association between violence and low estradiol. Women 36-40 years of age had no evidence of a positive association between violence before adulthood and low estradiol, whereas first violence in adulthood was associated with an 11% increase in the estimate of risk difference [95% confidence limits (CL) = -0.14, 0.36]. Among women 41-45 years, there was a 17-23% increase in the estimate of risk difference for low estradiol, regardless of life stage at first experience of abuse (before adulthood, 95% CL = 0.06, 0.28; during adulthood, 95% CL = 0.01, 0.46). This investigation supports the credibility of a hypothesis that physical and sexual abuse may lead to neuroendocrine disruption, thereby affecting ovarian function and potentially leading to altered age at perimenopausal transition.

Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations.

Studies of the Hepatitis C virus (HCV) replication cycle have been made possible with the development of subgenomic selectable RNAs that replicate autonomously in cultured cells. In these replicons the region encoding the HCV structural proteins was replaced by the neomycin phosphotransferase gene, allowing the selection of transfected cells that support high-level replication of these RNAs. Subsequent analyses revealed that, within selected cells, HCV RNAs had acquired adaptive mutations that increased the efficiency of colony formation by an unknown mechanism. Using a panel of replicons that differed in their degrees of cell culture adaptation, in this study we show that adaptive mutations enhance RNA replication. Transient-transfection assays that did not require selection of transfected cells demonstrated a clear correlation between the level of adaptation and RNA replication. The highest replication level was found with an adapted replicon carrying two amino acid substitutions located in NS3 and one in NS5A that acted synergistically. In contrast, the nonadapted RNA replicated only transiently and at a low level. The correlation between the efficiency of colony formation and RNA replication was corroborated with replicons in which the selectable marker gene was replaced by the gene encoding firefly luciferase. Upon transfection of naive Huh-7 cells, the levels of luciferase activity directly reflected the replication efficiencies of the various replicon RNAs. These results show that cell culture-adaptive mutations enhance HCV RNA replication.

Significance of detecting Epstein-Barr-specific sequences in the peripheral blood of asymptomatic pediatric liver transplant recipients.

Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)-associated illnesses. The early identification and diagnosis of EBV-associated disorders is critical because disease progression can often be curtailed by modification of immunosuppression. We have previously shown that detection of EBV-specific sequences in the circulation by polymerase chain reaction (PCR) correlated well with the clinical symptoms of EBV infection. The purpose of the current study is to determine the significance of detecting EBV-specific sequences by PCR in asymptomatic pediatric liver transplant recipients. Peripheral-blood DNA was analyzed for the EBV genes, coding from the nuclear antigen 1 (EBNA-1) and the viral capsid antigen (gp220) by PCR. Samples from asymptomatic pediatric liver transplant recipients were analyzed from the immediate postoperative period and at 2- to 4-month intervals thereafter. We followed up 13 of these asymptomatic recipients who tested positive for EBV compared with 7 asymptomatic recipients who tested negative for EBV during the early posttransplantation period. Follow-up ranged from 1.5 to 4 years posttransplantation. Nine patients (69%) initially positive for EBV and asymptomatic ultimately developed symptoms of EBV infection, including fever, lymphadenopathy, rash, respiratory and gastrointestinal symptoms, and/or hepatitis. Five of these patients (56%) went on to develop posttransplant lymphoproliferative disorder based on histological examination of biopsied tissue and immunohistochemical identification of the EBV antigen/DNA in tissue. This is the first report suggesting that detection of EBV-specific sequences in the absence of symptoms may herald impending EBV-associated disorders. Thus, routine monitoring for circulating EBV sequences in asymptomatic recipients may be useful in the early identification of those at risk for developing EBV-associated disease and its ultimate prevention.

Relations between individual and neighborhood-based measures of socioeconomic position and bone lead concentrations among community-exposed men: the Normative Aging Study.

To examine the association between lead exposure and both individual and geographic area indicators of socioeconomic position, the authors measured tibia lead concentration, a biomarker of cumulative lead exposure, using K x-ray fluorescence in a cross-sectional survey of 538 white males aged 50-92 years who were healthy when enrolled in the Normative Aging Study (Boston, Massachusetts) in the 1960s. Data on individual risk factors, education, occupation, and income were collected by questionnaire. Using subjects' residential addresses at the time of the tibia lead measurements, the authors obtained geographic area-specific measures of education, social class, and poverty by linking records to 1990 US Census block group data. In multivariate linear regression analysis controlling for age and cumulative smoking, tibia lead concentrations were 10.39 microg/g (95% confidence interval (CI) 7.80-12.97) higher in men who did not graduate from high school than in men with > or =4 years of college. Among the former men (non-high school graduates), living in an undereducated area was associated with a 9.28 microg/g (95% CI 1.59-16.97) increase in tibia lead level compared with living in a non-undereducated area; among the latter men (college graduates), no difference existed by residential area education (beta = 0.72, 95% CI -5.35 to 6.78). The authors conclude that the influence of individual socioeconomic position on cumulative lead exposure is modified by geographic area conditions.

Power Doppler imaging of acute renal transplant rejection.

PURPOSE: We evaluated the usefulness of power Doppler imaging (PDI) in diagnosing acute renal-transplant rejection. METHODS: Twenty-eight patients underwent 33 renal-transplant biopsies for suspected acute rejection. Patterns of renal parenchymal vascularity revealed by PDI in patients with abnormal biopsy results were compared with patterns in a group who had normal biopsy results. PDI examinations were reviewed retrospectively by 2 independent radiologists who had no knowledge of the biopsy results. A PDI diagnosis of acute rejection required marked vascular pruning in both the cortex and medulla. PDI results then were compared with transplant-biopsy results. RESULTS: The sensitivity and specificity of PDI for diagnosing acute renal-transplant rejection were 40% and 100%, respectively. None of the patients with negative biopsy results had PDI abnormalities. The negative predictive value of PDI was 33%, and the positive predictive value was 100%. CONCLUSIONS: In our study, an abnormal sonogram was highly predictive of acute transplant rejection. However, a normal sonogram did not exclude the possibility of rejection.

Social class, race/ethnicity, and incidence of breast, cervix, colon, lung, and prostate cancer among Asian, Black, Hispanic, and White residents of the San Francisco Bay Area, 1988-92 (United States).

BACKGROUND: To date only eight US studies have simultaneously examined cancer incidence in relation to social class and race/ethnicity; all but one included only black and white Americans. To address gaps in knowledge we thus investigated socioeconomic gradients in cancer incidence among four mutually exclusive US racial/ethnic groups-- Asian and Pacific Islander, black, Hispanic, and white-- for five major cancer sites: breast, cervix, colon, lung, and prostate cancer. METHODS: We generated age-adjusted cancer incidence rates stratified by socioeconomic position using: (a) geocoded cancer registry records, (b) census population counts, and (c) 1990 census block-group socioeconomic measures. Cases (n = 70,899) were diagnosed between 1988 and 1992 and lived in seven counties located in California's San Francisco Bay Area. RESULTS: Incidence rates varied as much if not more by socioeconomic position than by race/ethnicity, and for each site the magnitude - and in some cases direction - of the socioeconomic gradient differed by race/ethnicity and, where applicable, by gender. Breast cancer incidence increased with affluence only among Hispanic women. Incidence of cervical cancer increased with socioeconomic deprivation among all four racial/ethnic groups, with trends strongest among white women. Lung cancer incidence increased with socioeconomic deprivation among all but Hispanics, for whom incidence increased with affluence. Colon and prostate cancer incidence were inconsistently associated with socioeconomic position. CONCLUSIONS: These complex patterns defy easy generalization and illustrate why US cancer data should be stratified by socioeconomic position, along with race/ethnicity and gender, so as to improve cancer surveillance, research, and control.

Prolongation of cardiac graft survival with anti-CD4Ig plus hCTLA4Ig in primates.

BACKGROUND: The aim of this study was to determine whether the use of combined immunotherapy with a brief course of humanized anti-CD4Ig and hCTLA4Ig would prolong heterotopic cardiac allograft survival in primates (rhesus monkeys). This model was based on work in "high responder" rats where a brief course of depletive anti-CD4mAb plus hCTLA4Ig was successful in inducing transplantation tolerance. METHODS: Heterotopic cardiac transplants were performed in rhesus recipients. Donor/recipient pairs between groups were confirmed to be reactive prior to transplantation by MLR matching. Humanized anti-CD4Ig, a recently developed anti-CD4mAb, was given at a dose of 20 mg/kg i.v. on days -3, -2, -1, and 0. hCTLA4Ig was administered at 6 mg/kg/dose i.v. on days 0 and 2 for the first recipient and days 0, 2, 4, and 6 for the second recipient. No further immunosuppression was administered. The treated (n = 2) or untreated (n = 5) recipients were followed for graft function by daily palpitation. RESULTS: Treatment with anti-CD4Ig plus hCTLA4Ig resulted in a significant prolongation of heart graft survival (42 days for the first recipient and 52 days for the second recipient) compared to untreated recipients (7 days x 4, 11 days x 1). FACS analysis demonstrated CD4 depletion of anti-CD4 treated animals to <2% on posttransplant day 1. The CD4+ T cells gradually repopulated to 50-70% pretransplant levels just prior to rejection. No adverse responses (fever, tachypnea, tachycardia, infections) were observed. CONCLUSIONS: These are the first results demonstrating that a brief course of combined specific induction immunotherapy with humanized anti-CD4Ig plus hCTLA4Ig, in the absence of adjuvant posttransplant immunosuppression, was well tolerated and resulted in marked prolongation of cardiac allograft survival in primates.

Association between high-density lipoprotein cholesterol and breast cancer varies by menopausal status.

A nested case-control study was conducted to investigate the hypothesis that women with high levels of high-density lipoprotein cholesterol (HDL-C) are at an increased risk of breast cancer. The source population was a cohort of 95,000 women enrolled in the Kaiser Permanente Medical Care Program who underwent a routine multiphasic health examination between 1964 and 1971. From the more than 2,000 breast cancer cases diagnosed in this cohort, 200 cases were randomly selected for this study. For each case, one control who matched on age and date of examination was chosen. Lipid and lipoprotein levels were measured in archived serum samples collected at the time of the women's examinations. Breast cancer risk factor information was obtained from questionnaires completed by the women when their blood was drawn and was supplemented with information from medical records. HDL-C levels were not significantly different between the cases and controls overall; however, a statistically significant interaction between the HDL-C level and menopausal status at diagnosis was detected. Premenopausal cases had mean HDL-C levels 3.48 mg/dl lower than matched controls [95% confidence interval (CI), -7.05, 0.09], whereas postmenopausal cases had levels 2.05 mg/dl higher than controls (95% CI, -0.94, 5.03). In multivariate conditional logistic regression analyses, the odds ratio associated with each 1 mg/dl increase in HDL-C was 0.96 (95% Cl, 0.93-1.0) for premenopausal women and 1.02 (95% CI, 0.99-1.05) for postmenopausal women. Although many breast cancer risk factors are associated with high HDL-C, the relationship between breast cancer and HDL-C was independent of other factors evaluated.

Parathyroid hormone, prostaglandin E2, and 1,25-dihydroxyvitamin D3 decrease the level of Na+-Ca2+ exchange protein in osteoblastic cells.

We previously described Na+-Ca2+ exchange in osteoblastic rat osteosarcoma cells (UMR-106) and demonstrated that Na+-dependent Ca2+ transport was inhibited by 24-hour treatment of cells with parathyroid hormone (PTH), prostaglandin E2 (PGE2), or 1,25(OH)2D3. To determine whether this inhibition of Na+-Ca2+ exchange is at the level of exchanger protein synthesis we have examined exchanger protein levels using immunoblot analysis. UMR-106 cells were treated for 24 hours with or without PTH, PGE2, or 1,25(OH)2D3. Plasma membrane fractions (7500 g) were obtained and proteins were separated by SDS-PAGE, transferred to nylon membranes, and immunoblotted with a polyclonal antibody to the canine cardiac Na+-Ca2+ exchanger. In rat cardiac membranes, we detected 125 and 75 kD bands, similar to findings for the canine exchanger. In the osteoblastic UMR cell membranes, a specific band was detected at 90 kD that decreased 65% after treatment of cells with PTH. Inhibition by PTH was dose dependent, was maximal with 10(-7) M PTH, and required 16-24 hour treatment time. Similar inhibition was observed after a 24 hour treatment with 10(-6) M PGE2 or 10(-8) M 1,25(OH)2D3. These results demonstrate the presence of a specific protein in UMR cells that cross-reacts with antibody directed against the cardiac Na+-Ca2+ exchanger. Thus, the previously reported inhibition of Na+-Ca2+ exchange activity by calcemic agents in osteoblasts appears to be due to regulation of exchanger protein levels in these osteoblastic cells.

Race/ethnicity, social class, and prevalence of breast cancer prognostic biomarkers: a study of white, black, and Asian women in the San Francisco bay area.

We assessed distributions of breast cancer prognostic biomarkers by race/ethnicity and socioeconomic position among paraffin-embedded tumor biopsy specimens from 135 US women (48 white women, 44 black women, 43 Asian women) diagnosed with breast cancer between 1966 and 1990. No racial/ethnic or socioeconomic differences in distributions were observed for tumor stage, lymph node involvement, estrogen, progesterone, and epidermal growth factor receptors, oncogenes such as Her2/neu and p53, cytoplasmic proteins cathepsin-D and ps2, and two indices of cell growth, Ki67 and DNA ploidy, adjusting for age at diagnosis, menopausal status, place of birth and, for racial/ethnic comparisons, working class composition of census block-group at diagnosis. Black and Asian women, however, were 3.5 times (95% confidence interval [CI] = 1.2, 10.1) and 3.7 times (95% CI = 1.3, 10.6), respectively more likely than white women to have a tumor size of > or = 20 mm, and Asian women were 3.4 times (95% CI = 1.1, 10.4) more likely than black women to be positive for androgen receptor, adjusting for these same factors. No differences in distributions by socioeconomic position were observed for these latter two tumor characteristics. These data suggest that racial/ethnic and socioeconomic disparities in breast cancer survival are unlikely to be explained solely by differential distributions of molecular breast cancer prognostic biomarkers.

Can we monitor socioeconomic inequalities in health? A survey of U.S. health departments' data collection and reporting practices.

OBJECTIVE: To evaluate the potential for and obstacles to routine monitoring of socioeconomic inequalities in health using U.S. vital statistics and disease registry data, the authors surveyed current data collection and reporting practices for specific socioeconomic variables. METHODS: In 1996 the authors mailed a self-administered survey to all of the 55 health department vital statistics offices reporting data to the National Center for Health Statistics (NCHS) to determine what kinds of socioeconomic data they collected on birth and death certificates and in cancer, AIDS, and tuberculosis (TB) registries and what kinds of socioeconomic data were routinely reported in health department publications. RESULTS: Health departments routinely obtained data on occupation on death certificates and in most cancer registries. They collected data on educational level for both birth and death certificates. None of the databases collected information on income, and few obtained data on employment status, health insurance carrier, or receipt of public assistance. When socioeconomic data were collected, they were usually not included in published reports (except for mothers educational level in birth certificate data). Obstacles cited to collecting and reporting socioeconomic data included lack of resources and concerns about the confidentiality and accuracy of data. All databases, however, included residential addresses, suggesting records could be geocoded and linked to Census-based socioeconomic data. CONCLUSIONS: U.S. state and Federal vital statistics and disease registries should routinely collect and publish socioeconomic data to improve efforts to monitor trends in and reduce social inequalities in health.

Induction of tolerance to small bowel allografts in high-responder rats by combining anti-CD4 with CTLA4Ig.

This study was designed to investigate the effectiveness of combined perioperative anti-CD4 and human (h)CTLA4Ig therapy in preventing allorejection of small bowel transplantation in high-responder Lewis rat recipients of ACI grafts. Anti-CD4 (5 mg/kg x 4 days) or hCTLA4Ig (0.5 mg/rat x 2 days) therapy alone delayed, but did not prevent, allograft rejection after small bowel transplantation of ACI into Lewis rats. All grafts were rejected in 18 and 10 days, respectively. However, a regimen of anti-CD4 (5 mg/kg x 4 days) combined with hCTLA4Ig (0.5 mg/rat x 2 days) allowed indefinite survival of ACI small bowel allografts. Second donor-matched heart grafts were permanently accepted, whereas third-party (Sprague-Dawley) heart allografts were rejected by the tolerant recipients. These data suggest that these two reagents produced a synergistic effect in preventing allorejection of small bowel transplantation.