A multicenter controlled, randomized, open trial of interferon alpha2b treatment of anti-human immunodeficiency virus-negative hemophilic patients with chronic hepatitis C. Hepatitis Study Group of the Association of Italian Hemophilia Centers

There is limited information about the long-term efficacy of prolonged therapy (more than 6 months) with interferon alpha in hemophilic patients with chronic hepatitis C who are not coinfected with the human immunodeficiency virus (HIV-1). One hundred and seven hemophiliacs were randomly assigned to 3 million U of interferon alpha2b three times weekly for 12 months or no therapy. The patients were followed up for at least 12 months posttreatment. Response was assessed by both serial alanine aminotransferase (ALT) levels and hepatitis C virus (HCV)-RNA measured by reverse transcribed polymerase chain reaction (RT-PCR) method. Before treatment, serum levels of HCV-RNA were measured quantitatively by second-generation branched-DNA assay and the HCV genotype was determined by RT-PCR. Serum HGV-RNA, a marker of infection with the hepatitis G virus, was also measured by RT-PCR. Normalization of ALT was sustained and serum HCV-RNA was cleared in 6 of 45 treated patients, compared with none of the 50 untreated controls (13% v 0% P < .01). Low pretreatment viremia was the only feature that was associated with an increased likelihood of sustained response (P < .01). This study shows that multitransfused hemophiliacs with chronic hepatitis C not coinfected with HIV-1 respond at low rates to prolonged interferon therapy.     

Nanomolar quantification and identification of various nitrosothiols by high performance liquid chromatography coupled with flow reactors of metals and Griess reagent

To evaluate the histological findings in patients with chronic hepatitis C and autoimmune features, liver tissue specimens from 60 patients were graded under code for individual features and composite patterns that denoted autoimmune, viral, combined autoimmune and viral, and nondiscriminative changes. Portal, interface, and acinar hepatitis in any combination with plasma cell infiltration connoted an autoimmune pattern that was associated with higher serum levels of gamma-globulin (2.4 +/- 0.2 g/dL vs. 1.7 +/- 0.1 g/dL; P = .0003) and immunoglobulin G (2,211 +/- 227 mg/dL vs. 1,508 +/- 83 mg/dL; P = .001) than patients with other patterns. Patients with the autoimmune pattern also had a greater frequency of cirrhosis (43% vs. 8%; P = .003), higher mean Knodell score (13.2 +/- 0.9 vs. 6.8 +/- 0.9; P < .0001), and a greater occurrence of high-titer smooth muscle antibodies (SMA) (13% vs. 0%; P = .05) than patients with other histological findings. HLA DR3 also occurred more frequently in these individuals than in other patients (48% vs. 15%; P = .01) and normal subjects (43% vs. 16%; P = .01). Patients with nondiscriminative patterns and interface hepatitis had clinical findings similar to those with autoimmune patterns, except for a lower mean serum level of gamma-globulin. We conclude that the composite histological pattern that resembles autoimmune hepatitis is associated with greater immunoreactivity, inflammatory activity, and disease severity than other patterns. Interface hepatitis may be the most important histological finding associated with these clinical manifestations.     

Lipoprotein lipase activity and plasma triglyceride clearance are elevated in endurance-trained women

Numerous studies have examined factors regulating high-density lipoprotein cholesterol (HDL-C) levels in male endurance athletes, but few studies have examined HDL-C regulation in female athletes. The present study compared lipid and lipoprotein concentrations, postheparin lipolytic activities, and the clearance rate (K2) of triglycerides following an intravenous fat infusion in 12 female distance runners (aged 33 +/- 9 years, mean +/- SD) and 13 sedentary women (33 +/- 9 years). Runners were leaner and had greater maximum oxygen uptake values than controls. Runners also had nonsignificantly lower triglyceride (53 +/- 15 v 65 +/- 13 mg/dL) and higher HDL-C (62 +/- 14 v 52 +/- 8 mg/dL, P = .06). Lipoprotein lipase activity (LPLA) was 33% greater (P < .05) and fat clearance (K2) was 27% faster (P < .01) in the trained women, and LPLA correlated directly with K2 (r = .61) and HDL-C (r = .62) in this group (P < .05 for both). K2 was directly related to HDL-C in the athletes (r = .57, P = .06), and also when the active and sedentary women were combined (r = .43, P < .05). These results suggest that increased LPLA and enhanced plasma triglyceride clearance may contribute to the HDL-C levels of physically active premenopausal women.     

On the experimental distinction between ssbs and dsbs in circular DNA

Positive serum anti-nuclear antibody (ANA) and anti-smooth muscle antibody (SMA) have been reported in 10-66% of patients with chronic hepatitis C virus (HCV) infection from Western countries. However, the mechanism involved in this immunological disorder is still unknown. This study was carried out to evaluate the prevalence and clinical significance of positive serum auto-antibodies in Chinese patients with chronic hepatitis C and to assess the role of serum HCV-RNA titre and HCV genotype in the presence of serum auto-antibodies. Serum ANA, SMA and anti-mitochondrial antibody (AMA) were measured in 122 patients with chronic hepatitis C. Clinical, biochemical and virological data (serum HCV-RNA titre and HCV genotype) were compared between patients with and without serum auto-antibodies. Fifty-eight (48%) patients were associated with positive serum auto-antibodies: 42 (34%) positive for ANA, six (5%) positive for SMA, nine (7%) positive for both ANA and SMA and one (1%) positive for AMA. Clinical parameters (age, sex, blood transfusion history), liver biochemical tests, the presence of cryoglobulinaemia or cirrhosis, and the response to interferon treatment were not significantly different between patients with and without positive serum auto-antibodies. Serum HCV-RNA levels and HCV genotypes were also not significantly different between the two groups. Logistic regression analysis showed that none of the previously mentioned parameters were significant predictors to associate with serum auto-antibodies in chronic hepatitis C. We concluded that 48% of Chinese patients with chronic hepatitis C were associated with positive serum auto-antibodies. Hepatitis C virus genotypes and serum HCV-RNA levels were not correlated to the presence of serum auto-antibodies. The clinical significance and actual pathogenesis of this phenomenon remain to be clarified.     

The neuroprotective effect of the glycine site antagonist 3R-(+)-cis-4-methyl-HA966 (L-687,414) in a rat model of focal ischaemia

BACKGROUND: Cardiovascular conditioning reduces resting myocardial oxygen demand by lowering systolic blood pressure and heart rate. Lower myocardial oxygen demand at rest would be expected to be associated with a decrease in resting myocardial blood flow and, consequently, an increase in myocardial flow reserve as the ratio of hyperemic to resting blood flow. However, the effect of controlled exercise together with a low-lipid diet on myocardial blood flow and flow reserve has not been examined in humans. METHODS AND RESULTS: Myocardial blood flow at rest and after dipyridamole-induced hyperemia (0.56 mg/kg i.v.) was quantified with [13N]ammonia and positron emission tomography in 13 volunteers before and upon completion of a 6-week program of cardiovascular conditioning and a low-fat diet. Exercise capacity and serum lipid profiles were also assessed at the start and finish of the program. Eight normal volunteers of similar age not participating in the conditioning program served as a control group. Cardiovascular conditioning lowered the resting rate-pressure product (8859 +/- 2128 versus 7450 +/- 1496, P < .001), serum cholesterol (217 +/- 36 versus 181 +/- 26 mg/dL), LDL cholesterol (140 +/- 32 versus 114 +/- 24 mg/dL), and triglycerides (145 +/- 53 versus 116 +/- 33 mg/dL, all P < .05). Exercise tolerance (metabolic equivalent of the task, METs) improved significantly from 10.0 +/- 3.0 to 14.4 +/- 3.6 (P < .01). Resting blood flow decreased (0.78 +/- 0.18 versus 0.69 +/- 0.14 mL.g-1.min-1, P < .05), whereas hyperemic blood flow increased (2.06 +/- 0.35 versus 2.25 +/- 0.40 mL.g-1.min-1, P < .05), resulting in an improved myocardial flow reserve (2.82 +/- 1.07 versus 3.39 +/- 0.91, P < .05). Overall, the myocardial flow reserve was significantly related to exercise performance (METs). In the control group, no changes in resting rate-pressure product, serum cholesterol levels, exercise performance, resting or hyperemic myocardial blood flow, or flow reserve were observed. CONCLUSIONS: Short-term cardiovascular conditioning together with a low-fat diet results in an improved myocardial flow reserve by lowering resting blood flow and increasing coronary vasodilatory capacity. These changes are associated with an improved exercise capacity and may offer a protective effect in patients with coronary artery disease.     

Molecular epidemiology of hepatitis C in Australia

The aim of this study was to determine the distribution of hepatitis C virus (HCV) genotypes in Australian patients with hepatitis C and to identify factors associated with particular genotypes. Serum isolates of HCV-RNA were genotyped using a commercial oligonucleotide hybridization (line probe) assay. Relationships between demographic factors, mode of HCV transmission and HCV genotype were assessed by logistic regression analysis. Among 463 patients with hepatitis C, 425 tested positive for HCV-RNA and a single HCV genotype was identified in 420 cases. The patients' places of birth were Australia or New Zealand (62%), Asia (13%), Europe (12%), Mediterranean (6%), Middle East (6%) and other countries (< 1%). The most common genotypes were type 1 (52%) or type 3 (32%); type 2 (9.3%), type 4 (5.5%) and type 6 (1.7%) were less common. Patients with genotype 1b were older (48 +/- 13 years, P< 0.001) and patients with genotype 3 were younger than the remaining patients (37 +/- 11 years vs 42 +/- 12 years, P< 0.001). Among type 1 isolates, 1b was more common for patients born outside Australia compared with those born in Australia (50% vs 13%, P< 0.001) whereas non-1b subtypes were more common among Australian-born patients. Likewise, 21 of 23 (91%) patients with type 4 were from Egypt and six of seven (86%) with type 6 were from Vietnam. The relative importance of parenteral risk factors for HCV also varied according to geographic origin. Thus, a definite risk factor for HCV acquisition was identified in > 95% of Australian-born patients, but in only 33% of Asian or Mediterranean-born patients. Logistic regression analysis indicated that region of birth and risk factor (intravenous drug use or not) would allow 98% of type 4 cases and 76% of type 1b cases to be identified correctly. In summary, region of birth, patterns of migration over time and risk factors for transmission of HCV interact to determine the distribution of HCV genotypes in a multi-racial community like Australia.     

Hepatitis C virus and non-Hodgkin's lymphomas

Hepatitis C virus (HCV) seems to be the aetiologic agent of mixed cryoglobulinaemia, and as this 'benign' lymphoproliferative disorder can frequently develop into more aggressive haematological disorders, this study was undertaken to determine the prevalence of HCV infection in non-Hodgkin's lymphomas. 199 unselected subjects treated by three haematological centres in Northeast Italy were investigated for the presence of HCV infection. As controls, the prevalence of HCV infection was determined in a group of patients affected by other haematological malignancies (153 subjects) and in the general population of the same geographical area in the cohort study called the Dyonisos project (6917 subjects). The presence of anti-HCV antibodies was determined by a commercial kit and, in positive cases, by PCR amplification of the 5' untranslated region of the virus. The HCV genotype was also obtained by PCR amplification of the Core region with type-specific primers. The presence of serum cryoglobulins was determined in each case of NHL. HCV infection was significantly (P < 0.00000001) higher in patients with non-Hodgkin's lymphomas (28.0%) when compared with that of the general population (2.9%), and with the group of patients affected by other malignancies (3.1%). The prevalence is particularly high in low-grade (38.4%), as compared with intermediate (11.4%), or high-grade (15.2%) lymphomas. The presence of the virus is significantly (P < 0.000001) associated with the presence of detectable levels of cryoglobulins. On the basis of these findings. HCV seems to play an important role in the development of low-grade non-Hodgkin's lymphomas.     

Immunosuppression may lead to progression of hepatitis C virus-associated liver disease in hemophiliacs coinfected with HIV

OBJECTIVE: The aim of this study was to examine the interaction between HIV and hepatitis C virus (HCV) in hemophiliacs coinfected with the viruses and to investigate the possible relationship between immunosuppression and liver failure. METHODS: To identify risk factors for impending liver failure in hemophiliacs coinfected with HIV and HCV, we analyzed clinical and laboratory parameters, including CD4 count, aminotransferases (ALT, AST), cholinesterase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase, during 3 yr of follow-up (1990-1993) in four groups of patients: hemophiliacs with progressive immunodeficiency who were coinfected with HCV and HIV (group A, n = 49); hemophiliacs with stable immune function who were seropositive for HIV and HCV (group B, n = 95); hemophiliacs who were infected with HCV but not HIV (group C, n = 72); and homosexuals with progressive immunodeficiency who were infected with HIV but not HCV (group D, n = 24). RESULTS: Univariate analysis of data for group A showed a significant rise in gamma-glutamyltransferase and alkaline phosphatase (p < 0.01) that was not seen in groups B, C, and D. In a multivariate Cox regression analysis, age (odds ratio, 1.054 per yr; 95% confidence interval, 1.014-1.096 per yr), decline in CD4 count (odds ratio, 1.063 per cell/microl; 95% confidence interval, 1.037-1.091 per cell/microl), and alkaline phosphatase level (odds ratio, 1.012 per U/L; 95% confidence interval, 1.002-1.021 per U/L) emerged as independent determinants of death. CONCLUSIONS: Our data suggest that progressive immune dysfunction in hemophiliacs coinfected with HIV and HCV may influence progression of liver failure. In these patients cholestasis is an additional prognostic marker for survival that may reflect both exhausted immunity and impaired liver function.     

Physicochemical changes in HDL3 after bezafibrate treatment: influence on free cholesterol efflux from human fibroblasts

Presently, aluminum utensils are widely used in the world, especially in the developing countries. However, whether aluminum leaching from such utensils contributes to aluminum accumulation or causes any damage in patients with renal disease remains unknown. We designed a prospective study to evaluate this problem. After excluding patients who were not examined at follow-up or who poorly complied during the study period, the opened randomized study consisted of 42 patients with chronic renal insufficiency (creatinine clearance <60 mL/min and >10 mL/min). All patients had not taken any aluminum-containing agents for 3 months, but used aluminum kitchen utensils for more than 1 year. Twelve patients comprised the control group; the other 30 patients comprised the study group. The aluminum kitchen utensils used by the study group patients were replaced with stainless steel utensils for 3 months, but those used by the control group were not. After 3 months, the decrements of serum aluminum (5.5 +/- 4.6 microg/L v 2.1 +/- 3.5 microg/L; P = 0.012) and daily urine aluminum excretion (14.3 +/- 15.2 microg/d v 2.1 +/- 5.6 microg/d; P = 0.005) in the study group patients were greater than those in the control group patients. The increments of transferrin saturation of the study group patients (1.8% +/- 9.5% v -3.7% +/- 9.5%; P = 0.052) were greater than those of the control group patients. In addition, the increments of iron (r = 0.368, P = 0.035) and transferrin saturation (r = 0.345, P = 0.049) positively correlated with the decrements of daily aluminum excretion in all patients. The study group patients with greater decrements of serum aluminum (>5.5 microg/L) had greater serum iron levels (90.2 +/- 27.7 microg/dL v 71.9 +/- 27.8 microg/dL; P = 0.047) and transferrin saturation (30.5% +/- 11.0% v 23.0% +/- 9.5%; P = 0.046) than those with less decrements of serum aluminum (<5.5 microg/L) after the study. Our study demonstrates that aluminum kitchen utensils may be the important aluminum exposure source for patients with chronic renal insufficiency who are not taking aluminum-containing agents, and hints that the long-term exposure of aluminum leaching from aluminum utensils probably affects iron levels in patients with chronic renal insufficiency. Further studies are clearly needed to confirm this observation.     

Variations in plasma volume affect total and low-density lipoprotein cholesterol concentrations during the menstrual cycle

Serum lipids are known to vary during the menstrual cycle. To determine if changes in plasma volume contribute to this effect, we determined serum lipids, lipoproteins, and estimated changes in plasma volume in 18 premenopausal women at the start of and at 5-day intervals after menstruation. Eleven men served as a comparison group. Changes in plasma volume were estimated from changes in hemoglobin and hematocrit. Total and low-density lipoprotein (LDL) cholesterol (mean +/- SD) increased 15 +/- 14 mg/dL (9% +/- 10%) and 11 +/- 13 (11% +/- 14%) within 10 days after the start of menstruation (P < .05) and then decreased toward baseline during the rest of the cycle. High-density lipoprotein (HDL) cholesterol increased 3 mg/dL, or 5%, (P < .05) on days 10 and 15 after menstruation. Plasma volume decreased 4% +/- 9% (P < .06) 10 days after the start of menstruation, and this maximum decrease in plasma volume coincided with peak increases in total, LDL, and HDL cholesterol. Except for an 8-mg/dL increase in LDL cholesterol at day 5, lipid changes were no longer significant after adjusting for changes in plasma volume. We conclude that alterations in plasma volume account for approximately half of the increase in total and LDL cholesterol during the menstrual cycle.     

Therapeutic efficiency of lipoprotein(a) reduction by low-density lipoprotein immunoapheresis

This study was performed to investigate the effect of low-density lipoprotein (LDL) immunoapheresis on lipoprotein(a) [Lp(a)] reduction in patients with heterozygous and homozygous familial hyperlipidemia (N=16) and insufficient response to lipid-lowering agents. By desorption of approximately 5,700+/-500 mL of plasma, a mean reduction in total cholesterol of 62% (P < .001) and in LDL-cholesterol of 70% (P < .001) was achieved. Lp(a), which was elevated at study entry in seven of these patients (82.1+/-34.3 mg/dL; range, 48 to 148 mg/dL), was reduced during the initial LDL-apheresis procedure by 74.8%+/-14.1% (P < .001). Long-term apheresis treatment performed at weekly intervals resulted in an mean reduction in Lp(a) pretreatment values to 39.1+/-28.5 mg/dL (-54%; P < .001). Desorbed Lp(a) was measured at the waste of the columns for 31 apheresis treatments. Lp(a) concentration of the column waste was higher in patients with elevated serum Lp(a) pretreatment values as compared with those with Lp(a) serum values within the normal range (elevated Lp(a), 1,420+/-380 mg; without elevated Lp(a), 235+/-190 mg; P < .001). The rate of return of Lp(a) following apheresis treatment scheduled at weekly intervals was comparable to that of LDL-cholesterol.     

Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats

Alpha lipoic acid (lipoate [LA]), a cofactor of alpha-ketodehydrogenase, exhibits unique antioxidant properties. Recent studies suggest a direct effect of LA on glucose metabolism in both human and experimental diabetes. This study examines the possibility that LA positively affects glucose homeostasis in streptozotocin (STZ)-induced diabetic rats by altering skeletal muscle glucose utilization. Blood glucose concentration in STZ-diabetic rats following 10 days of intraperitoneal (i.p.) injection of LA 30 mg/kg was reduced compared with that in vehicle-treated diabetic rats (495 +/- 131 v 641 +/- 125 mg/dL in fed state, P = .003, and 189 +/- 48 v 341 +/- 36 mg/dL after 12-hour fast, P = .001). No effect of LA on plasma insulin was observed. Gastrocnemius muscle crude membrane GLUT4 protein was elevated both in control and in diabetic rats treated with LA by 1.5- and 2.8-fold, respectively, without significant changes in GLUT4 mRNA levels. Gastrocnemius lactic acid was increased in diabetic rats (19.9 +/- 5.5 v 10.4 +/- 2.8 mumol/g muscle, P < .05 v nondiabetic rats), and was normal in LA-treated diabetic rats (9.1 +/- 5.0 mumol/g muscle). Insulin-stimulated 2-deoxyglucose (2 DG) uptake into isolated soleus muscle was reduced in diabetic rats compared with the control group (474 +/- 15 v 568 +/- 52 pmol/mg muscle 30 min, respectively, P = .05). LA treatment prevented this reduction, resulting in insulin-stimulated glucose uptake comparable to that of nondiabetic animals. These results suggest that daily LA treatment may reduce blood glucose concentrations in STZ-diabetic rats by enhancing muscle GLUT4 protein content and by increasing muscle glucose utilization.     

Effect of intensive glycemic control on fibrinogen, lipids, and lipoproteins: Veterans Affairs Cooperative Study in Type II Diabetes Mellitus

BACKGROUND: The Veterans Affairs Cooperative Study in Type II Diabetes Mellitus prospectively studied insulin-treated patients with type 2 (non-insulin-dependent) diabetes mellitus, achieving 2.1% glycosylated hemoglobin separation between intensive- and standard-treatment arms (P<.001) for 2 years. OBJECTIVE: To assess the effect of intensive therapy on serum fibrinogen and lipid levels, compared with standard treatment. METHODS: One hundred fifty-three male subjects with type 2 diabetes mellitus and who required insulin treatment were recruited from 5 Veterans Affairs medical centers. The subjects were divided into intensive- and standard-treatment arms for a randomized prospective study. Dyslipidemia was managed identically in both arms (diet, drugs). Fibrinogen levels and lipid fractions were measured in the full cohort. Lipid fractions are separately reported in patients not treated with hypolipidemic agents. RESULTS: There were no baseline differences between arms. Fibrinogen levels rose in the intensive-treatment arm at 1 year (from 3.34+/-0.12 to 3.75+/-0.15 g/L; P<.001) but returned to baseline at 2 years (3.47+/-0.12 g/L). There was no change in the standard-treatment arm. Triglyceride levels decreased in the intensive-treatment arm from 2.25+/-0.27 to 1.54+/-0.14 mmol/L (199+/-24 to 136+/-12 mg/ dL) at 1 year (P = .004) and to 1.74+/-0.18 mmol/L (154+/-16 mg/dL) at 2 years (P = .03); there was no change in the standard-treatment arm. Cholesterol levels decreased in the intensive-treatment arm at 1 year from 5.4+/-0.21 to 4.99+/-0.13 mmol/L (207+/-8 to 193+/-5 mg/dL) (P = .02); there was no change in the standard-treatment arm. Levels of low- and high-density lipoprotein cholesterol decreased in the standard-treatment arm only by 2 years, from 3.44+/-0.13 to 3.16+/-0.10 mmol/L (133+/-5 to 122+/-4 mg/ dL) (P =.02) and from 1.10+/-0.03 to 1.00+/-0.03 mmol/L (42+/-1 to 38+/-1 mg/dL) (P<.001) for low-density and high-density lipoprotein cholesterol, respectively. Levels of apolipoprotein B decreased in both treatment arms (P<.001), and apolipoprotein A1 levels decreased in the standard-treatment arm (P<.01). Lipoprotein (a) levels did not change in either treatment arm. Lipid results were essentially identical whether examined in the full cohort or excluding those patients receiving hypolipidemic agents. CONCLUSIONS: Intensive insulin therapy led to a potentially beneficial reduction in serum triglyceride levels and preservation of high-density lipoprotein cholesterol and apolipoprotein A1 levels. However, it caused transient elevation in plasma fibrinogen levels, a possible thrombogenic effect.     

Possible mechanisms by which alcohol may influence the development of oral cancer--a review

Hepatitis C virus (HCV) infection is one of the major causes leading to orthotopic liver transplantation (OLT) worldwide. Although viral infection persists in almost all patients, the pathology of recurrent HCV infection after OLT is not well characterized. To address this issue, we compared the pathological findings of 28 patients who underwent transplantation for HCV-related cirrhosis (group A, aged 47 +/- 15 years; 23 men, 5 women) with those of 21 patients who underwent transplantation for nonviral indications (group B, aged 45 +/- 21 years; 13 men, 8 women) during the first year after transplantation. Patients from group A were assessed for serum HCV RNA by 5' untranslated region nested polymerase chain reaction before and 1 year after OLT. Patients underwent protocol liver biopsies 3 months and 1 year after transplantation. Group A patients more frequently had histological evidence of hepatic steatosis than group B patients, both at 3 months (P = .003) and 1 year (P = .003) after OLT. Fibrosis and portal inflammation were statistically more frequent in group A 1 year after transplantation. The sensitivity of steatosis in detecting histological disease recurrence was 100% at 3 months and 94% at 1 year; the specificity was 40% and 60%, respectively. Conversely, steatosis was 100% specific in detecting viral recurrence, with a sensitivity of 89%. The 1-year actuarial incidence of abnormal transaminase levels was 52% in group A and 13% in group B (P = .05). No biochemical or histological differences between patients infected with genotype 1b and patients with other HCV genotypes were found. Hepatic steatosis is a specific sign of viral recurrence after liver transplantation and a less specific sign of disease recurrence. HCV-infected liver transplant recipients often develop abnormal transaminase levels and liver fibrosis 1 year after OLT; these features are unrelated to HCV genotypes.     

Variation in incidence of indinavir-associated nephrolithiasis among HIV-positive patients

BACKGROUND: Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation. OBJECTIVE: To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to hemophilia and hepatitis C virus (HCV) infection. METHODS: Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and hematuria after initiation of therapy, was analyzed in relation to hemophilia status and HCV infection. RESULTS: There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with hemophilia, 50% developed IAN as compared with 17% of patients without hemophilia (P = 0.03). Median days to first IAN was 22 (range 7-110 days) for hemophiliacs and 156 (range 5-611 days) for those without hemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02). CONCLUSION: Overall incidence of IAN was higher than that previously reported and was significantly greater in hemophiliacs than in non-hemophiliacs. HCV may be a contributing factor.     

Oncotic pressure and edema formation in hypoalbuminemic HIV-infected patients with proteinuria

Human immunodeficiency virus nephropathy (HIVN) continues to challenge nephrologic consultative services at major urban institutions. Although noted in the literature, the decreased incidence of peripheral edema in HIVN has been unexplained to date. In HIV patients, total proteins frequently are found to be elevated due to an elevated globulin fraction. The impact that plasma proteins, specifically globulins, have on the total oncotic pressure has not been reported in HIVN, but may play a role in the paucity of edema noted in this proteinuric population. To evaluate the contributions of serum globulin to the total oncotic pressure and the presence or absence of edema in HIVN, we randomly selected 27 patients with proteinuria greater than 2.5 g/24 hr and serum albumin less than 3.1 g/dL from patients presenting to the nephrology outpatient clinic at the University of Miami/Jackson Memorial Hospital. Seventeen of the patients (63%) had a known diagnosis of HIV infection (group 1). These patients were subdivided into two subgroups: those presenting with clinically evident edema on physical examination (n = 7 [41%]; group 1A) and those who had an absence of edema (n = 10 [59%]; group 1B). Conversely, group 2 comprised 10 patients without known HIV infection, of whom six (60%) had edema (group 2A) and four (40%) did not (group 2B). Blood pressures were noted, and mean arterial pressure was calculated using standard formulas. Serum albumin, serum total proteins, and urine total proteins were measured using standard laboratory methods. Oncotic pressures for albumin (alpha), globulin (beta), and total protein (c) were calculated using the following formula: COPpl = alpha(2.8c + 0.18c2 + 0.012c3) + beta(0.9c + 0.12c2 + 0.004c3). We used Student's t-test to analyze the data. There is no significant difference between the albumin concentrations of HIV patients without edema (group 1B) and non-HIV patients with edema (group 2A), with mean concentrations of 2.3 +/- 0.1 g/dL versus 2.3 +/- 0.15 g/dL, respectively (P = NS). Group 1B, however, has a total oncotic pressure of 17.1 +/- 1.5 mm Hg, whereas both groups with edema (groups 1A and 2A) have statistically significant lower total oncotic pressures (12.1 +/- 2.3 mm Hg and 12.9 +/- 1.1 mm Hg, respectively; P < 0.05). The globulin oncotic pressures may account for some of the differences in total oncotic pressures, being significantly higher for those patients without edema in group 1B compared with group 2A (7.1 +/- 0.9 mm Hg v 3.9 +/- 0.4 mm Hg, respectively; P < 0.05). In patients with HIV, however, the presence or absence of edema is mandated by albumin concentration because both groups have similar globulin concentrations (group 1A 3.1 +/- 0.1 g/dL v group 1B 3.8 +/- 0.3 g/dL; P = NS). Mean arterial pressure does not play a role in edema formation in this study because the HIV patients without edema had the higher blood pressures (group 1B 97.8 +/- 4.7 mm Hg v group 2A 84.7 +/- 5.5 mm Hg; P < 0.05). We conclude that globulins play an important role in maintaining oncotic pressure in low albumin states. HIVN patients with increased serum immune globulin may benefit from higher globulin oncotic pressure, delaying the onset of clinical edema in the setting of proteinuria.     

Predictors of patient and graft survival following liver transplantation for hepatitis C

End-stage liver disease secondary to hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the United States. Recurrence of HCV infection is nearly universal. We studied the patients enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database to determine whether pretransplantation patient or donor variables could identify a subset of HCV-infected recipients with poor patient survival. Between April 15, 1990, and June 30, 1994, 166 HCV-infected and 509 HCV-negative patients underwent liver transplantation at the participating institutions. Median follow-up was 5.0 years for HCV-infected and 5.2 years for HCV-negative recipients. Pretransplantation donor and recipient characteristics, and patient and graft survival, were prospectively collected and compared. Cumulative patient survival for HCV-infected recipients was similar to that of recipients transplanted for chronic non-B-C hepatitis, or alcoholic and metabolic liver disease, better than that of patients transplanted for malignancy or hepatitis B (P = .02 and P = .003, respectively), and significantly worse than that of patients transplanted for cholestatic liver disease (P = .001). Recipients who had a pretransplantation HCV-RNA titer of > or = 1 x 10(6) vEq/mL had a cumulative 5-year survival of 57% versus 84% for those with HCV-RNA titers of < 1 x 10(6) vEq/mL (P = .0001). Patient and graft survival did not vary with recipient gender, HCV genotype, or induction immunosuppression regimen among the HCV-infected recipients. While long-term patient and graft survival following liver transplantation for end-stage liver disease secondary to HCV are generally comparable with that of most other indications, higher pretransplantation HCV-RNA titers are strongly associated with poor survival among HCV-infected recipients.     

Coronary vasodilatory capacity is impaired in patients with dilated cardiomyopathy

Increases in wall stress because of left ventricular enlargement and/or alterations in coronary vasomotor tone might affect myocardial blood flow and vasodilatory capacity in patients with dilated cardiomyopathy. To test this hypothesis myocardial blood flow was measured at rest and during intravenous administration of dipyridamole (0.56 mg/kg) using dynamic nitrogen 13-ammonia positron emission tomography (two-compartment model) in 10 patients with dilated cardiomyopathy (mean left ventricular ejection fraction 28 +/- 8% 1 woman, 9 men; 47 +/- 13 years of age). Ten age and gender matched healthy volunteers served as controls. Coronary artery disease was ruled out by coronary angiography and left ventricular hypertrophy by two dimensional-echocardiography. Baseline heart rate (70 +/- 13 v 64 +/- 12 bpm), systolic blood pressure (111 +/- 20 v 114 +/- 12 mm Hg) and rate pressure product (7,686 +/- 1264 v 7,306 +/- 1,645) were similar in patients and controls. During dipyridamole administration, the rate pressure product increased similarly in both groups. Myocardial blood flow at rest did not differ between groups of patients and volunteers (0.69 +/ -0.27 v 0.67 +/- 0.17 mL/g/min) but correlated with the rate pressure product only in controls (myocardial blood flow, 0.18 + 0.000068214; rate pressure product, .67; P < .05). Hyperemic myocardial blood flow was lower in patients (1.57 +/- 0.39 v 1.92 +/- 0.31 mL/g/min, p < .05, whereas myocardial flow reserve did not differ between groups of patients and controls (2.57 +/- 1.15 v 3.02 +/- 0.94). Coronary vasodilatory capacity is reduced in patients with severe nonischemic cardiomyopathy. Increases in extravascular compressive forces or increased serum catecholamine levels, which in turn induce coronary vasoconstriction, might account for this finding.     

Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis

To elucidate the risk factors for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-related liver cirrhosis (LC), we examined 204 cirrhotic patients negative for hepatitis B surface antigen and positive for HCV antibodies. The independent influence of various clinical characteristics in these patients was analyzed by multiple logistic regression, and the risk factors for HCC were identified. Multiple logistic regression analysis identified and ranked the following four risk factors: male sex (P < 0.001), habitual heavy drinking (P < 0.005), hepatitis B virus antibody positivity (anti-HBs and/or anti-HBc, P < 0.05), and age greater than 60 years (P < 0.05). The odds ratio of HCC was 4.20 (95% confidence interval; CI, 1.80-9.78) in male patients, 3.27 (95% CI, 1.46-7.30) in habitual heavy drinkers, 2.01 (95% CI, 1.01-3.99) in patients positive for hepatitis B virus antibodies, and 2.06 (95% CI, 1.00-4.23) in patients older than 60 years. The cumulative occurrence rates of HCC after blood transfusion were significantly higher in habitual heavy drinkers (4.8%, 49.4%, and 74.7% at 10, 20, and 30 years, respectively) than in non-drinkers (0%, 21.0%, and 23.3% at 10, 20, and 30 years, respectively, P < 0.0003). The mean interval for progression to LC after blood transfusion was significantly shorter in the habitual heavy drinkers than in the non-drinkers (22.4 +/- 4.4 years vs 28.4 +/- 3.9 years; P < 0.0003). This multivariate analysis revealed that habitual heavy drinking and hepatitis B virus antibody positivity are significant risk factors for HCC in HCV-related liver cirrhosis.