Antibodies to single-stranded and double-stranded DNA in antinuclear antibody-positive type 1-autoimmune hepatitis

To determine the significance of antibodies to single-stranded (anti-ssDNA) and double-stranded DNA (anti-dsDNA) in antinuclear antibody (ANA)-positive type 1 autoimmune hepatitis, sera from 53 patients were tested by enzyme immunosorbent assay (ELISA) and indirect immunofluorescence using the Crithidia luciliae substrate. Anti-dsDNA were detected in 18 patients (34%) by ELISA and 12 patients (23%) by the Crithidia-based assay. Twenty patients with anti-dsDNA by either assay (38%) had higher serum levels of immunoglobulin G (3971 +/- 270 mg/dL vs. 3201 +/- 247 mg/dL, P = .05) than seronegative patients. They also had human leukocyte antigen (HLA) DR4 more commonly than other patients (83% vs. 41%, P = .006) and normal subjects (83% vs. 30%, P = .00007). In contrast to patients seropositive by the Crithidia-based assay, those seropositive by ELISA failed corticosteroid therapy more commonly (24% vs. 3%, P = .04). Anti-ssDNA were found in 45 patients (85%) and they did not distinguish patients with different clinical features or outcomes. We conclude that anti-dsDNA are common in ANA-positive type 1 autoimmune hepatitis. HLA DR4 is associated with their production, and seropositivity by ELISA characterizes patients who have a poorer immediate response to corticosteroid treatment. Anti-ssDNA are common but they do not have important clinical implications.     

Antinuclear antibodies and patterns of nuclear immunofluorescence in type 1 autoimmune hepatitis

To determine the significance of antinuclear antibodies and their patterns of indirect immunofluorescence in type 1 autoimmune hepatitis, sera from 99 patients were evaluated. Patients with antinuclear antibodies had a lower frequency of liver transplantation (6% vs 22%, P = 0.04) than seronegative patients. They were also more commonly HLA-DR4-positive than seronegative patients (56% vs 30%, P = 0.05) and normal subjects (56% vs 30%, P = 0.004). The 42 patients with antinuclear antibodies and a diffuse pattern of indirect immunofluorescence had higher serum titers of ANA (serum titers > or = 1:500, 71% vs 14%, P < 0.0001) and SMA (serum titers > or = 1:500, 69% vs 27%, P = 0.003) than the 22 patients with antinuclear antibodies and a speckled pattern. These patients, however, were otherwise not distinguished by clinical features and treatment response. Patients with a speckled pattern had A1-B8-DR3 more frequently than patients with a diffuse pattern (65% vs 23%, P = 0.005) and normal subjects (65% vs 13%, P < 0.0001), but they had no other salient features. We conclude that patients with antinuclear antibodies have a better long-term prognosis than seronegative patients, and they have HLA-DR4 more commonly. The patterns of indirect immunofluorescence associated with ANA positivity have no practical clinical implications.     

High prevalence of serum cryoglobulins in multitransfused hemophilic patients with chronic hepatitis C

The prevalence, clinical relevance, and risk factors of serum cryoglobulins in hemophilic patients with chronic hepatitis C virus (HCV) infection are unknown. We studied 135 consecutive hemophilic patients (median age, 31 years; range, 10 to 69 years) with chronic hepatitis C, exposed to the virus for 10 to 41 years. A total of 67 patients were coinfected with the human immunodeficiency virus (HIV), and 3 (2%) had signs of cirrhosis. Serum samples were tested for the presence of cryoglobulins, hepatitis B virus (HBV) markers, including HBV-DNA by hybridization assay, and antibody to HCV by enzyme immunoassay (EIA). Serum HCV-RNA was tested by polymerase chain reaction and typed with a hybridization technique. Samples were also tested for antitissue antibodies, immunoglobulins, rheumatoid factor, and C3 and C4 proteins of complement. Forty-two hemophiliacs (31%) circulated cryoglobulins (median levels, 166 mg/L; range, 66 to 480) predominantly type III (62%; and 29% type II). None of the patients had clinical signs or symptoms of systemic vasculitis. Cryoglobulinemic patients had more often serum HCV-RNA (95% v 80%, P < .05), rheumatoid factor (20% v 6%, P < .05), higher levels of IgG (2,354 +/- 682 mg/dL v 1,928 +/- 557 mg/dL, P < .0005) and IgM (323 +/- 226 mg/dL v 244 +/- 243 mg/dL, P < .05), and lower levels of serum C4 (19 +/- 8 mg/dL v 24 +/- 8 mg/dL, P < .05) than patients without cryoglobulins. The risk of producing cryoglobulins was greater for 114 patients circulating HCV-RNA than for 21 nonviremic patients (odds ratio [OR] = 4.9, 95% confidence interval [CI] = 1.1 to 22.0) and for the 31 patients with longer exposure to HCV (more than 26 years) than for the 24 patients with shorter (17 years or less) exposure (OR = 4.4 95% CI = 1.1 to 18.0). In conclusion a large number of multitransfused hemophiliacs with chronic HCV infection circulated serum cryoglobulins but none had clinical signs or symptoms of vasculitis. The risk of developing cryoglobulins parallels the duration of exposure to HCV.     

Chronic viral hepatitis enhances the risk of infection but not acute rejection in renal transplant recipients

To assess the impact of chronic viral hepatitis on host immune response, we analyzed the incidence of acute rejection and the frequency of infections in 86 patients infected with hepatitis B and C viruses and had developed clinical evidence of chronic liver disease and 1283 control patients who were transplanted at our center during the same period, but had no evidence of chronic viral hepatitis. To compare the mean number of rejections and the mean number of infections between the two groups, we used multivariate linear regression analysis, which allowed us to adjust simultaneously for the effects of 10 other risk variables with potential impact on graft rejection and posttransplant infection. During a mean follow up of 5.3+/-5.2 years, 62% of hepatitis patients and 54% of control patients had experienced an acute rejection (P=NS). The mean rejections/patient in the hepatitis group was 1.3+/-0.14 versus 1.03+/-0.03 in control (P=NS). In the linear regression analysis, the number of acute rejections in the hepatitis group was 0.16 higher than in control (P=NS). With reference to infection, 84% of hepatitis patients experienced an infectious complication in the posttransplant period, compared with 75% in the control (P=0.05). The mean number of infections/patient was 5.7+/-0.73 in the hepatitis group compared with 3.9+/-0.14 in the control group (P=0.002). The linear regression model had shown that the hepatitis group had a relative increase of 1.18 infections/pt, compared with control. Of the different sites of infection, the hepatitis group had a significant increase in bloodstream (0.48+/-0.08 vs. 0.25+/-0.02) P=0.003; pulmonary (0.60+/-0.09 vs. 0.38+/-0.03) P=0.03; and CNS infections (0.08+/-0.03 vs. 0.02+/-0.004) P=0.05 compared with control. Among the different microorganisms causing infection, the hepatitis patients had a significant increase in gram negative bacterial infections compared with the control group (74% vs. 61%) P=0.04. Our data suggest that chronic viral hepatitis is associated with a significant increase in overall infections, and that of potentially fatal infections involving CNS, lungs and bloodstream. Since there is no significant increase in the rate of graft rejection, one could consider a cautious reduction in the doses of maintenance immunosuppressive agents in renal transplant patients with chronic viral hepatitis. The reduced immunosuppression may in turn lower the death rate from sepsis and progressive hepatic failure.     

Left atrial "stunning" following radiofrequency catheter ablation of chronic atrial flutter

Patients with autonomic neuropathy are more susceptible to insulin-induced hypotension than normal subjects, but the mechanisms are unclear. We quantitated the hemodynamic and metabolic effects of two doses of i.v. insulin (1 and 5 mU/kg.min, 120 min each) and several aspects of autonomic function in 28 patients with insulin-dependent diabetes mellitus (IDDM) and in 7 matched normal subjects under standardized normoglycemic conditions. The autonomic function tests included those predominantly assessing the integrity of vagal heart rate control (the expiration inspiration ratio during deep breathing and high frequency power of heart rate variability) and tests measuring sympathetic nervous function (reflex vasoconstriction to cold and blood pressure responses to standing and handgrip). During hyperinsulinemia, heart rate increased less (2 +/- 1 vs. 6 +/- 2 beats/min; P < 0.04) and diastolic blood pressure fell more (-3.1 +/- 1.2 vs. 0.9 +/- 2.1; P = NS) in the patients with IDDM than in the normal subjects. Forearm vascular resistance decreased significantly in the patients with IDDM [by -7.1 +/- 1.4 mm Hg/(mL/dL.min); P < 0.001 for high vs. low dose insulin], but not in the normal subjects (-0.1 +/- 2.5 mm Hg/(mL/dL.min; P = NS). Reflex vasoconstriction to cold was inversely correlated with the decreases in diastolic (r = -0.51; P < 0.005) and systolic (r = -0.59; P < 0.001) blood pressure and forearm vascular resistance (r = -0.53; P < 0.005), but not with the change in heart rate. The expiration inspiration ratio was, however, directly correlated with the insulin-induced change in heart rate (r = 0.63; P < 0.001), but not with diastolic or systolic blood pressure or forearm vascular resistance. Whole body (48 +/- 2 vs. 67 +/- 5 mumol/kg.min; P < 0.005) and forearm (44 +/- 4 vs. 67 +/- 8 mumol/kg.min; P < 0.05) glucose uptake were significantly lower in the IDDM patients than in the normal subjects. The latter could be attributed to a defect in the forearm glucose arterio-venous difference (1.5 +/- 0.1 vs. 2.2 +/- 0.2 mmol/L, respectively; P < 0.01), but not in blood flow. We conclude that both impaired vagal heart rate control and sympathetic nervous dysfunction exaggerate the hemodynamic effects of insulin in patients with IDDM and could contribute to insulin-induced hypotension.     

Heart transplantation in patients over 54 years of age. Mortality, morbidity and quality of life

AIMS: As a consequence of recent advances in heart transplantation, upper age limits for the procedure have been liberalized in many centres. It was the purpose of this study to compare post-transplant mortality, morbidity and quality of life in a consecutive series of 72 patients > 54 years (mean age, 57.6 +/- 2.7 years) with a control group of 72 adult patients < or = 54 years (mean age, 42.4 +/- 9.5 years) transplanted at one centre between 1985 and 1991. METHODS AND RESULTS: Patients were followed for 41 +/- 27 months post-transplant. Actuarial 1-, 5- and 7-year survival rates were 78 +/- 5%, vs 81 +/- 5%, 52 +/- 7% vs 66 +/- 6% and 46 +/- 8% vs 63 +/- 6% in patients > 54 years and < or = 54 years, respectively (P = ns). Causes of death were not significantly different between the groups. Patients > 54 years experienced significantly fewer rejection episodes after the 6th month post-transplant (0.5 +/- 0.9 vs 0.9 +/- 1.0, P < 0.04), and incidence and treatment of rejection episodes as well as incidence of infection was comparable between the groups. Non-lymphoid malignancies, mainly skin cancer, occurred more often in the older age group (27% vs 13%, P < 0.05). Quality of life, as assessed by the Nottingham Health Profile, was better in 5/6 dimensions of social functioning in older patients and the difference reached statistical significance for the dimensions of emotional reactions (P = 0.005) and sleep (P = 0.0005). CONCLUSION: In conclusion, carefully selected patients > 54 years can undergo heart transplantation with mortality and morbidity comparable to younger patients. Quality of life post-transplant seems even to be slightly better in the older age group.     

Mechanism of renal calcium conservation with estrogen replacement therapy in women in early postmenopause--a clinical research center study

To assess the mechanism by which estrogen replacement therapy (ERT) enhances renal calcium conservation in perimenopausal women, we studied 18 normal women in early postmenopause before and after 6 months of ERT (cyclic treatment with transdermal estradiol at 100 micrograms/day and medroxyprogesterone acetate at 10 mg/day for the first 12 days of each cycle). The changes after ERT were: serum ionized calcium and ultrafiltrable calcium, no change; serum intact PTH, 38.2% increase (P < 0.0001); serum 1,25-dihydroxyvitamin D, 23.8% increase (P < 0.0001); urinary calcium excretion, 33.3% decrease (P < 0.001); and deoxypyridinoline (a marker for bone resorption), 19.5% decrease (P < 0.0001). Also, ERT increased tubular reabsorption of calcium (TRCa; 97.6% +/- 0.2% to 98.7% +/- 0.1%; P < 0.0001), and this increase correlated with that in serum PTH (r = 0.49; P < 0.05). After the infusion of human PTH-(1-34), the TRCa maximum was greater after ERT than at baseline (99.4% +/- 0.1% vs. 99.0% +/- 0.1%; P < 0.0001), resulting in decreased calcium excretion (0.9 +/- 0.20 vs. 1.43 +/- 0.20 mumol/dL glomerular filtrate; P < 0.001). Thus, in early postmenopause, the major mechanism of increased renal calcium conservation after ERT is an increase in TRCa due to an increase in serum PTH because of estrogen-induced inhibition of bone resorption. However, ERT also may directly increase the TRCa maximum in response to PTH.     

Frequency and significance of phenotypes for alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis

To evaluate the frequency and significance of alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis, 181 Caucasian patients were assessed for variant phenotypes. Three hundred three Caucasian patients with various other chronic liver diseases were similarly evaluated. Twenty-one of the 181 patients (12%) had heterozygous deficiencies, including the MS (6%) and MZ (6%) phenotypes. These patients were indistinguishable from those with normal phenotypes. Immediate outcomes after corticosteroid therapy were also similar in both groups. Variant phenotypes were present in 34 of the 303 patients with other chronic liver diseases (11%). Patients with nonalcoholic steatohepatitis had a significantly greater frequency of deficiency phenotypes than patients with chronic hepatitis C (20% vs 7%, P = 0.03). In conclusion, deficiency phenotypes are common in type 1 autoimmune hepatitis and they have no clinical or prognostic importance. In certain liver diseases, such as nonalcoholic steatohepatitis, variant phenotypes may be comorbid factors.     

Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on the disease profile

Antibodies to nuclei (ANA), smooth muscle (SMA), and liver/kidney microsomes type 1 (anti-LKM1) may occur in chronic hepatitis C. Distinct subspecificities, including ANA with the homogeneous pattern (ANA-H) and SMA with antiactin specificity (SMA-AA), are found in autoimmune hepatitis (AIH). This study was performed to characterize the hepatitis C virus (HCV)-associated autoantibodies and to evaluate their influence on the profile of the disease. Two hundred ninety consecutive patients with chronic hepatitis C and 35 control cases with AIH were screened for autoantibodies by indirect immunofluorescence (IFL) at 1:40 serum dilution. The ANA pattern was defined by IFL on HEp-2 cells and the SMA-AA identified by the presence of at least two of the following elements: 1) SMA(T) or SMA(G) pattern by IFL on kidney sections; 2) XR1 precipitating system by counterimmunoelectrophoresis; or 3) typical pattern by IFL on liver sections from phalloidin-intoxicated rats. ANA, SMA, and anti-LKM1 occurred in 9%, 20%, and 6% of chronic hepatitis C cases, respectively. The overall prevalence of autoantibodies was 30% (87 of 290). Compared with AIH, HCV-associated ANA and SMA exhibited ANA-H and SMA-AA at a lower prevalence (38% vs. 71%, P = .04 and 8% vs. 87%, P < .000001, respectively) and had a lower median titer (1:80 vs. 1:320, P < .001 and 1:40 vs. 1:320, P < .000001, respectively). The concomitant positivity for ANA-H and SMA-AA was detected in none of the HCV cases, but in 46% of AIH sera (P < .000001). Two parameters were independently associated with the autoantibodies in chronic hepatitis C: high alanine transaminase (ALT) serum levels (F = 14.04) and female gender (F = 5.03). At the univariate analysis, patients with autoantibodies had a more severe portal-periportal necroinflammation (median Scheuer's score: 2.05 vs. 1.64, P = .003). The presence of autoantibodies did not influence the response to interferon (IFN). In chronic hepatitis C, serum autoantibodies are common, but their subspecificities are distinct from those occurring in AIH. Whereas the absence of ANA-H and/or SMA-AA does not exclude AIH, the characterization of ANA and SMA may help to discriminate between the two conditions. As compared with the seronegative counterpart, autoantibody-positive chronic hepatitis C is more common in females and exhibits a more severe biochemical and histological activity. The response to IFN therapy, however, is similar.     

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.     

Electrophysiologic characteristics and anatomical complexities of accessory atrioventricular pathways with successful ablation of anterograde and retrograde conduction at different sites

INTRODUCTION: Catheter ablation may eliminate anterograde and retrograde accessory pathway conduction at closely adjacent but anatomically discrete sites. However, the mechanisms of this discrepancy, the electrophysiologic and anatomical characteristics, and information about systematic study from a large patient population are not available. The purpose of this study was to investigate the electrophysiologic characteristics and anatomical complexities of the accessory pathway in which anterograde and retrograde conduction was successfully ablated at different sites. METHODS AND RESULTS: Thirty-eight (10.9%) patients (19 men and 19 women; mean age 37 +/- 2.4 years) fulfilling the criteria of having separate ablation sites for anterograde and retrograde conduction were designated as group I, and the other 310 patients (215 men and 95 women; mean age 47 +/- 0.6 years) were designated as group II. The patients with right-sided free-wall pathways had the highest incidence (18.6%) of separate ablation sites. The anatomical distance between anterograde and retrograde directions (left anterior oblique view, 13 +/- 0.6 vs 8 +/- 0.9 mm, P < 0.01; right anterior oblique view, 17 +/- 0.6 vs 5 +/- 0.7 mm, P < 0.01), and incidence of conduction impairment in one direction after successful ablation of another direction (15% vs 78%, P < 0.05) differed significantly between left and right free-wall pathways. The mean distances obtained from left (7 +/- 0.4 vs 14 +/- 0.4 mm, P < 0.05) and right (7 +/- 1.1 vs 15 +/- 0.9 mm, P < 0.05) anterior oblique views were shorter in patients who had impairment of conduction properties than those in patients without impaired conduction after successful ablation of one direction. CONCLUSIONS: This study showed that anatomical and functional dissociation of the accessory pathway into anterograde and retrograde components was possible. Further study on the relation between electrophysiologic and pathologic characteristics would be helpful to confirm these findings.     

Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study

To evaluate rectal mucosal hemodynamics in patients with chronic hepatitis, we employed reflectance spectrophotometry and examined the results in relation to the presence and severity of chronic hepatitis. Twenty-six patients with histologically diagnosed chronic hepatitis and 21 controls were examined for rectal vascular findings by endoscopy. Indices (I) of rectal mucosal oxygen saturation (ISO2) and rectal mucosal hemoglobin (IHb) concentration were measured. To minimize the effects of systemic anemia, the IHb was divided by blood Hb concentration, giving the rectal index for Hb (RHb). The relationship between rectal mucosal hemodynamics and the histological grade of chronic hepatitis was studied. Rectal vascular lesions were observed in three patients with chronic hepatitis (11.5%). The RHb in patients with chronic hepatitis was significantly higher than that in the controls (5.74 +/- 0.71 and 4.82 +/- 1.12, respectively; P < 0.01). There was no significant difference in ISO2 levels (44.23 +/- 5.84 and 41.94 +/- 4.91, respectively). No significant correlation was observed between rectal mucosal hemodynamics and the histological severity of chronic hepatitis, although rectal mucosal hemodynamics changed in patients with chronic hepatitis. Early vascular changes were observed in the rectal mucosa of patients with chronic hepatitis.     

Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial

CONTEXT: Although the long-term health benefits of good glycemic control in patients with diabetes are well documented, shorter-term quality of life (QOL) and economic savings generally have been reported to be minimal or absent. OBJECTIVE: To examine short-term outcomes of glycemic control in type 2 diabetes mellitus (DM). DESIGN: Double-blind, randomized, placebo-controlled, parallel trial. SETTING: Sixty-two sites in the United States. PARTICIPANTS: A total of 569 male and female volunteers with type 2 DM. INTERVENTION: After a 3-week, single-blind placebo-washout period, participants were randomized to diet and titration with either 5 to 20 mg of glipizide gastrointestinal therapeutic system (GITS) (n = 377) or placebo (n = 192) for 12 weeks. MAIN OUTCOME MEASURES: Change from baseline in glucose and hemoglobin A1c (HbA1c) levels and symptom distress, QOL, and health economic indicators by questionnaires and diaries. RESULTS: After 12 weeks, mean (+/-SE) HbA1c and fasting blood glucose levels decreased with active therapy (glipizide GITS) vs placebo (7.5% 0.1% vs 9.3%+/-0.1% and 7.0+/-0.1 mmol/L [126+/-2 mg/dL] vs 9.3+/-0.2 mmol/L [168+/-4 mg/ dL], respectively; P<.001). Quality-of-life treatment differences (SD units) for symptom distress (+0.59; P<.001), general perceived health (+0.36; P= .004), cognitive functioning (+0.34; P=.005), and the overall visual analog scale (VAS) (+0.24; P=.04) were significantly more favorable for active therapy. Subscales of acuity (+0.38; P=.002), VAS emotional health (+0.35; P=.003), general health (+0.27; P=.01), sleep (+0.26; P=.04), depression (+0.25; P=.05), disorientation and detachment (+0.23; P= .05), and vitality (+0.22; P=.04) were most affected. Favorable health economic outcomes for glipizide GITS included higher retained employment (97% vs 85%; P<.001), greater productive capacity (99% vs 87%; P<.001), less absenteeism (losses = $24 vs $115 per worker per month; P<.001), fewer bed-days (losses = $1539 vs $1843 per 1000 person-days; P=.05), and fewer restricted-activity days (losses = $2660 vs $4275 per 1000 person-days; P=.01). CONCLUSIONS: Improved glycemic control of type 2 DM is associated with substantial short-term symptomatic, QOL, and health economic benefits.     

Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis

Antibodies to actin have been proposed as diagnostic markers for type 1 autoimmune hepatitis. Our aims were to determine 1) if testing for antibodies to actin is superior to testing for smooth muscle antibodies (SMA); 2) if these antibodies identify patients with distinctive clinical features; and 3) if the production of antibodies to actin is associated with genetic risk factors for autoimmune hepatitis. Sera from 99 patients with type 1 autoimmune hepatitis were tested. The frequencies of HLA B8, DR3, DR4, and A1-B8-DR3 in patient subsets were compared with those in 80 normal subjects. Seventy-three patients (74%) had antibodies to actin. Antibodies to actin were found more commonly in patients with SMA than in patients without them (86% vs. 7%, P < .0001). Screening only for antibodies to actin and antinuclear antibodies (ANA) failed to establish the diagnosis of autoimmune hepatitis in 5 patients. Patients with antibodies to actin were younger than seronegative patients. They were also more commonly DR3-positive than normal subjects and more frequently B8-positive than patients with non-actin-associated SMA (49% vs. 0%, P = .004). Only patients with antibodies to actin died of liver failure (6% vs. 0%), and 10 of 11 patients requiring liver transplantation were seropositive for these antibodies. Indeed, death and liver transplantation occurred more frequently in these patients than in actin-negative patients with ANA (19% vs. 0%, P = .03). We conclude that routine screening for antibodies to actin may miss patients with type 1 autoimmune hepatitis. Antibodies to actin are associated with HLA B8 and DR3, and they identify patients with a poor prognosis.     

Dyspnoea and exercise intolerance during cardiopulmonary exercise testing in patients with univentricular heart. The effects of chronic hypoxaemia and Fontan procedure

BACKGROUND: Patients with univentricular hearts have decreased exercise tolerance and may demonstrate exertional dyspnoea. It is not known if chronic hypoxaemia exacerbates exercise intolerance and contributes to symptomatic limitation. The extent to which surgical correction of a right-to-left shunt by a Fontan-type procedure can increase exercise tolerance by reducing arterial deoxygenation is not well documented. The cardiopulmonary exercise responses and the symptomatic status in two groups of univentricular patients, those who are cyanotic and those who are acyanotic with Fontan-type circulation, were compared. METHODS AND FINDINGS: Cardiopulmonary exercise testing was performed in 10 univentricular patients with rest or stress-induced cyanosis (age 30.5 +/- 2.3 [SE] years; 5 men) who had palliative or no surgery and eight patients (age 29.4 +/- 1.5 years; 4 men) with Fontan-type circulation. Peak oxygen consumption was comparable in both groups of univentricular patients (21.7 +/- 2.5 vs 21.0 +/- 1.9 ml.kg-1.min-1, P = 0.85) but was less than an age-matched group of 10 healthy subjects (34.7 +/- 1.9 ml.kg-1.min-1, P < 0.001 for both). Arterial oxygen saturation was 90.6% at rest in the cyanotic patients compared with 95.1% in the Fontan patients (P < 0.001) and at peak exercise, 66.2% compared with 90.5% (P < 0.001). Using a modified Borg scale (0-10), the symptoms of dyspnoea and fatigue were also assessed during exercise in the patient groups. The Borg scores for dyspnoea in the cyanotic and the corrected univentricular patients were, respectively, as follows: Stage 1: 0.5 vs 1.7; P= 0.04; Stage 2: 1.8 vs 2.3, P = 0.5; Stage 3: 3.0 vs 3.5, P = 0.7; Peak Exercise: 4.9 vs 4.8, P = 0.9. In addition, the Borg scores for fatigue were: Stage 1: 0.4 vs 1.6, P = 0.08; Stage 2: 2.0 vs 2.2, P = 0.9; Stage 3: 3.0 vs 4.3, P = 0.5; Peak Exercise: 4.9 vs 5.4, P = 0.5. The major limiting symptom at peak exercise was dyspnoea in four cyanotic patients compared with one in the Fontan group (Chi-square 0.982, P > 0.10). The arterial oxygen desaturation at peak exercise in the cyanotic patients limited by dyspnoea was not different from those limited by fatigue (67.5 +/- 10.1% vs 66.7 +/- 13.7%, P = 0.92). Exercise tolerance was also not related to the arterial oxygen saturation at peak exercise (r = 0.47, P = 0.17) in these patients. CONCLUSIONS: Despite correction with Fontan-type surgery, the exercise tolerance and symptoms of these univentricular patients remained similar to those who were cyanosed. Cyanotic patients have adjusted to chronic hypoxaemia and it does not appear to determine the exercise tolerance or the genesis of dyspnoea in these patients. Further randomized prospective studies are required to investigate the long-term benefits of Fontan-type procedures in these patients on exercise tolerance, symptoms and prognosis.     

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.     

Effectiveness of relative low-dose interferon treatment for patients with chronic hepatitis C

To demonstrate effectiveness by relative low-dose of interferon treatment for patients with chronic hepatitis C, we investigated the histological activity index (HAI) score of liver tissue, hepatitis C virus (HCV) genotype by polymerase chain reaction (PCR) with type-specific primers, HCV RNA levels by competitive PCR, serum aminotransferase, sex, age, history of blood transfusion and history of hepatitis in patients with chronic hepatitis C prior to treatment. Twenty-two patients were treated with human lymphoblastoid interferon (3 MU daily, 2 weeks, 3 MU thrice a week, 6 weeks, 1.5 MU thrice a week, 16 weeks) for 24 weeks, of whom 10 (45.5%) were responders within a 6 month follow-up. HAI score before treatment was significantly lower in responders than in a combined group of relapse patients and nonresponders (7.5 +/- 3.4 vs. 12.0 +/- 3.1, p < 0.01). The prevalence of responders in patients with genotypes III and IV was significantly higher than in those with genotype II (85.7% vs. 21.4%, p < 0.05). HCV RNA level (logarithmic transformed copy per 50 microliter of serum) was significantly lower in responders than in a combined group of relapse patients and nonresponders (4.8 +/- 1.2 vs. 5.7 +/- 0.8, p < 0.05). In case of other pretreatment factors, there were no significant differences between responders and a combined group relapse patients and nonresponders. Thus severe histological changes in the liver, HCV genotype II and high HCV RNA levels are markers of unfavorable effects of interferon treatment for patients with chronic hepatitis C.     

Clinical subgroup of autoimmune hepatitis type 1 sustaining remission without additional drugs

BACKGROUND/AIMS: Many patients with autoimmune hepatitis type 1 need additional non-steroidal immunosuppressants to maintain remissions, but the indication should be limited to avoid the unnecessary side effects. The aim of this study is to clarify the clinical subgroups of autoimmune hepatitis type 1 sustaining remission without additional drugs. METHODOLOGY: We studied 20 patients with autoimmune hepatitis type 1, in whom complete remissions were achieved in the natural course or by prednisolone alone. Remissions were maintained with none or less than 10 mg/day of prednisolone. RESULTS: In the course (average: 6 years), 8 patients (40%) remained in remission for more than three years. In the remitted group, initial values of serum gamma-globulin (p<0.05) and serum immunoglobulin G (p<0.01) were lower than those in the relapsed group. The group with less than 30 mg/ml of gamma-globulin and 3000 mg/dl of immunoglobulin G showed a significantly lower relapse rate than the other one (p<0.01). CONCLUSIONS: There is a clinical subgroup of autoimmune hepatitis type 1 that sustains remission with low-dose prednisolone alone. Additional immunosuppressive drugs may not be needed to maintain remissions in such patients.     

Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis

Racial differences in insulin secretion and insulin sensitivity in healthy children were studied by administering a 2-hour hyperglycemic clamp (225 mg/dL) to 14 black and 16 white healthy adolescents (Tanner II-V), and 12 black and 11 white prepubertal children, matched for age, body mass index, and Tanner I pubertal development. In prepubertal children, fasting and first-phase insulin concentrations were higher in blacks compared with whites (14.7+/-1.3 vs 10.4+/-1.2, P=0.02, and 76.9+/-6.8 vs 52.1+/-6.4 microu/mL, P=0.016). There were no differences in second-phase insulin levels and insulin sensitivity index. In pubertal adolescents, first-phase and second-phase insulin concentrations were higher in blacks compared with whites (first-phase: 157.3+/-18.3 vs 77.0+/-8.7 microu/mL, P=0.0003; second-phase: 175.0+/-24.3 vs 108.7+/-8.8 microu/mL, P=0.012). Insulin sensitivity index was 35% lower in black adolescents compared with whites (P=0.02). These findings indicate that significant differences in insulin secretion and sensitivity are detectable early in childhood in healthy African-American vs American whites. However, genetic (race) vs environmental factors (physical activity/fitness, energy balance) should be carefully scrutinized as potential factors responsible for such differences.     

Influence of hepatitis C virus genotypes and HIV infection on histological severity of chronic hepatitis C. The Hepatitis/HIV Spanish Study Group

OBJECTIVES: The factors influencing the histological severity of chronic hepatitis C (CHC) have not been well established. We therefore investigated the effect of hepatitis C virus (HCV) genotypes and human immunodeficiency virus (HIV) infection on histological liver damage in a cohort of intravenous drug users with CHC. METHODS: We analyzed the histological activity score and the HCV genotypes in 59 HCV-RNA-positive patients with biopsy-proven CHC. Forty-eight (81%) of them had concomitant HIV infection with a CD4+ cell count above 200 x 10(6) cells/L and an absence of AIDS-defining conditions. Multivariate analysis was performed to determine the features associated with the histological severity. RESULTS: Minimal/mild hepatitis was found in 16 patients (27%), moderate chronic hepatitis in 29 (49%), and severe chronic hepatitis in 14 (24%). Patients with HCV subtype 1b had a higher histological score than others (8.7 +/- 3.3 vs. 6.5 +/- 3.2, p = 0.012), either as single or mixed infections. In multivariate analysis, HIV-infected individuals had a higher score of piecemeal necrosis (OR = 21.7, p = 0.002) and a higher stage of fibrosis (OR = 17.9, p = 0.004) than patients without HIV infection. HIV infection and HCV genotype 1b were found to be independent factors of histological severity. CONCLUSIONS: Liver damage in patients with CHC seems to be directly influenced by HCV subtypes. Infection by HCV subtype 1b is closely associated with more severe forms of liver pathology. Furthermore, the presence of HIV infection is an independent factor associated with more aggressive histological damage. In these patients, higher degrees of piecemeal necrosis and fibrosis are commonly seen.