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PubMed2006

Impact of hemoglobin levels on tumor oxygenation: the higher, the better?

BACKGROUND AND PURPOSE: Tumor hypoxia has been linked to tumor progression, the development of treatment resistance, and thus poor prognosis. Since anemia is a major factor causing tumor hypoxia, the association between blood hemoglobin concentration (cHb) and tumor oxygenation status has been examined. PATIENTS AND METHODS: Published data on the relationship between pretreatment cHb values and tumor oxygenation (in terms of median pO(2) values, hypoxic fractions) have been summarized. Pretreatment O(2) tension measurements were performed in histologically proven experimental tumors, human breast cancers, squamous cell carcinomas of the head and neck, and cancers of the uterine cervix and of the vulva. In order to allow for a comparison between solid tumors and normal tissues, pO(2) measurements were also performed in healthy tissue in anemic and nonanemic patients. cHb was determined at the time of the pO(2) measurements. RESULTS: Based on current information from experimental and clinical studies there is increasing evidence that anemia is associated with a detrimental tumor oxygenation status. Increasing cHb values are correlated with significantly higher pO(2) values and lower hypoxic fractions. Maximum tumor oxygenation in squamous cell carcinomas is observed at normal (gender-specific) cHb values (approximately 14 g/dl in women and approximately 15 g/dl in men). Above this "optimal" Hb range, the oxygenation status tends to worsen again. In anemic patients, tumor oxygenation is compromised due to a decreased O(2) transport capacity of the blood. At the upper edge of the Hb scale, a substantial increase in the blood's viscous resistance to flow in "chaotic" tumor microvessels is thought to be mainly responsible for the observed restriction of O(2) supply. CONCLUSION: Review of relevant clinical data suggests that a maximum oxygenation status in solid tumors is to be expected in the range 12 g/dl < cHb < 14 g/dl for women and 13 g/dl < cHb < 15 g/dl for men. Considering the "optimal" cHb range with regard to tumor oxygenation, the concept of "the higher, the better" is therefore no longer valid. This finding has potentially far-reaching implications in the clinical setting (e. g., inappropriate erythropoietin treatment of nonanemic tumor patients).

Adult↗
PubMedDate not supplied

Long-term outcome of children with complete heart block diagnosed after the newborn period.

The aims of this study were to assess morbidity, mortality, and long-term cardiac outcome of children with congenital complete heart block (CHB) diagnosed between the ages of 3 months and 15 years. The study population consists of 61 children with CHB diagnosed in five tertiary referral centers in Finland. There were two study groups: CHB diagnosed 3 months to 2 years of age (group 1; n = 29) and CHB diagnosed between the age of 2 and 15 years (group 2; n = 32). Neonatal morbidity was significantly higher in group 1 than in group 2 (p = 0.047). In the whole study population, permanent pacemaker implantation with the main indications of low ventricular rate and syncope (52%) was performed in 80% of cases, with a median age of 11.2 years. Structural heart defect not causally associated with CHB was evident in 9 of 61 patients (15%). Of 8 patients with atrial septal defect (ASD) secundum, 6 (75%) were operated on and 7 (88%) were paced. One patient had small ventricular septal defect. The incidence of dilated cardiomyopathy was 7%. The mortality with cardiomyopathy was very high (75%). Of the 61 children, 3 (5%) died due to cardiomyopathy at the ages of 2, 26, and 31 years. In the long-term follow-up of 17 years (median, range 2.9-46 years) 17% of patients who survived had cardiac problems: arrhythmias in 5, mitral valve insufficiency in 3, ASD secundum in 1, and cardiomyopathy in 1. The long-term outcome did not depend on the age at which CHB was diagnosed. In conclusion, CHB diagnosed after the newborn period carries relatively low mortality and morbidity. Pacemaker application was indicated in most children. The possibility of an associated heart defect or dilated cardiomyopathy indicates regular echocardiographic monitoring in all children and young adults with CHB.

Adolescent↗
PubMed1996

N-Acetylglucosaminidase (chitobiase) from Serratia marcescens: gene sequence, and protein production and purification in Escherichia coli.

The chitobiase (Chb) encoding gene (chb) from Serratia marcescens (Sm) has been cloned, sequenced and expressed in Escherichia coli (Ec). Sequencing has revealed an open reading frame encodinga protein of 885 amino acids (aa). Ec cells harbouring plasmids containing chb can produce enzymatically active Sm Chb protein which is secreted into the periplasm. An efficient purification scheme using cation-exchange chromatographyis presented. This yields about 3 mg of > 95% pure Sm Chb per litre of Ec culture. The deduced aa sequence is 27-aa longer at the N terminus than that determined by sequencing of the purified protein, suggesting that a leader sequence is removed during transport of the enzyme across the cell membrane. Comparison with the other members of the family 20 of glycosyl hydrolases revealed that Chb has a conserved central region which aligns with almost all members of this family. According to the crystal structure of Sm Chb, this region comprises the catalytic domain of Chb which has an alpha/beta barrel fold.

Acetylglucosaminidase↗
PubMed2004

Metabolism of chlorambucil by rat liver microsomal glutathione S-transferase.

Clinical efficacy of alkylating anticancer drugs, such as chlorambucil (4-[p-[bis [2-chloroethyl] amino] phenyl]-butanoic acid; CHB), is often limited by the emergence of drug resistant tumor cells. Increased glutathione (gamma-glutamylcysteinylglycine; GSH) conjugation (inactivation) of alkylating anticancer drugs due to overexpression of cytosolic glutathione S-transferase (GST) is believed to be an important mechanism in tumor cell resistance to alkylating agents. However, the potential involvement of microsomal GST in the establishment of acquired drug resistance (ADR) to CHB remains uncertain. In our experiments, a combination of lipid chromatography/electrospray ionization mass spectrometry (LC/ESI/MS) was employed for structural characterization of the resulting conjugates between CHB and GSH. The spontaneous reaction of 1mM CHB with 5 mM GSH at 37 degrees C in aqueous phosphate buffer for 1 h gave primarily the monoglutathionyl derivative, 4-[p-[N-2-chloroethyl, N-2-S-glutathionylethyl] amino]phenyl]-butanoic acid (CHBSG) and the diglutathionyl derivative, 4-[p-[2-S-glutathionylethyl] amino]phenyl]-butanoic acid (CHBSG2) with small amounts of the hydroxy-derivative, 4-[p-[N-2-S-glutathionylethyl, N-2-hydroxyethyl] amino]phenyl]-butanoic acid (CHBSGOH), 4-[p-[bis[2-hydroxyethyl] amino]phenyl]-butanoic acid (CHBOH2), 4-[p-[N-2-chloroethyl, N-2-S-hydroxyethyl]amino]phenyl]-butanoic acid (CHBOH). We demonstrated that rat liver microsomal GST presented a strong catalytic effect on these reactions as determined by the increase of CHBSG2, CHBSGOH and CHBSG and the decrease of CHB. We showed that microsomal GST was activated by CHB in a concentration and time dependent manner. Microsomal GST which was stimulated approximately two-fold with CHB had a stronger catalytic effect. Thus, microsomal GST may play a potential role in the metabolism of CHB in biological membranes, and in the development of ADR.

Animals↗
PubMed2005

In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B.

BACKGROUND: Both the hepatitis B virus (HBV) and the immune response of the hosts to HBV play important roles in the pathogenesis of chronic hepatitis B (CHB). Lamivudine is a potent antiviral agent with minimal immune modulator capacity. Moreover, lamivudine causes severe side effects like breakthrough of HBV DNA and breakthrough hepatitis in patients with CHB. On the other hand, vaccine therapy, a recently-developed immune therapy, exhibits potent immune modulatory potentials and almost no side effects, but possesses little antiviral capacity in patients with CHB. OBJECTIVES: The aim of this clinical trial is to evaluate the efficacy of a combination therapy of lamivudine and vaccine in patients with CHB. STUDY DESIGN: Seventy-two patients with CHB (hepatitis B e antigen (HBeAg)-positive, 40; antibody to HBeAg (anti-HBe)-positive, 32). All patients received lamivudine at a dose of 100 mg daily for 12 months. Fifteen patients (HBeAg+, 9; anti-HBe+, 6) receiving oral lamivudine were also given a vaccine containing 20 microg of hepatitis B surface antigen, intradermally, once every 2 weeks for 12 times (combination therapy). RESULTS: Twelve months after the start of therapy, serum HBV DNA became negative in 9 of 9 (100%) HBeAg+ CHB patients receiving combination therapy and in 15 of 31 (48%) HBeAg+ CHB patients receiving lamivudine monotherapy (P < 0.05). The rate of seroconversion from HBeAg to anti-HBe was also significantly higher in patients receiving combination therapy (56% versus lamivudine monotherapy, 16%, P < 0.05). Of the 57 patients receiving lamivudine monotherapy, breakthrough of HBV DNA was found in 10 and breakthrough hepatitis was found in 4; however, these were not seen in any patient receiving combination therapy. CONCLUSIONS: Combination therapy represents a better therapeutic regimen with few complications in patients with CHB.

Adult↗
PubMed2005

Ethanol induction of complete heart block in swine.

OBJECTIVES: A method for the induction of complete heart block (CHB) by ethanol injection and its success rate in a pig model of acute right ventricular failure is reported. Additionally, a review of the literature for the induction of CHB in laboratory animals is detailed. The literature review was undertaken to both compare our rate of success with other methods and provide insight into our technique and refine its implementation. BACKGROUND: Animal models of CHB have facilitated the understanding of therapeutics for various cardiac pathologies in humans. In our laboratory, CHB in pigs is used for complete control of heart rhythm in studies of biventricular pacing. MATERIALS AND METHODS: Experiments carried out on pigs in our laboratory that required the induction of CHB were reviewed retrospectively. In addition, review of the literature for creating CHB in animals was undertaken. Our success rate was compared to that of other groups. RESULTS: Our success rate (93%) is similar to other models of CHB, in general, and to those models that used the injection of caustic substances with thoracotomy. CONCLUSIONS: Review of the literature indicates that our success rate is comparable to other groups and that, although many approaches have been described in both open- and closed-chest models, success is likely dependent on the practice and skill of the experimenter. In addition, review of the literature has afforded us new perspectives on the experimental induction of CHB.

Animals↗
PubMed1975

The relative risk of spontaneous complete atrioventricular block in elderly patients with impaired intra-ventricular conduction.

We reviewed 144 consecutive patients with symptomatic high grade atrioventricular block. Cases due to congenital heart disease, acute myocardial infarction, cardiac surgery or digitalis toxicity were excluded. Of the remaining, we chose 71 patients in whom atrioventricular conduction was observed either intermittently during complete heart block (CHB) or in electrocardiograms taken within two years prior to documentation of CHB. The mean age was 69 years, with the peak incidence in the seventh decade in 43 men and eight decade in 28 women. Bundle branch block (BBB) was present in 76% of patients as follows: 47% had right BBB (20% with normal QRS axis, 20% with left axis deviation and 7% with right axis deviation), 17% had left BBB (11% with normal QRS axis and 6% with left axis deviation) and 12% had either alternating BBB, right BBB with alternating axis deviation or atypical BBB. "Trifascicular block" patterns accounted for 21% of the total group of CHB. We also studied the prevalence of various patterns of BBB in a group of 2000 random hospital patients of comparable age and sex exclusive of those with acute myocardial infarction and heart surgery. The risk of CHB for the various patterns of BBB was calculated relative to normal intraventricular conduction. All patterns of BBB carried a considerably increased relative risk of CHB, (P smaller than .01). The relative risk was highest for RBBB with left axis deviation and lowest for LBBB with normal or left axis deviation. In the men, 74% had QRS patterns of "bifascicular" or "trifascicular" block during atrioventricular conduction. By contrast, 71% women had atrioventricular beats showing either no BBB or right BBB with normal QRS axis. QRS pattern during CHB was unchanged from that during atrioventricular conduction in 52% if cases (rabge 38%-76% with different QRS patterns) suggesting idiojunctional pacemaker. CHB in these cases was thought to be due probably to coexistent disease in the AV node or His bundle. Although the concept of uni-, bi- and trifascicular block patterns has been useful in identifying patients at greater risk of CHB, the predictability of the electrocardiogram has obvious limitations, particularly in women.

Aged↗
PubMed1998

Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry.

OBJECTIVES: The present study describes the demographics, mortality, morbidity and recurrence rates of autoimmune-associated congenital heart block (CHB) using information from the Research Registry for Neonatal Lupus. BACKGROUND: Isolated CHB detected at or before birth is strongly associated with maternal autoantibodies to 48-kD SSB/La, 52-kD SSA/Ro and 60-kD SSA/Ro ribonucleoproteins and is a permanent manifestation of the neonatal lupus syndromes (NLS). Available data are limited by the rarity of the disease. RESULTS: The cohort includes 105 mothers whose sera contain anti-SSA/Ro or anti-SSB/La antibodies, or both, and their 113 infants diagnosed with CHB between 1970 and 1997 (56 boys, 57 girls). Of 87 pregnancies in which sufficient medical records were available, bradyarrhythmia confirmed to be CHB was initially detected before 30 weeks of gestation in 71 (82%) (median time 23 weeks). There were no cases in which major congenital cardiac anatomic defects were considered causal for the development of CHB; in 14 there were minor abnormalities. Twenty-two (19%) of the 113 children died, 16 (73%) within 3 months after birth. Cumulative probability of 3-year survival was 79%. Sixty-seven (63%) of 107 live-born children required pacemakers: 35 within 9 days of life, 15 within 1 year, and 17 after 1 year. Forty-nine of the mothers had subsequent pregnancies: 8 (16%) had another infant with CHB and 3 (6%) had a child with an isolated rash consistent with NLS. CONCLUSIONS: Data from this large series substantiate that autoantibody-associated CHB is not coincident with major structural abnormalities, is most often identified in the late second trimester, carries a substantial mortality in the neonatal period and frequently requires pacing. The recurrence rate of CHB is at least two- to three-fold higher than the rate for a mother with anti-SSA/Ro-SSB/La antibodies who never had an affected child, supporting close echocardiographic monitoring in all subsequent pregnancies, with heightened surveillance between 18 and 24 weeks of gestation.

Autoimmune Diseases↗
PubMed2000

Molecular and ionic basis of congenital complete heart block.

Congenital heart block (CHB), detected at or before birth in a structurally normal heart, is strongly associated with autoantibodies reactive with the intracellular soluble ribonucleoproteins 48kD SSB/La, 52kD SSA/Ro, and 60kD SSA/Ro. CHB is presumed to be due to the transplacental passage of autoantibodies from the mother into the fetal circulation. Varying degrees of heart block have been reported. Although second degree block has, on rare occasion, reverted to normal sinus rhythm, complete atrio-ventricular (AV) block is irreversible. CHB carries substantial mortality and morbidity, with > 60% of affected children requiring lifelong pacemakers. The recurrence rate exceeds, by at least twofold, that of the first birth and is likely to influence the decision to have more children. Curiously, the mother's heart is almost never affected (with complete heart block) despite exposure to identical circulating autoantibodies. As part of our continuing effort to understand the complex factors contributing to the pathogenesis of CHB, we have established an animal model of CHB by immunizing female mice with recombinant proteins/antigens, reproduced the human complete AV block in an isolated Langendorff perfused fetal heart, and correlated these findings with L-type Ca channel inhibition by maternal antibodies from mothers of children with CHB. In addition, we established a passive animal model by directly injecting maternal antibodies into pregnant mice and reported significant sinus bradycardia, indicating that the spectrum of conduction abnormalities may extend beyond the AV node. All together, the data provided strong evidence supporting an etiologic role of antibody/Ca channel involvement in the pathogenesis of CHB. However, other yet unknown factors seem necessary to explain the full expression of CHB.

Animals↗
PubMed2002

World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants.

Hepatitis B is a serious disease that is endemic in many parts of the world. A significant proportion of patients with chronic hepatitis B (CHB) are infected with a variant form of the hepatitis B virus (HBV) which decreases or abolishes the production of hepatitis B e-antigen (HBeAg). The purpose of this literature review is to describe the epidemiology of HBeAg-negative CHB (e-CHB) worldwide. A literature search was conducted to identify studies pertaining to e-CHB and underlying variants (precore and core promoter). Fifty studies were included in our analysis. The median prevalence of e-CHB among patients with chronic HBV infection was 33% in the Mediterranean, 15% in Asia Pacific, and 14% in the USA and Northern Europe. The pre core stop codon variant was detected in a median of 60% (range 0-100%) of HBeAg-negative patients overall, 92% in the Mediterranean, 50% in Asia Pacific and 24% in the USA and Northern Europe. There were very few data on the prevalence of core promoter variants outside Asia where the median prevalence among HBeAg-negative patients was 77%. This literature review revealed that e-CHB is more common than previously suspected and that it is present worldwide with marked variations in the prevalence of associated HBV variants across different geographical regions. Additional research using population based samples of adequate size based on a consensus definition of e-CHB and using standardized HBV DNA assays is needed to better estimate the true prevalence of e-CHB and its associated HBV variants.

Genetic Variation↗
PubMedDate not supplied

Cost of chronic hepatitis B infection in China.

GOALS: The objective of this study was to estimate the direct medical costs associated with the treatment of chronic hepatitis B (CHB) infection and its complications in China. BACKGROUND: CHB infection is a major health problem in China, with an estimated 112 million chronic carriers. However, the economic burden associated with CHB and its complications has not been well characterized. STUDY: A retrospective analysis of the medical records of a sample of patients with CHB from Beijing, China was conducted. The utilization and costs were estimated for four illness stages associated with CHB (CHB infection, compensated cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma). Annual utilization and costs were estimated for inpatient, outpatient, and medications for each illness stage and valued in year 2002 U.S. dollars (currency conversion was based on a 2002 exchange rate of 8.271 Chinese Yuan Renminbi = U.S. 1 dollar). RESULTS: A total of 837 patients were identified for inclusion in the study. The average annual treatment costs per person were as follows: CHB, US 142 dollars; compensated cirrhosis, US 185 dollars; decompensated cirrhosis, US 1702 dollars; and hepatocellular carcinoma, US 4741 dollars. CONCLUSIONS: The results from this analysis provide estimates of the costs associated with CHB and its complications in China and show that progression of the disease is associated with increasing healthcare costs. These estimates can be used to evaluate the cost-effectiveness of intervention.

Adult↗
PubMed2006

Hepatitis B virus genotypes and G1896A precore mutation in 486 Spanish patients with acute and chronic HBV infection.

This study aims to determine the prevalence of hepatitis B virus (HBV) genotypes (A-F) and their association with the G1896A precore mutation in 486 patients positive for HBV surface antigen. Genotypes were determined by RFLP and precore mutation by real-time PCR. Genotypes D (48.1%) and A (39.5%) were the most common, followed by F (4.1%) and B, C and E (<1%). The A to D ratio (A:D) was 1.4 in HBeAg+ chronic hepatitis B (CHB), 0.6 in HBeAg- CHB and 1.4 in HBeAg- inactive carriers. Distribution of these genotypes was different between HBeAg+ CHB and HBeAg- CHB (P = 0.02), and between HBeAg- CHB and HBeAg- inactive carriers (P = 0.009). Genotype A was the most prevalent in HBeAg+ CHB with elevated alanine aminotransferase (ALT) (68.6%) and genotype D in HBeAg+ CHB with fluctuating ALT (60.7%). There was a difference in genotype prevalence between chronic and acute infection (P = 0.03). The precore mutant correlated with high levels of HBV-DNA in genotype d HBeAg- CHB. Genotype D is not as highly prevalent in Spanish patients as would be expected in a Mediterranean area. The unequal prevalence of genotypes between acute and chronic infection suggests that genotype A is associated with a higher tendency to cause chronic infection.

Adolescent↗
PubMed1999

Fcgamma receptor expression on hepatic macrophages and histological activity of chronic hepatitis.

AIMS/BACKGROUND: Activated liver macrophages in chronic hepatitis express a high affinity receptor for IgG named FcgammaRI. This study was performed to find the difference in FcgammaRI expression between chronic hepatitis B (CHB) and C (CHC) with reference to histological activity. METHODS: Consecutive patients with CHB (20 cases) and CHC (25 cases) were enrolled in the study. Inflammatory activity was evaluated using the modified histological activity index (HAI). FcgammaRI-positive macrophages were quantitatively measured by computer assisted morphometry. RESULTS: Total HAI score was significantly higher in CHB than in CHC. Confluent necrosis was observed in significantly higher frequency in CHB at Stages 3 5 than in CHC. The percentage area of FcgammaRI-positive macrophages was significantly higher in CHB than in CHC. In CHB, the percentage area of FcgammaRI-positive macrophages correlated with total HAI (<0.01) as well as the degree of confluent necrosis (<0.01), interface hepatitis (<0.05) and portal inflammation (<0.05). FcgammaRI-positive macrophages accumulated mainly at the site of confluent necrosis. In CHC, no correlation was observed between activated macrophages and any histological categories. CONCLUSION: These results suggest that FcgammaRI-positive macrophages are associated with confluent necrosis in CHB, which is more common in CHB patients than in CHC.

Adult↗
PubMed2003

Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block.

Although Abs to SSA/Ro-SSB/La are necessary for the development of congenital heart block (CHB), the low frequency suggests that fetal factors are contributory. Because CHB involves a cascade from inflammation to scarring, polymorphisms of the TNF-alpha promoter region and codons 10 and 25 of the TGF-beta gene were evaluated in 88 children (40 CHB, 17 rash, 31 unaffected siblings) and 74 mothers from the Research Registry for Neonatal Lupus (NL). Cytokine expression was assessed in autopsy material from two fetuses with CHB. Significantly increased frequency of the -308A (high-producer) allele of TNF-alpha was observed in all NL groups compared with controls. In contrast, the TGF-beta polymorphism Leu(10) (associated with increased fibrosis) was significantly higher in CHB children (genotypic frequency 60%, allelic frequency 78%) than unaffected offspring (genotypic frequency 29%, p = 0.016; allelic frequency 56%, p = 0.011) and controls, while there were no significant differences between controls and other NL groups. For the TGF-beta polymorphism, Arg(25), there were no significant differences between NL groups and controls. In fetal CHB hearts, protein expression of TGF-beta, but not TNF-alpha, was demonstrated in septal regions, extracellularly in the fibrous matrix, and intracellularly in macrophage infiltrates. Age-matched fetal hearts from voluntary terminations expressed neither cytokine. TNF-alpha may be one of several factors that amplify susceptibility; however, the genetic studies, backed by the histological data, more convincingly link TGF-beta to the pathogenesis of CHB. This profibrosing cytokine and its secretion/activation circuitry may provide a novel direction for evaluating fetal factors in the development of a robust animal model of CHB as well as therapeutic strategies in humans.

Arginine↗
PubMed2002

[The value of gamma-glutamyltransferase in the diagnosis of chronic hepatitis B].

OBJECTIVE: To explore the change of serum gamma-glutamyltransferase (GGT) and its diagnosis value in chronic hepatitis B (CHB) patients with different degrees of liver damage. METHODS: Alanine-aminotransferase (ALT), aspartate-aminotransferase (AST) and GGT were measured in 221 CHB patients. Liver biopsy was conducted simultaneously to determine the inflammation grade and fibrosis stage of the liver tissues. RESULTS: The rate of normal GGT in pathologically diagnosed mild and severe CHB patients was 90.4% and 12.3%, respectively (P<0.01). Increased level of GGT was parallel to the degree of liver pathological change (P<0.01). In active CHB patients, GGT rose with the ALT increase with a positive linear correlation between them (r=0.464, P<0.001). In pathologically diagnosed mild CHB patients, GGT had a tendency of rapidly declining to normal levels with ALT. In moderate CHB patients, GGT fluctuated at a relatively high level, and in severe CHB patients GGT exhibited a deviation from GGT. CONCLUSIONS: GGT is conducive to improve the coincident rate between the clinical and pathological diagnosis of CHB.

Adult↗
PubMed1993

In vitro metabolism of cyanohydroxybutene: formation of a glutathione-S-transferase catalyzed product.

The pancreatotoxin cyanohydroxybutene (CHB) causes a significant and prolonged elevation in glutathione (GSH) in liver and pancreas (Wallig and Jeffery, 1990). Here we report that urinary thiols also increase. This suggests that CHB may react with GSH, either directly or following phase I oxidation, to form an adduct, which is further metabolized to the corresponding mercapturic acid for urinary excretion. Metabolism of CHB by hepatic mixed function oxidase and cytosolic alcohol dehydrogenase enzymes was evaluated by monitoring microsomal NADPH consumption and alcohol dehydrogenase-dependent NADH generation, respectively. There was no apparent increase in the rate of microsomal NADPH consumption or alcohol dehydrogenase-dependent NADH generation in the presence of CHB. To evaluate in vitro formation of a glutathione-S-transferase (GST) catalyzed adduct, [3H-glycyl]-GSH and [14C-cyano]-CHB were incubated at 37 degrees C for 1 h, with or without GST. Dinitrophenol derivatization and high performance liquid chromatographic (HPLC) analysis (Farris & Reed, 1987) revealed no double-labeled peaks, suggesting that no stable conjugate was formed. However a tritiated product, not present in control samples, and with an identical retention time to cysteinyl-glycine (cys-gly) was formed. In addition, the product has a fast atom bombardment mass-spectrum consistent with cys-gly. These results suggest that while CHB may not undergo phase I oxidation, in the presence of CHB, GSH may break down to form cys-gly. A mechanism for CHB-dependent breakdown of GSH to cys-gly is proposed, and the pharmacological implications of this finding are discussed.

Alcohol Dehydrogenase↗
PubMed1993

Isolated congenital heart block. Long-term outcome of mothers and characterization of the immune response to SS-A/Ro and to SS-B/La.

OBJECTIVE: To study the long-term outcome of mothers of children with isolated congenital heart block (CHB) and to characterize the maternal autoantibody response to SS-A/Ro and SS-B/La. METHODS: A retrospective clinical study of 33 mothers a mean of 11.2 years (SD 9.2 years, range 0-32 years) after the delivery of their first child with CHB. A clinical and immunologic study of 31 of these mothers, compared with 89 healthy mothers, 45 mothers with systemic lupus erythematosus (SLE), and 19 mothers with primary Sjögren's syndrome (SS), all of whom had healthy children. The specificity of the autoantibody responses to SS-A/Ro and SS-B/La was studied by enzyme-linked immunosorbent assays using purified human recombinant antigens and affinity-purified antigens. RESULTS: By the time of the analysis, 2 (6%) of the 33 mothers of CHB children had died and 6 (18%) had met the criteria for SLE. As a group, mothers of CHB children had clinical and immunologic characteristics more closely related to primary SS than to SLE or any other connective tissue disease. The predominant autoantibody response was to the SS-A/Ro antigens, notably to the 52-kd SS-A/Ro protein (prevalence 97%). Compared with controls with SLE, mothers of CHB children had higher titers of antibodies to recombinant 52-kd and 60-kd SS-A/Ro proteins and to the affinity-purified SS-A/Ro antigen (P < 0.05, P < 0.01, and P < 0.001, respectively). Compared with controls with primary SS, the autoantibody responses were similar. CONCLUSION: The predominant autoimmune disorder in mothers of children with CHB is subclinical primary SS. Antibodies to SS-A/Ro appear to be a prerequisite for the development of CHB.

Adolescent↗
PubMed2000

Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.

Hepatitis B e antigen-negative chronic hepatitis B (e-CHB) has been reported in Asia but its prevalence and clinical significance have not been determined. The aims of this study were to determine the prevalence of e-CHB in Hong Kong and the frequency of precore and core promoter mutations in these patients. A cross-sectional study was performed in 350 consecutive Chinese patients (230 men and 120 women; mean age +/-SD, 42 +/- 13 years) with chronic hepatitis B virus infection. A total of 243 (69%) patients were hepatitis B e antigen (HBeAg)-negative of whom 15% had clinical cirrhosis. In the remaining 85% of patients, 63% had normal and 22% had elevated transaminases. Serum hepatitis B virus (HBV) DNA was detectable using branched DNA assay in 46% of HBeAg-negative patients with clinical cirrhosis/elevated transaminases. Forty-five percent of the patients with e-CHB had the precore stop codon mutation, and an additional 41% had core promoter changes. There was no correlation between the presence of precore/core promoter mutations and liver disease or HBV-DNA levels. Overall, 17% of HBeAg-negative patients were viremic and had evidence of chronic liver disease (e-CHB) with mean HBV-DNA levels comparable with that in HBeAg-positive patients. In summary, we found that e-CHB may be present in up to 17% of HBeAg-negative patients seen in a tertiary referral center in Hong Kong. e-CHB may be a heterogeneous condition and is not invariably associated with the precore HBV mutant. Population studies are needed to determine the true prevalence of e-CHB in Asia and to assess its natural course and response to treatment.

Adolescent↗