Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy.

The potential contribution of maturity-onset diabetes of the young (MODY) genes to NIDDM susceptibility in African-American and Caucasian NIDDM-affected sibling pairs with a history of adult-onset diabetic nephropathy has been evaluated. Evidence for linkage to NIDDM was found with polymorphic loci that map to the long arms of human chromosomes 20 and 12 in regions containing the MODY1 and MODY3 genes. Nonparametric analysis of chromosome 20 inheritance data collected with the MODY1-linked marker D20S197 provides evidence for linkage to NIDDM with a P value of 0.005 in Caucasian sib pairs using affected sibpair (ASP) analyses. Non-parametric analysis of chromosome 12 inheritance data collected with the MODY3-linked markers D12S349 and D12S86 provides evidence for linkage to NIDDM with P values of 0.04 and 0.006, respectively, in Caucasian sib pairs using similar analyses. No evidence for linkage of MODY1 and MODY3 markers to NIDDM in African-American sib pairs was observed. In addition, no evidence for linkage to MODY2 (glucokinase-associated MODY) was observed with either study population. Results of multipoint maximum logarithm of odds (LOD) score analysis were consistent with the ASP results. A maximum LOD score of 1.48 was calculated for linkage to MODY1-linked loci and 1.45 to MODY3-linked loci in Caucasian sib pairs. Tabulation of allele sharing in affected sib pairs with D20S197 and D12S349 suggests that affected sibling pairs may inherit susceptibility genes simultaneously from chromosome 20 and chromosome 12. The results suggest that genes contributing to NIDDM in the general Caucasian population are located in the regions containing the MODY1 and MODY3 genes.

Identification of human plasma kallikrein gene polymorphisms and evaluation of their role in end-stage renal disease.

Kallikreins are serine proteases that release kinins from kininogens. Kinins, via their effects on cardiovascular and renal function, may be involved in the pathogenesis of hypertension and renal failure. Two groups of kallikreins exist, glandular or tissue kallikrein and plasma kallikrein. In this study, we examined the human plasma kallikrein gene KLK3 to determine whether it contributed to end-stage renal disease (ESRD) susceptibility. We identified two novel polymorphic sequences closely linked to the KLK3 gene, designated KLK3b and KLK3c (heterozygosities: 0.64 to 0.68 and 0.48 to 0.52, respectively). We mapped the KLK3 gene and the marker KLK3c to the long arm of human chromosome 4 between F11 and D4S426 using a radiation hybrid panel. The study population consisted of 142 sibling pairs concordant for ESRD from 121 African American families. The 142 sibling pairs were stratified into 78 pairs with hypertension- and chronic glomerulonephritis-associated ESRD and 64 with non-insulin-dependent diabetes mellitus-associated ESRD. Linkage analyses, using SIBPAL of SAGE, and exclusion analysis, using MAPMAKERS/SIBS, were performed. Linkage analysis of affected sibling pairs did not reveal any evidence of linkage of KLK3 to ESRD in all 142 sib-pairs or in the two stratified subsets. Exclusion analysis indicated that the KLK3 gene could be excluded from contributing to ESRD at a relative risk of 3 when the maximum log of the odds score of -2 was used as the criterion for exclusion. However, an association analysis using the relative predispositional effect technique showed that alleles 7 and 9 of KLK3b were consistently associated with ESRD. Alleles 7 and 9 were present in 11.2% and 10.8% of the 113 unrelated ESRD probands and in 6.6% and 6.6% of the 204 race-matched control subjects without renal disease (allele P=.0041 and .0016, respectively). Alleles 7 and 9 were also present in 13% and 10.4% of the proband's first siblings (allele P=.00014 and .0087, respectively). The association of KLK3b alleles with ESRD raises the possibility that polymorphisms in KLK3 may play a role in ESRD susceptibility. The lack of linkage might reflect our relatively small family set.

Plasma low density lipoprotein cholesterol concentration in cynomolgus monkeys; differing effects of age and body weight in animals consuming low and high cholesterol diets.

It has been reported in cross-sectional studies that plasma cholesterol concentration does not increase with age in nonhuman primates who consume a cholesterol-free diet over their lifetimes. However, dietary composition and body weight may confound any change in plasma cholesterol concentration during aging, as is the case in humans in industrialized societies. To determine if the relationship between age and plasma cholesterol concentration is affected by dietary cholesterol and body weight in nonhuman primates, we compared post-pubertal male cynomolgus monkeys consuming low cholesterol (0.04 mg cholesterol/kcal; n = 10) and high cholesterol (0.39 mg cholesterol/kcal: n = 21) diets. A univariate repeated measures analysis of covariance of low density lipoprotein (LDL) cholesterol concentration was performed from a longitudinal data set (monkeys aged 5 to 20 years), containing an average of 34 observations per animal. The interaction of age and body weight on LDL cholesterol concentration differed among the two dietary groups. In monkeys consuming the low cholesterol diet, an increase in age was associated with a small increase in mean LDL cholesterol concentration. This effect of age increased with increasing body weight. Monkeys on the high cholesterol diet had higher mean LDL concentration, but showed no significant effect of aging on concentration. Instead, at all ages, LDL concentration was strongly affected (positively) by body weight in this group. A qualitatively similar (but quantitatively smaller) effect of body weight was observed only at older ages in the low dietary cholesterol group. We conclude that the associations of LDL concentration with age and body weight in cynomolgus monkeys are strongly influenced by dietary cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of effects of unmodified niacin on fasting and postprandial plasma lipids in normolipidemic men with hypoalphalipoproteinemia.

PURPOSE: The aim of this study was to define the effects of unmodified niacin on basal lipids and lipoproteins and on the plasma triglyceride response to a fatty meal--postprandial or alimentary lipemia--in individuals with low levels of high-density lipoprotein cholesterol (HDL-C) and normal fasting cholesterol and triglyceride concentrations (normolipidemic hypoalphalipoproteinemia, isolated low HDL-C). PATIENTS AND METHODS: Twenty-eight normolipidemic men (total plasma cholesterol concentration [TC] < 230 mg/dL [< 6 mmol/L], plasma triglyceride [Tg] < 250 mg/dL [2.75 mmol/L]) with low plasma concentrations of HDL-C were randomly assigned to increasing doses of crystalline niacin (up to 3,000 mg/d) or no drug for 12 weeks, then crossed over to the alternate regimen. Outcome measures included changes in plasma lipoproteins and alimentary lipemia. RESULTS: Fifteen participants completed the study. Mean baseline HDL-C +/- SD was 31.7 +/- 6.2 mg/dL (0.82 +/- 0.16 mmol/L). Mean baseline TC, plasma concentration of low-density lipoprotein cholesterol (LDL-C), and Tg were 192 +/- 29.4 mg/dL (4.97 +/- 0.76 mmol/L), 123 +/- 27 mg/dL (3.17 +/- 0.69 mmol/L), and 197 +/- 75 mg/dL (2.17 +/- 0.83 mmol/L), respectively. Unmodified niacin treatment resulted in significant (P < 0.001) reductions of 14% in TC (to 165 mg/dL, 4.26 mmol/L), 40% in Tg (to 119 mg/dL, 1.31 mmol/L), and 18% in LDL-C (to 101 mg/dL, 2.60 mmol/L) and significant increases of 30% in HDL-C (to 42 mg/dL, 1.07 mmol/L), 100% in HDL2 cholesterol (from 5 mg/dL to 9 mg/dL, 0.12 mmol/L to 0.24 mmol/L), and 21% in HDL3 cholesterol (from 27 mg/dL to 33 mg/dL, 0.70 mmol/L to 0.85 mmol/L). Unmodified niacin treatment reduced alimentary lipemia by 45% (P < 0.02). CONCLUSIONS: Crystalline niacin effectively raises HDL-C, lowers LDL-C, and reduces alimentary lipemia in patients with isolated low HDL-C. However, many patients have difficulty tolerating the drug, and supervision may be required to sustain patient compliance and avoid toxicity.

Evaluation of markers on human chromosome 10, including the homologue of the rodent Rf-1 gene, for linkage to ESRD in black patients.

There is abundant evidence supporting the contribution of genetic factors to the development of end-stage renal disease (ESRD) in blacks. Two renal failure susceptibility genes, Rf-1 and Rf-2, have been identified in the fawn-hooded rat, an animal model of hypertension and nephrosclerosis. The human homologous region containing the rodent Rf-1 gene has been localized to chromosome 10q. We tested for genetic linkage between 21 polymorphic markers on human chromosome 10 and chronic renal failure in 129 black sibling pairs concordant for ESRD. Two adjacent markers on 10p, D10S1435 and D10S249 (4 centiMorgans from D10S1435), approached significance for linkage to ESRD in sibling pairs with nondiabetic causes of ESRD (P = 0.035 pairwise, P = 0.082 multipoint for D10S1435; P = 0.074 pairwise, P = 0.063 multipoint for D10S249). The markers spanning the homologous region of Rf-1 did not show evidence for linkage to ESRD in sibling pairs concordant for diabetic ESRD, sibling pairs concordant for nondiabetic causes of ESRD, or in the entire family set. These results suggest that the human homologue of Rf-1 is unlikely to contribute substantially to renal failure susceptibility from the common causes of kidney disease in blacks.

The effect of complete decongestive therapy on the quality of life of patients with peripheral lymphedema.

Lymphedema is a chronic disorder which can adversely affect quality of life (QOL). The purpose of this study was 1) to evaluate whether QOL was improved in patients with lymphedema following Complete Decongestive Therapy (CDT), and 2) whether limb volume change as a result of treatment correlated with change in QOL. Thirty-six patients with peripheral lymphedema from varying causes were enrolled in the study. The QOL of each participant, with regard to physical, functional, and psychosocial concerns, was measured by pre- and post-treatment questionnaires. Percent edema volume reduction was calculated for each patient with only one affected limb. QOL pre- and post-treatment scores were assessed by multivariate repeated measures analysis. QOL scores differed significantly (p<0.05) between pre- and posttreatment in all areas of inquiry. Patients with lower extremity lymphedema had significantly greater mean improvement in QOL scores compared with patients with upper extremity lymphedema (p=0.02). There was no correlation between percent edema volume reduction and post-treatment QOL improvement. This study suggests that significant improvements are made in the QOL of patients exhibiting peripheral lymphedema following CDT, which is not necessarily correlated with limb volume reduction.

Genetic estimates for plasma lipids and lipoproteins in cynomolgus monkeys under assortative mating.

Data obtained from cynomolgus monkeys selected for total plasma cholesterol (TPC) response to dietary cholesterol and nonselected controls were used to estimate heritability of TPC and lipoprotein concentrations. A total of 345 observations were collected on 57 progeny from 18 sires. Heritability estimates obtained by a paternal half-sib analysis and by regression of offspring on mid-parent values were 0.45 +/- 0.24 and 0.69 +/- 0.18 for TPC, 0.63 +/- 0.30 and 0.64 +/- 0.17 for LDLC, and 0.80 +/- 0.36 and 0.59 +/- 0.14 for HDLC, respectively. These results suggest that TPC and lipoprotein concentrations are influenced by additive genetic effects in cynomolgus monkeys, establishing their importance as an animal model for studying the genetics of lipoproteins.

Familial predisposition to nephropathy in African-Americans with non-insulin-dependent diabetes mellitus.

Nephropathy clusters in Pima Indian families with non-insulin-dependent diabetes mellitus (NIDDM), suggesting that susceptibility to nephropathy is distinct from NIDDM per se. The authors compared the family history of end-stage renal disease (ESRD) from 52 African-American patients with NIDDM-induced ESRD (cases) with 45 age-, sex-, and and race-matched non-insulin-dependent diabetics without nephropathy (controls) to assess whether the risk of renal disease was independent from NIDDM in African-Americans as well. Thirty-seven percent (19 of 52) of NIDDM-induced ESRD patients had either a first-, second-, or third-degree relative with ESRD, in contrast to only 7% (3 of 45) of diabetic controls. African-American individuals with NIDDM were at eightfold increased risk for developing subsequent ESRD in the presence of a close relative with ESRD (odds ratio = 8.06; 95% confidence interval, 2.2 to 29.6; P < or = 0.0005). No significant differences were observed in yearly income, years of formal education, total serum cholesterol level, prevalence of smoking, or hypertension between the groups. Diabetic control (assessed by glycosylated hemoglobin and random glucose levels) was suboptimal in nonrenal disease controls, suggesting that hyperglycemia alone fails to cause nephropathy in patients with NIDDM. Family size was unlikely to have influenced the results because diabetic cases had significantly fewer first-degree relatives than did diabetic controls. Familial clustering of ESRD is present in certain African-American families with NIDDM. Differences in family size and degree of diabetic control are unlikely to account for the differences observed between families.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA associations in IgA nephropathy and focal and segmental glomerulosclerosis.

Twenty percent of patients initiating Medicare-supported end-stage renal disease (ESRD) therapy in the United States have chronic glomerulonephritis-induced ESRD. IgA nephropathy (IgAN) and focal and segmental glomerulosclerosis (FSGS) likely account for many of these incident dialysis cases, although patients presenting with advanced renal insufficiency may not receive renal biopsies. To determine whether HLA phenotype associations existed in the subset of IgAN and FSGS patients who develop ESRD, we analyzed HLA frequencies by race in patients with these etiologies of ESRD entered in the South Eastern Organ Procurement Foundation (SEOPF) database. Serologically determined HLA frequencies from 605 renal transplant recipients with ESRD due to FSGS and 196 renal transplant recipients with ESRD due to IgAN were compared with those of 4,506 race-matched cadaveric kidney-donor controls. Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between the HLA system and ESRD due to IgAN and FSGS. Values reported were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-B27 and HLA-DR1 frequencies were increased and HLA-DR2 frequency was decreased in African-American and white IgAN-induced ESRD cases compared with race-matched controls (race-combined OR of 2.10, 1.89, and 0.57, respectively; all P < or = 0.004). HLA frequency differences were not observed in FSGS-induced ESRD patients compared with controls. The results of this study indicate that HLA-B27 and HLA-DR1 are positively associated and HLA-DR2 is negatively associated with IgAN-induced ESRD in patients of both races.(ABSTRACT TRUNCATED AT 250 WORDS)

The familial risk of end-stage renal disease in African Americans.

African Americans have higher overall incidence rates of end-stage renal disease (ESRD) compared with American whites. Hypertensive nephrosclerosis (HN), nephropathy secondary to diabetes mellitus types I and II, and chronic glomerulonephritis (CGN) all occur more frequently in African Americans. To explore the possibility that hereditary factors may play a role in the increased risk of ESRD in African Americans, the family history of 131 African American hemodialysis patients (cases) was compared with 115 age-, sex-, and race-matched non-ESRD controls. Odds ratios (ORs) were calculated to define the prevalence of a relative with ESRD among cases versus controls. Chi-square values were estimated from a log-linear model, while controlling for gender, to test for significance of ORs. Forty percent (12/30) of HN cases, 35% (18/51) of type II diabetes mellitus-induced renal failure cases, and 13% (5/38) of CGN cases had a first-, second-, or third-degree relative with ESRD. The presence of a first-degree relative with ESRD increased an African American's risk for developing ESRD ninefold (OR, 9.13; 95% confidence interval [CI], 2.6 to 31.8; P < 0.001). The presence of a first- or second-degree relative increased the risk fivefold (OR, 5.23; 95% CI, 2.2 to 12.3; P < 0.0002). First-, second-, or third-degree relatives with ESRD were more prevalent among cases with ESRD due to hypertension and type II diabetes mellitus compared with CGN (P < or = 0.05). Gender differences among the ORs were nonsignificant (P > 0.2) and socioeconomic class (level of education and income) did not differ markedly between cases and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial risk, age at onset, and cause of end-stage renal disease in white Americans.

A strong familial clustering of ESRD has been reported among African Americans, suggesting that factors predisposing to renal failure, whether genetic, environmental, or both, may disproportionately affect certain families. A case-control study was undertaken to determine if a familial risk of ESRD was present among white Americans, if this risk differed among causes of ESRD, and if variability in age at onset was attributed to familial factors. Data were obtained from 103 white American patients (cases) with ESRD receiving dialysis treatments at the Bowman Gray School of Medicine's affiliated dialysis facility in Winston-Salem, NC. One hundred three age-, sex- and race-matched non-ESRD controls were consecutively selected from the Wake Forest University Physicians internal medicine clinic. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated to signify the prevalence of a relative with ESRD among cases versus controls. The presence of either a first- or second-degree relative increased a white American's risk for developing ESRD nearly threefold (OR = 2.7, 95% CI 1.1 to 7.2; P = 0.038), whereas the presence of either a first-, second- or third-degree relative with ESRD increased the risk nearly fourfold (OR = 3.5, 95% CI 1.5 to 8.4; P = 0.004). Cases with chronic glomerulonephritis and Type II diabetic nephropathy as the cause of ESRD had relatives with ESRD more often than cases with Type I diabetic nephropathy, interstitial nephritis, or renal artery stenosis. The average correlation (f) of ages at onset of ESRD among individuals in a single family (cases and their relatives) was 55%.(ABSTRACT TRUNCATED AT 250 WORDS)

A twenty-year retrospective analysis of the efficacy of epidural analgesia-anesthesia when administered and/or managed by obstetricians.

OBJECTIVE: The purpose of this study was to retrospectively determine the safety and efficacy of epidural anesthesia when administered by obstetricians in a community hospital. STUDY DESIGN: Data containing 14,598 epidural procedures from 31,818 births were obtained from delivery room logs over a period of 20 years, from 1972 through 1991. Data were displayed graphically to view trends over time. Odds ratios were calculated to determine the associations of epidural anesthesia with oxytocin stimulation, episiotomy, assisted vaginal delivery (forceps or vacuum extraction), and cesarean section. Particular scrutiny was given to any listed complication during labor or delivery. RESULTS: Over the 20-year period epidural anesthesia was administered without serious complication by various obstetricians with different training. Technique improved as procedures became standardized, resulting in an increase in the number of epidural procedures over the 20-year period. Incidence was also increased among women requiring oxytocin augmentation, episiotomies, and assisted vaginal deliveries. Of the total number performed, < 5% of patients required additional anesthesia. CONCLUSION: Over a 20-year period epidural analgesia or anesthesia has been an effective and safe procedure when performed and supervised by obstetricians-gynecologists in a community hospital.

Linkage analysis between loci in the renin-angiotensin axis and end-stage renal disease in African Americans.

The factors that initiate chronic renal failure in patients with hypertension, diabetes mellitus, and chronic glomerular disease are largely unknown. The likely genetic contribution to ESRD, particularly in African Americans, suggests that linkage analysis may be useful to evaluate the role of candidate genes in the pathogenesis of chronic renal failure. The renin-angiotensin-aldosterone (RAA) axis has been intensively evaluated for its contribution to cardiovascular disease and nephropathy. This study tested for linkage between candidate genes in the RAA axis and chronic renal failure, using 85 African-American sibling pairs (from 65 families) concordant for ESRD. Angiotensinogen was selected because of the putative link between it and mild to moderate essential hypertension and nephrosclerosis; angiotensin-converting enzyme because of its possible contribution to diabetic nephropathy; and renin, the angiotensin II receptor, and kallikrein because of their roles in hypertension and renal perfusion. These candidate loci did not demonstrate linkage to either diabetic or nondiabetic renal disease in this study's collection of sibling pairs. These results suggest that polymorphisms at these RAA axis loci do not make major contributions to the pathogenesis of renal disease in African Americans.

HLA associations in end-stage renal disease due to membranous glomerulonephritis: HLA-DR3 associations with progressive renal injury. Southeastern Organ Procurement Foundation.

Membranous glomerulonephritis (MGN) is the most common cause of idiopathic glomerulonephritis in American adults. African-Americans develop end-stage renal disease (ESRD) due to chronic glomerulonephritis four times more often than whites. To determine whether HLA phenotype associations existed in the subset of MGN patients with ESRD we analyzed HLA frequencies, by race, in patients with MGN entered in the Southeastern Organ Procurement Foundation registry between 1982 and 1992. HLA frequencies from 250 renal transplant patients with MGN (190 whites and 60 African-Americans) were compared with 4,506 race-matched cadaveric kidney donor controls (4,039 whites and 467 African-Americans). Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between MGN and HLA frequencies. The reported values were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-DR3 and HLA-DR5 frequencies were increased in cases of both races compared with race-matched controls (race-combined ORs, 2.22 and 1.61, respectively; all P < 0.02). Interracial analyses revealed that HLA-DR7 frequency was decreased solely in whites with MGN (OR, 0.53; P < 0.04). The results of this study indicate that HLA-DR3 and HLA-DR5 are positively associated with ESRD due to MGN in patients of both races and that HLA-DR7 is negatively associated with MGN in whites. These analyses confirm the published reports of HLA-DR3 association with MGN in Chinese, French, British, Chilean, and American white populations. The novel association of HLA-DR5 may reflect the fact that the MGN cases in this study all had ESRD.(ABSTRACT TRUNCATED AT 250 WORDS)

A race-controlled human leukocyte antigen frequency analysis in lupus nephritis. The South-Eastern Organ Procurement Foundation.

Systemic lupus erythematosus (SLE) has higher incidence and mortality rates in addition to a greater risk for nephropathy in African Americans (blacks), compared with whites. We analyzed the South-Eastern Organ Procurement Foundation (SEOPF) database from 1982 through 1986 to determine if variation in human leukocyte antigen (HLA) frequencies, beyond those normally present between the races, were associated with lupus nephritis (LN). HLA antigen frequencies in 271 black and 230 white renal transplant recipients with LN as the cause of end-stage renal disease (ESRD) were compared with 4,506 race-matched cadaveric kidney donor controls. Odds ratios (ORs) and chi-square values were computed to assess the prevalence of each HLA phenotype among the cases versus the controls separately for blacks and whites. HLA-B8 and -DR2 frequencies were increased, and HLA-DR4 frequency was decreased in cases of both races compared with race-matched controls (race-combined ORs, 1.68, 1.46, and 0.49, respectively; all P < 0.01). Race-specific analyses showed that HLA-DR6 was decreased in black cases versus black controls (OR, 0.48; P < 0.001) and HLA-DR3 was increased in white cases versus white controls (OR, 1.88; P < 0.001). HLA-B8 and DR2 are positively associated and HLA-DR4 is negatively associated with LN in patients of both races. HLA-DR3 and -DR6 demonstrate race-specificity in LN and place whites at a disadvantage relative to blacks. It is likely that non-HLA-mediated genetic factors and/or environmental factors contribute to the increased risk of nephritis observed in black patients with SLE.(ABSTRACT TRUNCATED AT 250 WORDS)

Collateral perfusion through overlapping vessels reduces canine right ventricular ischemic injury from positive end-expiratory pressure.

OBJECTIVE: To test, in a canine model of right ventricular ischemia with 15 cm H2O positive end-expiratory pressure, whether collateral perfusion through overlapping vessels from the left ventricle to the right ventricular free wall can reduce infarct size. DESIGN: Randomized, prospective, controlled, experimental study in dogs. SETTING: Anesthesia research laboratory of an academic medical center. SUBJECTS: Twenty microfilaria-free mongrel dogs. INTERVENTIONS: Anesthetized, closed-chest dogs were managed with the application of 15 cm H2O positive end-expiratory pressure. The right coronary artery was ligated (90 mins) with occlusion (n = 10) and without occlusion (n = 10) of overlapping vessels. MEASUREMENTS AND MAIN RESULTS: Myocardial blood flow (using radioactive microspheres) was measured in the area at risk (gentian violet) and in the area of necrosis (triphenyltetrazolium chloride). With right coronary and overlapping vessel occlusion, blood flow in the area at risk decreased from 80.1 +/- 14.0 to 9.0 +/- 1.7 mL/min/100 g after 5 mins of ischemia (p = .0001) and remained depressed at 8.7 +/- 1.8 mL/min/100 g after 75 mins of ischemia. With right coronary occlusion alone, blood flow decreased after 5 mins of ischemia from 64.8 +/- 5.4 to 14.3 +/- 1.9 mL/min/100 g (p = .0001 compared with baseline), which was 60% greater than the group with occluded collateral vessels (p = .0055). Moreover, after 75 mins of ischemia, blood flow in the area at risk increased further to 28.9 +/- 5.4 mL/min/100 g with patent overlapping vessels (p = .0001 compared with 5-min value). The patency of overlapping vessels during right ventricular free wall ischemia reduced the area at risk from 68.5 +/- 2.4% to 38.6 +/- 5.1% (p = .0001) and the area of necrosis/area at risk from 58.1 +/- 8.4% to 16.9 +/- 3.6% (p = .0007). CONCLUSIONS: Despite 15 cm H2O positive end-expiratory pressure, perfusion through overlapping vessels improved peri-ischemic blood flow in the area at risk, thereby reducing the size of the risk area and the amount of right ventricular free wall necrosis.

Familial clustering of end-stage renal disease in blacks with lupus nephritis.

The factors that determine a patient's susceptibility to specific target organ involvement in systemic lupus erythematosus (SLE) remain unknown. Lupus nephritis can be a particularly devastating complication, with an increased mortality and the risk of progressive renal damage resulting in end-stage renal disease (ESRD). This analysis was performed to determine whether renal disease aggregated in select families or was a sporadic complication in patients with SLE. We compared the family history of ESRD in 50 patients with SLE complicated by lupus nephritis with 37 controls who had SLE but lacked nephritis after a mean follow-up duration of more than 11 years. The frequency of relatives with ESRD in the lupus nephritis cases was compared with that in controls using Fisher's exact test (significance at P < or = 0.05). Fifty percent (25) of the 50 lupus nephritis patients were black and 50% (25) white, in contrast to 35% (13) and 65% (24) of the 37 lupus non-nephropathy controls, respectively. A first-, second-, or third-degree relative with ESRD was present in 16% (eight) of the 50 lupus nephritis cases and in 0% of the 37 SLE non-nephropathy controls (P = 0.019, Fisher's exact test, two-tail). Twenty-eight percent (seven) of the 25 black patients with lupus nephritis had relatives with ESRD compared with 0% of the 13 black lupus non-nephritis controls (P = 0.07). Only one of the eight relatives with ESRD had SLE or a collagen vascular disease. Lupus nephritis patients and the non-nephritis controls had similar ages (mean +/- SD: 38.5 +/- 10.0 years v 46.6 +/- 11.8 years; P = 0.28), family sizes (6.27 +/- 2.61 first-degree relatives v 6.35 +/- 3.25 first-degree relatives; P = 0.16), and duration of SLE (9.26 +/- 5.94 years v 11.35 +/- 6.43 years; P = 0.60). Familial clustering of ESRD was observed in black patients with SLE who had nephritis. This was unlikely to be related to differences in patient age, family size, or duration of SLE. This data, coupled with the known familial aggregation of ESRD in blacks with hypertensive and diabetic ESRD, supports the contention that genetic factors contribute to the familial clustering. The presence of relatives with etiologies of ESRD other than SLE suggests that there is an inherited susceptibility to progressive renal failure, independent of the etiology of ESRD.

Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans.

Hypertension, diabetes mellitus and chronic glomerular diseases reportedly cause in excess of 80% of the incident cases of end-stage renal disease (ESRD) in the U.S. The factors that initiate progressive renal failure in patients with these disorders remain unknown. Several investigators have reported enhanced synthesis and activity of cytokines in the kidneys of patients with renal failure. The ensuing inflammation and fibrosis have been postulated to contribute to the development of progressive renal failure. There is also abundant evidence supporting the contribution of genetic factors in ESRD susceptibility based upon the strong familial clustering of ESRD, particularly in African Americans. Therefore, genetic linkage analysis may be useful to evaluate the role of candidate genes in several cytokine cascades that could contribute to the pathogenesis of chronic renal failure. We tested for genetic linkage between eight cytokine candidate genes and chronic renal failure in a collection of African American sibling pairs concordant for ESRD. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta 1, TGF-beta 2 and TGF-beta 3, and tumor necrosis factor (TNF)-alpha and TNF-beta candidate genes were selected for analysis due to their putative roles in diabetic renal disease and chronic glomerulonephritis. The interleukin-1 receptor antagonist gene (IL1RN) was also genotyped due to its reported association with diabetic nephropathy. Non-parametric (genetic model independent) affected sib pair linkage analysis was used to evaluate evidence for linkage. In order to genotype TGF-beta 3, we identified four closely linked, previously unidentified, highly polymorphic microsatellite loci near the TGF-beta 3 gene. Linkage of ESRD and transforming growth factor beta 2 polymorphisms on human chromosome 1 approached significance for non-diabetic nephropathy (predominantly chronic glomerular disease, hypertensive nephrosclerosis and unknown etiology) (P = 0.08), but showed no linkage to diabetic nephropathy. The other candidate loci did not demonstrate linkage to ESRD in the total population or in the subgroups with diabetic or non-diabetic etiologies of ESRD. The IL1RN gene did not show significant evidence for linkage to ESRD; however, we did confirm an association between allele 2 of IL1RN and ESRD (as reported in diabetic nephropathy). Overall, these results suggest that these growth factor loci do not make major contributions to the pathogenesis of ESRD in African Americans.

Dobutamine increases heart rate more than epinephrine in patients recovering from aortocoronary bypass surgery.

To determine whether epinephrine might prove to be a cost-effective substitute for dobutamine, two 8-minute infusions of either epinephrine (10 and 30 ng/kg/min, n = 28) or dobutamine (2.5 and 5 micrograms/kg/min, n = 24) were administered to 52 patients recovering in the intensive care unit (ICU) after aortocoronary bypass (CABG) surgery. At the higher dose, both drugs significantly (P < .05) increased cardiac index (CI), epinephrine from 2.8 +/- 0.1 at baseline to 3.3 +/- 0.1 L/min/m2, and dobutamine from 3.2 +/- 0.1 at baseline to 4.1 +/- 0.2 L/min/m2. Epinephrine increased CI significantly less than dobutamine. Both drugs significantly increased stroke volume index (SVI), epinephrine from 32 +/- 1 at baseline to 36 +/- 1 mL/beat/m2, and dobutamine from 36 +/- 1 at baseline to 40 +/- 2 mL/beat/m2. At the higher dose, the effects of the two drugs on SVI were indistinguishable. On the other hand, while the higher dose of both drugs significantly increased heart rate (HR), epinephrine from 88 +/- 2 at baseline to 90 +/- 2 beats/min and dobutamine from 89 +/- 2 at baseline to 105 +/- 3 beats/min, the increase following the higher dose of dobutamine was significantly greater than that seen after epinephrine. Effects of the two drugs on mean arterial pressure, central venous pressure, pulmonary artery occlusion pressure, systemic vascular resistance, pulmonary vascular resistance, and left-ventricular stroke work did not significantly differ. Similar results were obtained in the subset of patients with baseline CI less than 3 L/min/m2 who more closely resembled patients who might acutely require inotropic drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined inotropic effects of amrinone and epinephrine after cardiopulmonary bypass in humans.

Amrinone, a phosphodiesterase inhibitor, and epinephrine, an alpha- and beta-adrenergic receptor agonist, are inotropic drugs used during cardiac surgery to reverse myocardial depression after cardiopulmonary bypass. However, these drugs have not been compared separately, or in combination, in this patient population. We hypothesized that the combination might have complementary actions in improving myocardial function. We, therefore, compared amrinone, epinephrine, and the combination of amrinone and epinephrine in a randomized, blinded, placebo-controlled study in patients undergoing coronary artery bypass grafting. Forty patients with ejection fractions > 0.45 were studied. Right ventricular ejection fraction pulmonary artery catheters and radial arterial catheters were inserted before fentanyl-midazolam anesthesia. After separation from bypass, patients received either a placebo (n = 20) or amrinone bolus (1.5 mg/kg, n = 20) at time 0 and a placebo (n = 20) or epinephrine (30 ng.kg-1.min-1, n = 20) infusion at time 5 min. This resulted in four study groups, n = 10 in each group. Data were collected every 2.5 min for 10 min. Epinephrine, amrinone, and the combination of both drugs significantly increased cardiac output, stroke volume, O2 delivery, and left ventricular stroke work. The increase in stroke volume (P < 0.05) was 12 +/- 6, 16 +/- 4, and 30 +/- 4 mL/beat with epinephrine, amrinone, and the combination of amrinone and epinephrine, respectively. The amrinone-epinephrine combination increased stroke volume as much as the sum of amrinone and epinephrine given separately. Systemic vascular resistance and pulmonary vascular resistance decreased with amrinone and amrinone-epinephrine, but not with epinephrine. Epinephrine increased mean arterial and mean pulmonary arterial pressures. Right ventricular ejection fraction did not significantly increase (P = 0.09) with epinephrine, but increased significantly with amrinone (0.45 to 0.53, P = 0.01), and with the combination (0.43 to 0.55, P = 0.006). These data indicate that amrinone and epinephrine effectively increase myocardial performance during cardiac surgery. Right ventricular function especially was improved with amrinone and the combination of amrinone and epinephrine. The combined effects of amrinone and epinephrine may be useful in patients recovering from the ischemia and reperfusion injury resulting from coronary artery bypass grafting.