Genetic Covariation between Serum {gamma}-Glutamyltransferase Activity and Cardiovascular Risk Factors

Background: Several studies have shown that variation in serum gamma-glutamyltransferase (GGT) in the population is associated with risk of death or development of cardiovascular disease, type 2 diabetes, stroke, or hypertension. This association is only partly explained by associations between GGT and recognized risk factors. Our aim was to estimate the relative importance of genetic and environmental sources of variation in GGT as well as genetic and environmental sources of covariation between GGT and other liver enzymes and markers of cardiovascular risk in adult twin pairs. Methods: We recruited 1134 men and 2241 women through the Australian Twin Registry. Data were collected through mailed questionnaires, telephone interviews, and by analysis of blood samples. Sources of variation in GGT, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and of covariation between GGT and cardiovascular risk factors were assessed by maximum-likelihood model-fitting. Results: Serum GGT, ALT, and AST were affected by additive genetic and nonshared environmental factors, with heritabilities estimated at 0.52, 0.48, and 0.32, respectively. One-half of the genetic variance in GGT was shared with ALT, AST, or both. There were highly significant correlations between GGT and body mass index; serum lipids, lipoproteins, glucose, and insulin; and blood pressure. These correlations were more attributable to genes that affect both GGT and known cardiovascular risk factors than to environmental factors. Conclusions: Variation in serum enzymes that reflect liver function showed significant genetic effects, and there was evidence that both genetic and environmental factors that affect these enzymes can also affect cardiovascular risk. (C) 2002 American Association for Clinical Chemistry.

Reactogenicity of yellow fever vaccines in a randomized, placebo-controlled trial

OBJECTIVE: To compare the reactogenicity of three yellow fever (YF) vaccines from WHO-17D and Brazilian 17DD substrains (different seed-lots) and placebo. METHODS: The study involved 1,087 adults eligible for YF vaccine in Rio de Janeiro, Brazil. Vaccines produced by Bio-Manguinhos, Fiocruz (Rio de Janeiro, Brazil) were administered ("day 0") following standardized procedures adapted to allow blinding and blocked randomization of participants to coded vaccine types. Adverse events after immunization were ascertained in an interview and in diary forms filled in by each participant. Liver enzymes were measured on days 0, 4-20 and 30 of the study. Viremia levels were measured on days 4 to 20 of follow-up. The immune response was verified through serologic tests. RESULTS: Participants were mostly young males. The seroconversion rate was above 98% among those seronegative before immunization. Compared to placebo, the excess risk of any local adverse events ranged from 0.9% to 2.5%, whereas for any systemic adverse events it ranged from 3.5% to 7.4% across vaccine groups. The excess risk of events leading to search for medical care or to interruption of work activities ranged from 2% to 4.5%. Viremia was detected in 3%-6% of vaccinees up to 10 days after vaccination. Variations in liver enzyme levels after vaccination were similar in placebo and vaccine recipients. CONCLUSIONS: The frequency of adverse events post-immunization against YF, accounting for the background occurrence of nonspecific signs and symptoms, was shown for the first time to be similar for vaccines from 17D and 17DD substrains. The data also provided evidence against viscerotropism of vaccine virus.

Antibodies against non-structural c100/3 and structural core antigen of hepatitis C virus (HCV) in hemodialysis patients

Two groups of patients undergoing hemodialysis (HD) maintenance were evaluated for their antibody response to non-structural c100/3 protein and structural core protein of hepatitis C virus (HCV). Forty-six patients (Group 1) never presented liver abnormalities during HD treatment, while 52 patients (Group 2) had either current or prior liver enzyme elevations. Prevalence rates of 32.6% and 41.3% were found for anti-c100/3 and anti-HCV core antibodies, respectively, in patients with silent infections (Group 1). The rate of anti-c100/3 in patients of Group 2 was 71.15% and reached 86.5% for anti-HCV core antibodies. The recognition of anti-c100/3 and anti-core antibodies was significantly higher in Group 2 than in Group 1. A line immunoassay composed of structural and non-structural peptides was used as a confirmation assay. HBV infection, measured by the presence of anti-HBc antibodies, was observed in 39.8% of the patients. Six were HBsAg chronic carriers and 13 had naturally acquired anti-HBs antibodies. The duration of HD treatment was correlated with anti-HCV positivity. A high prevalence of 96.7% (Group 2) was found in patients who underwent more than 5 years of treatment. Our results suggest that anti-HCV core ELISA is more accurate for detecting HCV infection than anti-c100/3. Although the risk associated with the duration of HD treatment and blood transfusion was high, additional factors such as a significant non-transfusional spread of HCV seems to play a role as well. The identification of infective patients by more sensitive methods for HCV genome detection should help to control the transmission of HCV in the unit under study.

Portal vein embolization with N-butyl cyanoacrylate before partial hepatectomy in patients with hepatocellular carcinoma and underlying cirrhosis or advanced fibrosis.

PURPOSE: To describe the safety, complications, and liver regeneration associated with the left liver after embolization of the right portal vein (PV) in patients with hepatocellular carcinoma (HCC) developed in the setting of advanced liver fibrosis and cirrhosis. MATERIALS AND METHODS: Forty patients (31 men, nine women; mean age, 62 years) with HCC underwent PV embolization over a 4-year period. Embolization was performed from a left PV percutaneous access with use of n-butyl cyanoacrylate (NBCA) mixed with iodized oil. Computed tomography (CT) volumetry was performed before and 1 month after PV embolization to measure the left lobe volume as well as the functional liver ratio defined by the ratio between the left lobe and the total liver volume minus tumoral volume. PV pressure and liver enzyme levels were compared before and 1 month after the procedure and complications were registered. Factors potentially affecting regeneration (age, sex, diabetes, chemoembolization, functional liver ratio before PV embolization, and Knodell histologic score) were evaluated by one-way and stepwise regression analysis. RESULTS: PV embolization could be achieved successfully in all cases. Two patients had partial PV thrombosis on the 1-month follow-up CT and two patients developed transient ascites after PV embolization. The left lobe volume increase was 41% +/- 32% after PV embolization and the functional liver ratio increased from 28% +/- 10% to 36% +/- 10% (P < .0001). Hypertrophy of the left lobe was greater in patients with a low functional liver ratio before PV embolization and those with an F3 fibrosis score. Other factors had no influence on left lobe regeneration. CONCLUSION: PV embolization with use of NBCA is feasible in patients with advanced fibrosis and cirrhosis. Hypertrophy of the left lobe of the liver after PV embolization has a statistically significant correlation with lower functional liver ratio and lower degrees of fibrosis.

In vivo evaluation of the anti-tumoral effect of sunitinib eluting beads in the rabbit VX2 tumor model

Purpose: To study the anti-tumoral effect of sunitinib eluting beads in the rabbit VX2 tumor modelMaterials: VX2 tumor were implanted in the left liver lobe of New-Zealand white rabbits. Seven animals received 0.2ml of DC Beads loaded with 6mg of sunitinb (group 1), 6 animals received 0.2ml of DC Beads (group 2) and 6 animals received NaCl 0.9% intra arterially in the left hepatic artery. One animal in each group was sacrificed at 24 hours and the others were left to survive. Liver enzyme were measured daily. In group 1 plasmatic sunitinib concentration were measured daily by LC MS/MS tandem mass spectroscopy. At day 15 all living animals were sacrficed. After sacrifice, or premature euthanasia the livers were harvested for determination of the VEGF receptor tyrosine kinase activity by western blot and histopathological examination.Results: In group 1, no animal died during follow-up. In group 2 and 3, respectively 2 and 3 animals died during follow-up. In group 1 plasmatic sunitinib level remained under therapeutic concentration during the whole experiment. There was an evident lack of phosphorylation of the RTK In group 1 and there was an augmentation of the RTK phosphorylation in group 2 at 24 hours. No difference in RTK activity was noticable at 15 days. From the histopathological point of view it was unpossible to differentiate treatment induced from spontaneous necrosis of tumors.Conclusions: Administration of sunitinib eluting Beads in VX2 carrying rabbits inhibits the activation of RTK's triggered by ischemia. It also seems to prolong survival of the treated animals.

Les spirochètes dans tous leurs etats [A short journey through spirochetal infections]

Spirochetal infections present with a variety of clinical syndromes and epidemiologic features. Diagnosis remains challenging for the clinician because of the often protean clinical presentation and poor performance of stan-dard microbiological tests. We present 3 clinical cases, illustrating interesting or unusual features of these infections. First, we present a case of leptospirosis acquired in Switzerland after a rat bite. We then present a case of early disseminated Lyme disease with multiple erythema migrans, lymphopenia, thrombocytopenia and liver enzyme elevation. Finally, we present a case of secondary syphilis in an HIV-positive man, complicated by sensorineural deafness. For each case we highlight and discuss the specific epidemiological, clinical and therapeutic features.

Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10-8).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

Influence of Gilbert's syndrome on the formation of ethyl glucuronide.

A drinking experiment with participants suffering from Gilbert's syndrome was performed to study the possible influence of this glucuronidation disorder on the formation of ethyl glucuronide (EtG). Gilbert's syndrome is a rather common and, in most cases, asymptomatic congenital metabolic aberration with a prevalence of about 5 %. It is characterized by a reduction of the enzyme activity of the uridine diphosphate glucuronosyltransferase (UGT) isoform 1A1 up to 80 %. One of the glucuronidation products is EtG, which is formed in the organism following exposure to ethanol. EtG is used as a short-term marker for ethyl alcohol consumption to prove abstinence in various settings. After 2 days of abstinence from ethanol and giving a void urine sample, 30 study participants drank 0.1 L of sparkling wine (9 g ethanol). 3, 6, 12, and 24 h after drinking, urine samples were collected. 3 hours after drinking, an additional blood sample was taken, in which liver enzyme activities, ethanol, hematological parameters, and bilirubin were measured. EtG and ethyl sulfate (EtS), another short-term marker of ethanol consumption, were determined in the urine samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS); creatinine was measured photometrically. In all participants, EtG and EtS were detected in concentrations showing a wide range (EtG: 3 h sample 0.5-18.43 mg/L and 6 h sample 0.67-13.8 mg/L; EtS: 3 h sample 0.87-6.87 mg/L and 6 h sample 0.29-4.48 mg/L). No evidence of impaired EtG formation was found. Thus, EtG seems to be a suitable marker for ethanol consumption even in individuals with Gilbert's syndrome.

Sex-dependent differences in the activities of acetylsalicylic acid-esterases in mouse kidneys

Acetylsalicylic acid (ASA), the most used drug worldwide, is hydrolyzed to salicylic acid and acetate by esterases present in tissues of several species including humans. Sex differences in drug metabolism by rodent liver are documented in the literature. In this paper we report a difference in the activities of the esterases (ASA-esterase I and II) in the kidneys of male and female mice. In this species there is no difference between males and females in liver ASA-esterases (ASA-esterase I: males 38.5 ± 7.9 (N = 5) and females 31.6 ± 7.6 (N = 5) nmol of salicylic acid formed min-1 mg protein-1, P>0.05; ASA-esterase II: males 77.3 ± 17.4 (N = 5) and females 61.4 ± 15.1 (N = 5) nmol of salicylic acid formed min-1 mg protein-1, P>0.05). However, in the kidneys males presented a much higher enzyme activity than females (ASA-esterase I: males 25.2 ± 6.3 (N = 5) and females 6.8 ± 0.6 (N = 5) nmol of salicylic acid formed min-1 mg protein-1, P<0.0002; ASA-esterase II: males 79.8 ± 10.1 (N = 5) and females 13.0 ± 1.1 (N = 5) nmol of salicylic acid formed min-1 mg protein-1, P<0.0001). The difference between sexes observed in mouse kidneys could serve as a model to study the molecular basis of this sex difference and also to determine the possible involvement of pituitary and gonadal hormones in this difference in ASA-esterase activities since these hormones control the sex differences in rodent liver enzyme activity.

Biomarkers, medical treatment and fetal intrapartum surveillance in intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder characterized by maternal pruritus and elevated liver enzymes. It usually begins in the third trimester of pregnancy and resolves spontaneously after delivery. ICP is considered benign for the pregnant woman, but it is associated with an increased risk for unexplained term stillbirth and preterm delivery. There are no specific laboratory markers to diagnose ICP. The diagnosis is currently based on the presence of maternal pruritus and elevated values of alanine aminotransaminases (ALT) and serum bile acids (BA). Recently, ursodeoxycholic acid (UDCA) has been used for treatment. Mechanisms leading to intrauterine fetal death (IUFD) may be multifactorial and are unknown at present. For this thesis, 415 pregnant women with ICP were studied. The aim was to evaluate the value of the liver enzyme glutathione S-transferase alpha (GSTA) as a specific marker of ICP and to assess the effect of maternal UDCA therapy on maternal laboratory values and fetal outcome. The specific markers predisposing the fetus to heart arrhythmia were studied by comparing waveform analysis of fetal electrocardiograms (FECG) during labor in pregnancies complicated by ICP with controls. The levels of maternal GSTA were high and the values correlated with the value of ALT in patients with ICP. UDCA therapy reduced the values of the liver enzymes and alleviated maternal pruritus, but it did not influence maternal hormonal values. Although the newborns experienced an uneventful perinatal outcome, severe ICP was still associated with preterm birth and admission to the neonatal intensive care unit (NICU). There were no significant differences in intrapartum FECG findings between fetuses born to ICP women and controls.

A comparative study of protoheme and heme d catalases : role of the heme and the heme pocket in catalysis and ligand binding

Catalase dismutes H20 2 to O2 and H20. In successive twoelectron reactions H20 2 induces both oxidation and reduction at the heme group. In the first step the protoheme prosthetic group of beef liver catalase forms compound I, in which the heme has been oxidized from Fe3+ to Fe4+=0 and a porphyrin radical has been created. Compound II is formed by the oneelectron reduction of comp I. It retains Fe4+=0 but lacks the porphyrin radical and is catalytically inert. Molecular structures are available for Escherichia coli Hydroperoxidase II, Micrococcus Iysodeiktus, Penicillium vitale and beef liver enzymes, which contain different hemes and heme pockets. In the present work, the pockets and substrate access channels of protoheme (beef liver & Micrococcus) and heme d (HPII of E. coli and Penicillium) catalases have been analysed using Quanta™ and CharmMTM molecular modeling packages on the Silicon Graphics Iris Indigo 2 computer. Experimental studies have been carried out with two catalases, HPII (and its mutants) and beef liver. Fluoride and formate' are inhibitors of both enzymes, and their binding is modulated by the heme and by distal residues N201 & H128. Both HPII and beef liver enzymes form compound I with H202 or peracetate. The reduction of beef liver enzyme compound I to II and the decay of compound II are accelerated by fluoride. The decay of compound II is also accelerated by formate, and this reagent acts as a 2-electron donor towards compound I of both enzymes. It is concluded that heme d enzymes (Penicillium and HPII of E. coli) are formed by autocatalytic transformation of protoheme in a modified pocket which contains a characteristic serine residue as well as a partially occluded heme channel. They are less active than protoheme enzymes but also do not form the inactive compound II species. Binding of peroxide as well as fluoride and formate is prevented by mutation of H128 and modulated by mutation of N201.

Uveítis pediática no infecciosa, una experiencia de una cohorte colombiana

Resumen: •Antecedentes: La uveítis pediátrica no infecciosa tiene el potencial de desencadenar severas complicaciones visuales y su manejo farmacológico convencional está asociado a importantes efectos secundarios. 1 Infliximab (INF) y Adalimumab (ADA), son dos medicamentos biológicos disponibles para el manejo de la uveítis pediátrica refractaria. Se unen específicamente al TNFα y previenen la unión del mismo con los receptores celulares; interacción directamente implicada en el proceso inflamatorio y el subsecuente daño tisular. 2,3 •Métodos: Se realizó estudio de tipo cohorte retrospectiva mediante revisión de historias clínicas de 35 pacientes pediátricos diagnosticados con uveítis durante los años 2009-2015. Se comparó control de la inflamación ocular, tiempo de respuesta y eventos adversos en pacientes tratados con ADA o INF con dosis bajas de Metotrexate vs. Metotrexate (MTX) como única terapia. •Resultados: El 45.7% de la población estudiada correspondía al sexo femenino, cuya edad promedio de inicio de síntomas y de diagnósticos fue de 9 años. El 80% de los casos fueron uveítis idiopáticas, seguido por Vogt-Koyanagi-Harada (8,5%) y AIJ (5,7%). El 91,4% presentó compromiso ocular bilateral y se documentaron 2 casos de ambliopía. El 12,9% de los pacientes que recibieron MTX como tratamiento de primera línea requirieron escalonamiento terapéutico por presentar eventos adversos (Elevación de enzimas hepáticas e intolerancia gastrointestinal (GI)). El tiempo promedio para alcanzar control de la inflamación con MTX fue 9 semanas, y para Adalimumab fue de 8,75 semanas (P: 0,90). Se comparó la capacidad de controlar la inflamación del MTX vs Anti-TNF, y no se observaron diferencias significativas (P: 0.88).

Síndromes hipertensivas da gestação: identificação de casos graves

A hipertensão arterial está entre as causas mais freqüentes de morte materna. Entre os tipos presentes na gravidez destacam-se as manifestações específicas, isto é, a pré-eclâmpsia e a hipertensão gestacional, definidas clinicamente por aumento dos níveis da pressão arterial após a 20ª semana de gestação, associado (pré-eclâmpsia) ou não (hipertensão gestacional) à proteinúria. Na fase inicial a doença é assintomática, porém, quando não tratada ou não se interrompe a gestação, sua evolução natural é desenvolver as formas graves, como a eclâmpsia e a síndrome HELLP. Eclâmpsia é definida pela manifestação de uma ou mais crises convulsivas tônico-clônicas generalizadas e/ou coma, em gestante com hipertensão gestacional ou pré-eclâmpsia, na ausência de doenças neurológicas. Pode ocorrer durante a gestação, durante o trabalho de parto e no puerpério imediato. É comumente precedida pelos sinais e sintomas de eclâmpsia iminente (distúrbios do sistema nervoso central, visuais e gástricos). A associação de hemólise, plaquetopenia e disfunção hepática já era relatada na literatura na década de cinqüenta. em 1982, Weinstein reuniu estas alterações sob o acrônimo de HELLP, significando hemólise (H), aumento de enzimas hepáticas (EL) e plaquetopenia (LP), e denominou-as de síndrome HELLP. A literatura diverge em relação aos valores dos parâmetros que definem a síndrome. Sibai et al. (1986) propuseram sistematização dos padrões laboratoriais e bioquímicos para o diagnóstico da mesma, que foi adotada pelo Ministério da Saúde do Brasil. As manifestações clínicas podem ser imprecisas, sendo comuns queixas como dor epigástrica, mal-estar geral, inapetência, náuseas e vômitos. O diagnóstico precoce é, eminentemente, laboratorial e deve ser pesquisado de maneira sistemática nas mulheres com pré-eclâmpsia grave/eclâmpsia e/ou dor no quadrante superior direito do abdome. Diferenciar a síndrome HELLP de outras ocorrências, com manifestações clínicas e/ou laboratoriais semelhantes, não é tarefa fácil. O diagnóstico diferencial é particularmente difícil para doenças como púrpura trombocitopênica trombótica, síndrome hemolítico-urêmica e fígado gorduroso agudo da gravidez, devido à insuficiente história clínica e à semelhança dos aspectos fisiopatológicos. O conhecimento da fisiopatologia da pré-eclâmpsia, o diagnóstico precoce e a atuação precisa no momento adequado nas situações complicadas pela eclâmpsia e/ou síndrome HELLP permitem melhorar o prognóstico materno e perinatal.

General aspects of drug interactions with systemic antifungals in a retrospective study sample

Estudo retrospectivo avaliando alterações laboratoriais hepáticas e potenciais interações medicamentosas em pacientes tratados para onicomicose. Foram avaliados 202 pacientes, sendo 82% do sexo feminino. em 273 exames de enzimas hepáticas, houve alterações em apenas 6%. Potenciais interações medicamentosas foram identificadas em 28% dos pacientes para imidazólicos e 14% para terbinafina. O risco de interações potenciais aumentou com a idade do paciente e o uso de múltiplas medicações.

Bezafibrate for the treatment of hypertriglyceridemia in HIV1-infected patients on highly active antiretroviral therapy

The use of highly active antiretroviral therapy (HAART) in HIV-infected patients has been associated with the development of risk factors for cardiovascular diseases (CD) including dyslipidemia and insulin resistance, hypertriglyceridemia being the most frequent metabolic disturbance in these patients. Fibrates are indicated when hypertriglyceridemia is accentuated and persists for over six months. We evaluated the efficacy and safety of bezafibrate for the treatment of hypertriglyceridemia in HIV-infected individuals on HAART. All patients received 400mg/day of bezafibrate and were evaluated three times: Mo (pre-treatment), M1 (one month after treatment), and M2 (six months after treatment). Fifteen adult individuals, eight males and seven females with mean age = 41.2 ± 7.97 years and triglyceride serum levels ≥400mg/dL were included in the study. Smoking, alcohol ingestion and sedentarism rates were 50%, 6.66% and 60%, respectively. Family history of CD, hypertension and diabetes mellitus was reported in 33.3%, 40% and 46.7% of the cases, respectively, while dyslipidemia was reported by only 13.3%. More than half of the patients were using a protease inhibitor plus a nucleotide analog transcriptase inhibitor. Eutrophy and tendency toward overweight were observed at all three study time points. There were significant reductions in triglyceride serum levels from Mo to M1 and from Mo to M2. No significant changes were observed in the serum levels of creatine phosphokinase, hepatic enzymes, CD4 +, CD8 + and viral load. Therefore, bezafibrate seems to be safe and effective for the reduction of hypertriglyceridemia in HIV-infected patients on HAART. © 2006 by The Brazilian Journal of Infectious Diseases and Contexto Publishing. All rights reserved.