FK 506 in simultaneous pancreas/kidney transplantation: the University of Miami experience.
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Florida↗
Biomedical subjects
G Burke
Publications and source records attributed to G Burke.
Urodynamic findings following bladder-drained simultaneous pancreas-kidney transplantation.
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Acute Disease↗
Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings.
Mycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimus (Prograf) as well in renal transplant patients, there is a lack of pharmacokinetic studies clarifying drug interactions between the three agents. A pharmacokinetic study was performed on 18 stable renal transplant patients receiving MMF and tacrolimus together, and four control groups, one receiving tacrolimus alone, two receiving CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion (Neoral). Area-under-the-curve values were calculated for each drug to assess if there was a reciprocal effect on the respective bioavailability of each. In vitro, the immunosuppressive effect of trough level plasma from each patient group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions spiked with various combinations of each drug. There was a minimal effect of MMF on tacrolimus pharmacokinetics. However, patients receiving tacrolimus and MMF displayed significantly higher levels (Cmin and area under the curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmune or Neoral) and the same dose of MMF (50.2 +/- 16.5 vs 32.1 +/- 16.7 micrograms h/ml AUC, p < 0.02). Equivalent MPA levels could be attained in patients receiving CsA if the MMF dose was increased by 50% (1.5 g bid). There were also significantly lower levels of the glucuronide metabolite of MPA (MPAG) (755 +/- 280 vs 1230 +/- 250 micrograms h/ml AUC, p = 0.02), suggesting a specific inhibition (either direct or indirect) of the conversion of MPA to MPAG in tacrolimus patients, as opposed to those receiving CsA. For each drug combination, there was a positive correlation between the plasma immunosuppressive effect seen in MLC assays and the MMF dose. In addition, trough plasma from patients receiving tacrolimus and MMF was significantly more MLC inhibitory than from those receiving CsA or CsA microemulsion and equivalent-dose MMF. Culture media containing MPA and tacrolimus equal to clinical therapeutic trough concentrations (10 ng/ml) were significantly more MLC inhibitory than CsA at equivalent clinical therapeutic trough concentrations (200 ng/ml) with equivalent MPA levels. These studies in renal transplant patients suggest that tacrolimus in combination with MMF may result in a greater degree of immunosuppression than may be anticipated.
Adult↗
Relations between family environment and adjustment outcomes in young adults with spina bifida.
Thirty-two young adults with spina bifida completed a questionnaire (Family Environment Scale) assessing their perceptions of family social environment while growing up. Additionally, subjects responded to a structured interview addressing their current employment status, residential situation, level of community mobility, and extent of social activity. Multiple logistic regression analyses were used to assess the relation between family environment and adjustment as a young adult. With this limited sample, results indicated that perceived family environment explained variance in employment, community mobility, and social activity as an adult, even beyond that explained by lesion level and intelligence. Regression coefficients showed positive relations between perceived family encouragement of independence and achievement and young adult outcomes. In contrast, perceived moral/religious emphasis of the family and degree of family involvement with intellectual/cultural activities evidenced negative relations with the measures of young adult adjustment.
Adaptation, Psychological↗
The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study.
White matter lesions (WMLs) detected by cerebral magnetic resonance imaging (MRI) are putatively a consequence of cerebral hypoperfusion or ischemia. We investigated the prevalence, severity and correlates of WMLs in a population-based sample of 1,920 African-American and European-American men and women aged 55-72 years, during the second follow-up examination of the Atherosclerosis Risk in Communities Study. The spin density images from 1.5-tesla MRI scans were used to define WMLs using a 0-9 scale with 0 for normal and 9 for most severe WMLs. Age was positively associated with the prevalence (percent) and severity of WMLs. African-Americans had lower overall prevalence of WMLs, but a higher prevalence of relatively more severe WMLs, than European-Americans. After adjusting for age, sex, and ethnicity, WMLs were significantly associated with smoking, lower education, hypertension, systolic blood pressure, and pulse pressure, and weakly associated with diastolic blood pressure. The associations of smoking, alcohol intake, systolic and diastolic blood pressure, pulse, pressure, and hypertension were stronger in African-Americans than in European-Americans (p < 0.15 for interactions by ethnicity). This population-based MRI study documents significant relationships between several cardiovascular disease risk factors and WMLs. The findings suggest that such factors play a role in the pathogenesis of WMLs, an elements linked to hypoperfusion and/or fluid accumulation, which presumably lead to WMLs. African-Americans exhibited both a higher proportion of normal white matter and a higher proportion of relatively more severe WMLs than European-Americans.
Age Factors↗
Familial history of stroke and stroke risk. The Family Heart Study.
BACKGROUND AND PURPOSE: Although familial history of stroke is generally perceived to be an important marker of stroke risk, very few epidemiological studies have been published to address this hypothesis. We sought to examine whether familial history of stroke is associated with the prevalence of stroke in the Family Heart Study, a National Heart, Lung, and Blood Institute-supported multicenter study of the familial, genetic, and nongenetic determinants of cardiovascular disease in populations. METHODS: The personal and familial histories of stroke were assessed in 3168 individuals (probands) who were at least 45 years old and 29,325 of their first-degree relatives with the use of a standardized questionnaire. RESULTS: The age-, ethnicity-, and sex-adjusted stroke prevalences were 4.8%, 4.9%, and 3.9% in probands with a positive familial, paternal, and maternal history of stroke, respectively, in comparison with 2.0% in probands without any positive familial history (P < .01). The age-, ethnicity-, and sex-adjusted odds ratios (95% confidence interval) of stroke were 2.00 (1.13, 3.54) for a positive paternal and 1.41 (0.80, 2.50) for a positive maternal history of stroke. Additional statistical adjustment for the proband's history of elevated cholesterol level, cigarette smoking status, history of coronary heart disease, hypertension, and diabetes did not alter the associations. A similar pattern was seen for African Americans and European Americans. CONCLUSIONS: The increased risk of stroke among persons with a positive familial history of stroke compared with those without a familial history of stroke is consistent with the expression of genetic susceptibility, a shared environment, or both in the etiology of stroke.
Black or African American↗
Long-term function (6 years) of islet allografts in type 1 diabetes.
Eight type 1 diabetic patients, ages 29-41 years, with mean diabetes duration of 23 years (range 18-29 years) received islet transplants from 1 to 5 donors. Seven patients had stable kidney allografts 1-11 years before the islet transplant, and one patient had a simultaneous islet-kidney allograft. Patients' blood glucose control was poor as reflected by the mean +/- SD HbA1c of 9.1 +/- 1.7% before transplant. Of the first three patients, two (1 and 3) achieved insulin independence for 36 and 38 days, respectively. Two recipients rejected their islet grafts within 1 month (2 and 8) and therefore were excluded from analysis. The HbA1c and insulin requirement of the six remaining patients who had persistent islet function for more than 60 days was significantly reduced from 9.3 +/- 1.9 to 6.4 +/- 1.0% (P = 0.002) and from 0.75 +/- 0.15 to 0.35 +/- 0.12 U x kg(-1) x day(-1) (P < 0.001), respectively. The two patients with the longest graft survival (4 and 6) achieved a normalization or near-normalization of their HbA1c levels during 6 years in the absence of severe episodes of hypoglycemia. As demonstrated by a decline in C-peptide response during Sustacal challenge tests over a 6-year period, there was a diminution of islet allograft function over time, despite persistence of normal or near normal HbA1c. We concluded that transplantation of allogeneic islets with an islet mass comparable with whole or segmental pancreas transplants in type 1 diabetic patients can result in long-term islet allograft function; further, we concluded that, in conjunction with small dosages of exogenous insulin, a functioning islet allograft can result in near-normalization of blood glucose levels and significant improvement in HbA1c. The occurrence of severe hypoglycemic episodes observed for patients in the Diabetes Control and Complications Trial was not observed in recipients with functioning islet transplants, despite the continuous need for exogenous insulin therapy to sustain normal HbA1c over the 6-year follow-up. The significant improvement in metabolic control observed for the patients described in this study, and the potential to significantly decrease or halt the progression of diabetic complications, support the continued application of islet allotransplantation as a treatment modality for type 1 diabetic patients.
Adult↗
Process analysis and re-engineering: a survival tool.
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Admitting Department, Hospital↗
Hypertension and subclinical carotid artery atherosclerosis in blacks and whites. The Atherosclerosis Risk in Communities Study. ARIC Investigators.
OBJECTIVE: To describe the distribution of hypertension and its association with subclinical atherosclerosis in blacks and whites. DESIGN: Population-based survey of 15,587 middle-aged adults from the Atherosclerosis Risk in Communities Study. Ultrasound-measured carotid artery intima media thickness (IMT) was used to estimate atherosclerosis. Hypertension was defined by the revised fifth Joint National Committee categories. Continuous systolic and diastolic blood pressure measurements also were evaluated. RESULTS: Among participants not reporting use of antihypertensive medication, 43% to 52% of black and 68% to 78% of white participants had optimal to high-normal blood pressure across the 4 study centers; 11% to 22% of black and 6% to 9% of white participants had stage I or higher hypertension. Use of antihypertensive medications was reported by 34% to 45% of blacks and 20% of whites; 11% to 17% of blacks had stage I or higher hypertension compared with 4% to 7% of whites when treated. Higher hypertension categories were associated with thicker intima medias in all ethnic and gender groups, in participants who did and did not use medications. In participants who did not use medications, multiple linear regression models adjusted for diastolic blood pressure and other risk factors found that systolic blood pressure was positively associated with IMT except in black men; diastolic blood pressure was not related to IMT in blacks and had a negative relation with IMT in white men and a J-shaped relation with IMT in white women. Results of similar direction and magnitude were found in participants who used medications. CONCLUSIONS: Hypertension was higher in blacks than whites and was associated with subclinical atherosclerosis. The association of atherosclerosis with hypertension is accounted for predominantly by systolic blood pressure. The intriguing negative association of diastolic blood pressure and atherosclerosis implies that pulse pressure may be an important correlate of atherosclerosis.
Black or African American↗
Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness.
OBJECTIVE: To determine whether patients coinfected with Lyme disease and babesiosis in sites where both diseases are zoonotic experience a greater number of symptoms for a longer period of time than those with either infection alone. DESIGN: Community-based, yearly serosurvey and clinic-based cohort study. SETTING: Island community in Rhode Island and 2 Connecticut medical clinics from 1990 to 1994. STUDY PARTICIPANTS: Long-term residents of the island community and patients seeking treatment at the clinics. MAIN OUTCOME MEASURES: Seroreactivity to the agents of Lyme disease and babesiosis and number and duration of symptoms. RESULTS: Of 1156 serosurvey subjects, 97 (8.4%) were seroreactive against Lyme disease spirochete antigen, of whom 14 (14%) also were seroreactive against babesial antigen. Of 240 patients diagnosed with Lyme disease, 26 (11%) were coinfected with babesiosis. Coinfected patients experienced fatigue (P = .002), headache (P < .001), sweats (P < .001), chills (P = .03), anorexia (P = .04), emotional lability (P = .02), nausea (P = .004), conjunctivitis (P = .04), and splenomegaly (P = .01) more frequently than those with Lyme disease alone. Thirteen (50%) of 26 coinfected patients were symptomatic for 3 months or longer compared with 7 (4%) of the 184 patients with Lyme disease alone from whom follow-up data were available (P < .001). Patients coinfected with Lyme disease experienced more symptoms and a more persistent episode of illness than did those (n = 10) experiencing babesial infection alone. Circulating spirochetal DNA was detected more than 3 times as often in coinfected patients as in those with Lyme disease alone (P = .06). CONCLUSIONS: Approximately 10% of patients with Lyme disease in southern New England are coinfected with babesiosis in sites where both diseases are zoonotic. The number of symptoms and duration of illness in patients with concurrent Lyme disease and babesiosis are greater than in patients with either infection alone. In areas where both Lyme disease and babesiosis have been reported, the possibility of concomitant babesial infection should be considered when moderate to severe Lyme disease has been diagnosed.
Adolescent↗
A prospective study of hepatitis C virus infection in renal allograft recipients.
Hepatitis C virus (HCV) is the predominant cause of posttransplant non-A, non-B hepatitis among renal allograft recipients. Prior studies evaluating the impact of HCV in kidney transplantation have been retrospective in design and based largely on changes in serum transaminases. We studied a group of HCV-infected end-stage renal disease patients prospectively with pretransplant liver biopsies and close virologic and biochemical follow-up posttransplant. Fourteen patients have been followed a mean of 11.6 +/- 5.6 months posttransplant (range, 5-21 months). Six had changes of chronic hepatitis on pretransplant liver biopsy while 8 showed only mild histologic abnormalities. Circulating viral titers increased several-fold over baseline levels during posttransplant follow-up. Viral replication was particularly enhanced immediately following a course of antilymphocyte therapy. Although all patients showed a 2-3 fold increase in alanine aminotransferase (ALT) following transplantation, there were no association noted between pretransplant liver histology, the use of FK506 and/or cyclosporine-based immunosuppression, and the magnitude of ALT change posttransplant. The only clinical outcome found to differ significantly was a higher incidence of cytomegalovirus infection among patients with chronic hepatitis. All patients are alive with functioning grafts. There have been no episodes of fulmiinant or subfulminant liver failure. We conclude that HCV-infected patients can be safely transplanted with excellent short-term follow-up. Continued monitoring with sequential liver biopsies will be needed to define the long-term course of HCV infection in an immuno-suppressed population.
Adult↗
Blood pressure in young blacks and whites: relevance of obesity and lifestyle factors in determining differences. The CARDIA Study. Coronary Artery Risk Development in Young Adults.
BACKGROUND: Middle-aged black men and women have higher blood pressure, on average, than whites. However, this pattern is inconsistent in children and adolescents. This study explores how differences in lifestyle factors in young adulthood may influence blood pressure patterns in the two races. METHODS AND RESULTS: The Coronary Artery Risk Development in Young Adults (CARDIA) study is an ongoing collaborative investigation of lifestyle and the evolution of cardiovascular disease risk factors in a random sample of young adults ages 18 to 30 years at baseline (1985 to 1986). Data from four examinations over 7 years were analyzed with the use of a method that simultaneously examined cross-sectional and longitudinal relationships of lifestyle factors and blood pressure. This study included 1154 black women, 853 black men, 1126 white women, and 1013 white men. Blacks had higher systolic blood pressure and diastolic blood pressure than whites at every examination. Racial differences were much greater in women than in men and increased over time. Within each sex-race group, average diastolic blood pressure over four examinations was positively associated with baseline age, body mass index, and alcohol intake and negatively associated with physical activity, cigarette use, and intake of potassium and protein. Longitudinal change in diastolic blood pressure was positively associated with changes in body mass index and alcohol intake. After adjustment for obesity and other lifestyle factors, black-white diastolic blood pressure differences were reduced substantially: 21% to 75% for men and 49% to 129% for women. Results for systolic blood pressure were similar. CONCLUSIONS: Differences in obesity and other lifestyle factors in young adults largely explain the higher baseline blood pressure and greater increase over time of blacks relative to whites.
Adolescent↗
Transplant-associated autoimmune mechanisms in human hepatitis C virus infection.
In order to define factors which are important for the development of hepatitis C virus (HCV) infection and disease in transplant patients, we examined the role of class II MHC antigen restriction in viral antigen presentation to support a hypothesis of the association of this disease with an autoimmune pathogenesis. A greater degree of histocompatibility match between these donors and their HCV-negative recipients was associated with a greater predisposition to recipient HCV liver disease (ALT elevation) posttransplant. The HCV carrier state could be identified with significant amplification of autologous mixed lymphocyte reactivity (AMLR) in both long-term hemodialysis and long-term renal transplant patients, but the AMLR was absent in end-stage liver disease patients with HCV-associated cirrhosis and was insignificantly elevated in these patients with persistent infection in the first 2 years after a new liver was transplanted. There was also a moderate reduction in autologous reactivity as well as serum HCV titers among renal transplant patients who displayed biochemical evidence of chronic liver disease as opposed to those who did not. This appeared later in the course of the disease. HCV RNA could be detected in peripheral blood mononuclear cells (PBMC) of only a portion of HCV-infected renal transplant patients and these showed significantly higher autologous reactivity. In contrast, despite the fact that observations were earlier after de novo liver transplantation, HCV RNA (i.e., earlier in the course of a new or recurrent disease process) was found in PBMC of all liver transplant recipients tested. The AMLR of noninfected laboratory volunteers could be amplified by preincubating their stimulating cells (APCs) with enriched HCV possibly in immune complex (pHCV-IC). This amplification appeared only with specific combinations of HCV strains with HLA DR serotypes. In addition, HCV-primed T cells could be generated to the virus which displayed accelerated activation kinetics. Liver infiltrating lymphocytes extracted from HCV-positive end-stage diseased livers had significantly higher proliferative and cytotoxic reactivity to autologous (HCV-infected) hepatocytes than the extracted lymphocytes responding to autologous hepatocytes from HCV-negative livers. These findings offer evidence of dynamic autoimmune mechanisms in the spectrum of progression of HCV disease and may help to predict the effect of intervention at various intervals in this progression in organ transplant recipients.
Autoimmune Diseases↗
The annual guide to "America's best hospitals": the illusion of quality.
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Hospitals↗
Longitudinal induced IL-2 mRNA monitoring in renal transplant patients immunosuppressed with cyclosporine and in unmodified canine renal transplant rejection.
Immune monitoring of transplant patients to define optimal immunosuppression continues to be important, as rejection occurs despite adjustment of dosaging of CsA or even FK506 to achieve "therapeutic-range" blood levels. Because CsA is known to inhibit upregulation of IL-2 mRNA transcription, we prospectively sequentially measured (induced) IL-2 mRNA in PHA-stimulated PBMC cultures from transplant recipients of kidneys from living-related donors (n = 15) using a quantitative PCR assay, with a potential 24-hour turnaround time, to define immunologic events in real time. Reproducible individual patient sensitivity or refractoriness to CsA was determined pretransplant, by adding a range of CsA concentrations to the PBMC cultures and constructing induced IL-2 mRNA regression inhibition curves. However, this was not predictive of rejection episodes, but did correlate well with individual differences in IL-2 mRNA levels posttransplant, despite similar maintenance trough blood concentrations of CsA between patients. In this prospective study, seven patients experienced rejection episodes despite therapeutic CsA trough levels. Three of these, plus one not receiving CsA therapy, who happened to be prospectively tested at the time that rejection was clinically diagnosed, had a decrease in induced IL-2 mRNA before treatment was instituted. As a correlation to this observation in patients, induced IL-2 mRNA levels in unmodified rejection were sequentially measured in PBMC cultures in autologous vs allogeneic canine renal transplants and IL-2, IL-10, TNF-alpha, and IFN-gamma mRNA were also measured in kidney biopsies. Sequential PHA lymphoproliferation assays of [3H] thymidine incorporation on patient and dog PBMC cultures were also performed. Similar to the observations in patients, unmodified rejection in the canine renal allograft model also was accompanied by a decline of PHA-induced IL-2 mRNA in PBMCs as the serum creatinine concentrations became elevated. In the dog kidney biopsies at later phases of rejection, IL-10 mRNA levels were also significantly elevated (p = 0.032).
Animals↗
Abdominal pain and irritable bowel syndrome in adolescents: a community-based study.
OBJECTIVES: This study was undertaken to determine (1) the prevalence of gastrointestinal symptoms including abdominal pain in a community-based population of adolescents, (2) whether a subgroup of these subjects have symptoms resembling Irritable bowel syndrome (IBS), and (3) whether anxiety and depression are more commonly found in adolescents with IBS-type symptoms compared with unaffected adolescents. METHODS: We collected data by administration of a gastrointestinal symptoms questionnaire, State-Trait Anxiety Inventory, and Children's Depression Inventory to middle school and high school students. RESULTS: A total of 507 subjects participated (mean age of middle school students 12.6 years; mean age of high school students 15.6 years). Abdominal pain was noted by 75% of all students. The pain occurred weekly in 13% to 17% of the subjects and was severe enough to affect activities in approximately 21%. Irritable bowel syndrome-type symptoms were noted by 17% of high school students and 8% of middle school students (p <0.01) who reported abdominal pain (n = 381), representing 14% and 6% of all high school and middle school students (p <0.005), respectively. Anxiety and depression scores were significantly higher for students with IBS-type symptoms compared with those without symptoms. Eight percent of all students had seen a physician for abdominal pain in the previous year. These visits were correlated with abdominal pain severity, frequency, duration, and disruption of normal activities but not with anxiety, depression, gender, family structure, or ethnicity. CONCLUSION: Recurrent abdominal pain and symptoms of IBS are commonly noted in a community-based adolescent population and frequently result in use of health care resources. Health care providers who work with this age group need to be able to recognize the symptom complex associated with IBS, as well as the possible relationship to anxiety and depression.
Abdominal Pain↗
Ethnic differences in carotid wall thickness. The Insulin Resistance Atherosclerosis Study.
BACKGROUND AND PURPOSE: Ethnic differences in cardiovascular disease (CVD) morbidity and mortality have been observed in US adults. However, little data exist on differences in indices of preclinical atherosclerosis such as carotid wall intima-media thickness (IMT) for US non-Hispanic whites, Hispanics, and blacks. This study was undertaken to determine whether there were ethnic differences in carotid wall IMT. METHODS: Internal carotid artery (ICA) IMT and common carotid artery (CCA) IMT, indices of atherosclerosis, were assessed with the use of B-mode ultrasound in 1020 nondiabetic participants in the Insulin Resistance Atherosclerosis Study, a multicenter study designed to examine the association between insulin resistance and carotid atherosclerosis. The study included 281 blacks, 329 Hispanics, and 410 non-Hispanic whites aged 40 to 69 years. RESULTS: Blacks had significantly greater CCA IMT than non-Hispanic whites (865 versus 808 microns); this remained significant after adjustment for major CVD risk factors and insulin sensitivity (864 versus 823 microns). There were no significant differences in ICA IMT between blacks and non-Hispanic whites. Hispanics had significantly lesser CCA IMT than non-Hispanic whites (749 versus 776 microns), and these differences remained significant after adjustment for traditional cardiovascular risk factors and insulin sensitivity (750 versus 778 microns). There were no significant differences in ICA IMT between non-Hispanic whites and Hispanics. CONCLUSIONS: We conclude that ethnic differences exist in CCA but not in ICA IMT in nondiabetic subjects. These differences in IMT, which are indicators of atherosclerosis, are a non-invasive measure that is consistent with some of the data on clinical end points. These differences may be associated with the observed differences in CVD morbidity and mortality among major ethnic groups in the United States.
Arteriosclerosis↗