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Biomedical subjects

A Marrone

Publications and source records attributed to A Marrone.

At least 19 recordsLinked to original sources
PubMed2006

Hepatic steatosis and insulin resistance are associated with serum imbalance of adiponectin/tumour necrosis factor-alpha in chronic hepatitis C patients.

BACKGROUND: Steatosis and insulin resistance (IR) have a pathogenic role in chronic hepatitis C (HCV). Adipocytokines balance modulates hepatic lipid content and IR. AIM: To evaluate serum adipocytokines and relationship with virological, histological and metabolic parameters in chronic HCV. METHODS: Adiponectin and tumour necrosis factor-alpha (TNF-alpha) levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 161 non-diabetic chronic HCV patients. RESULTS: Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of TNF-alpha, HOMA, alanine aminotransferase, gamma-glutamiltransferase and Histological Activity Index (HAI) and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Higher tumour necrosis factor-alpha levels were observed in patients with low adiponectin levels. The extension of steatosis was inversely correlated with adiponectin levels. A correlation between grade of steatosis with HOMA-IR and fibrosis was observed. HCV genotype 3-infected patients showed lower adiponectin levels than those with other genotypes. An independent predictor of low adiponectin levels in genotype 3 infection was the extension of steatosis. Liver fibrosis score was associated with steatosis, HAI and age. CONCLUSIONS: Chronic HCV patients with steatosis showed a serum adiponectin/TNF-alpha imbalance that is associated with IR. Reduced adiponectin levels may be involved in the pathogenesis of steatosis, which in turn accelerates progression of fibrosis in chronic HCV.

Adiponectin↗
PubMed2005

Clinical reactivation during lamivudine treatment correlates with mutations in the precore/core promoter and polymerase regions of hepatitis B virus in patients with anti-hepatitis B e-positive chronic hepatitis.

BACKGROUND: Drug-resistant mutants may emerge in patients with chronic hepatitis B receiving lamivudine therapy. AIM: To evaluate whether different viral mutational patterns may be associated with clinical reactivation during lamivudine treatment in patients with chronic B hepatitis. METHODS: Eight anti-hepatitis B e-positive patients with (group A) and 14 patients without clinical exacerbation (five anti-hepatitis B e-positive, group B1; nine hepatitis B e antigen-positive, group B2) during lamivudine treatment were investigated. RESULTS: 'Polymerase region': M204V/I variants were found in all group A patients, but in none of group B1 (P=0.0007) and in four of nine of group B2 (44%; P=0.02) patients. The L180M substitution was detected in four of eight (50%) of group A and in none of groups B1 and B2. 'Core promoter': the double basic core promoter (A1762T/G1764A) variant was detected in seven of eight (87%) of group A and in one of five (20%; P=0.03) of group B1 and one of nine (11%; P=0.002) of group B2 patients. 'Precore': the G1896A stop codon mutation was present in seven of eight (87%) of group A and in zero of five (P=0.004) of group B1 and one of nine (11%; P=0.002) of group B2. CONCLUSIONS: Different mutational patterns were observed in the lamivudine-treated patients with and without exacerbation. There was an association of the basic core promoter and stop codon mutations with lamivudine resistance in patients with disease exacerbation.

Adult↗
PubMed2005

The polymorphisms -318C>T in the promoter and 49A>G in exon 1 of CTLA4 and the risk of aplastic anemia in a Caucasian population.

Aplastic anemia (AA) is a rare disease with a major autoimmune pathogenetic component. CTLA4 is a T-lymphocyte surface molecule involved in the maintenance of immune tolerance. Some polymorphisms associated with a reduced expression of CTLA4, and thus presumably with increased tendency to autoimmunity, have been associated with various autoimmune diseases. In this study, we evaluated the distribution of the low expression polymorphisms -318C > T and 49A > G of CTLA4 in a population of 67 patients with acquired AA and in 100 normal controls. There was no difference in the distribution of the tested polymorphism between patients and controls and, within the patient group, between those who responded to immunosuppression vs those who did not respond. This study indicates that the polymorphisms -318C > T and 49A > G of CTLA4 do not affect the risk of developing AA and do not influence the response to immunosuppression.

Adolescent↗
PubMed2005

Three-phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B.

Alpha-interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)-DNA was evaluated during treatment and core-promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV-DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti-HBe seroconversion. One patient presented core-promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three-phase sequential combined lamivudine/IFN treatment reduced HBV-DNA serum level, but did not lead to HBeAg and HBV-DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.

Adolescent↗
PubMed2003

Dyskeratosis congenita.

Dyskeratosis congenita is an inherited skin and bone marrow failure syndrome. There are X-linked, autosomal dominant and autosomal recessive forms of the disease. The X-linked form is due to mutations in the DKC1 gene at Xq28. The encoded protein, dyskerin, is a component of both small nucleolar ribonuclear protein particles and the telomerase complex. Mutations in DKC1 mainly lead to amino acid substitutions. The autosomal dominant form of the disease is due to mutations in hTR, the RNA component of telomerase, making it likely that the disease is due to defective telomerase activity. Mutations in hTR are predicted to either disrupt secondary structure or alter the template region. The gene or genes involved in the recessive forms of the disease remain elusive, though genes whose products are required for telomere maintenance are strong candidates.

Animals↗
PubMed2003

Low HBeAg serum levels correlate with the presence of the double A1762T/G1764A core promoter mutation and a positive response to interferon in patients with chronic hepatitis B virus infection.

OBJECTIVE: To investigate the correlation of serum hepatitis B e antigen (HBeAg) levels with the presence of core promoter (CP) mutations, hepatitis B virus (HBV) viremia and the response to interferon (IFN) in patients with chronic hepatitis B. METHODS: Fourteen HBeAg-positive patients received alpha-2a IFN. Diluted serum samples of responders were tested for HBeAg positivity at dilutions of 1:40, 1:160 and 1:640 at the following time points: T0 (before starting IFN), T1 [at peak alanine aminotransferase (ALT) preceding HBeAg seroconversion], T2 (at ALT normalisation) and T3 (end of treatment). Nonresponder samples were similarly tested at times T0 and T3. The HBV CP and precore regions were sequenced at the same time points as for HBeAg testing. RESULTS: Six of 14 patients (43%) responded to IFN treatment and had lower HBeAg levels than nonresponders at T0 (p = 0.003). Five of 6 responders (83%) and none of the nonresponders had the A1762T/G1764A CP mutations (0/8, p < 0.003). At T0, HBeAg was negative at the 1:640 dilution in 5 of the 6 responders, who also had lower HBV DNA levels than nonresponders (p = 0.003). During IFN treatment, HBeAg levels decreased and HBV DNA became negative at T1 in responders. CONCLUSIONS: Low serum HBeAg and HBV DNA levels correlate with the presence of CP mutations and response to IFN treatment and can be considered as predictive markers of response to IFN.

Adolescent↗
PubMed2002

Sequential analysis of hepatitis B virus core promoter and precore regions in cancer survivor patients with chronic hepatitis B before, during and after interferon treatment.

We analysed the hepatitis B virus (HBV) core-promoter (CP) and precore (PC) regions before, during and after interferon treatment in young Caucasian cancer survivors who had acquired HBV infection during chemotherapy for malignancies. Fourteen patients with chronic hepatitis B [hepatitis B e antigen (HBeAg) /HBV-DNA positive] received alpha-2a interferon (IFN), 5 MU/m2 t.i.w. for 12 months. HBV CP and PC region sequences were analysed following polymerase chain reaction (PCR) amplification. Sera from responders were studied at: T(0) (before starting IFN), T(1) [at alanine aminotransferase (ALT) peak preceding HBeAg seroconversion], T(2) (at ALT normalization), T(3) (at end of IFN) and T(4) (at one year after IFN) and in nonresponders at time points T(0), T(3) and T(4). Amplified HBV-DNA was cloned and sequenced automatically. Six of 14 patients (43%) responded to IFN treatment. Five of the six (83%) responders displayed the double CP mutation A1762T/G1764A always in association with a T1753C change. None of the nonresponders showed these mutations at any time point. The G1896A change creating the PC stop codon mutation was never detected in any of the patients. In our cancer survivors, IFN-induced HBeAg/anti-HBe seroconversion appeared to correlate with CP mutations and was not influenced by previous chemotherapy. These mutations in addition to low HBV DNA levels and elevated ALT can be considered favourable factors of response to IFN-induced anti-HBe seroconversion.

Adolescent↗
PubMed2001

The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.

Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA. Dyskerin is also associated with telomerase RNA (hTR), which contains a H/ACA consensus sequence. Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3' 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.

Cell Line↗
PubMed2000

Probing possible decoherence effects in atmospheric neutrino oscillations.

It is shown that the results of the Super-Kamiokande atmospheric neutrino experiment, interpreted in terms of nu(mu)<-->nu(tau) flavor transitions, can probe possible decoherence effects induced by new physics (e.g., by quantum gravity) with high sensitivity, supplementing current laboratory tests based on kaon oscillations and on neutron interferometry. By varying the (unknown) energy dependence of such effects, one can either obtain strong limits on their amplitude or use them to find an unconventional solution to the atmospheric nu anomaly based solely on decoherence.

Atmosphere↗
PubMed1999

The significance of hepatitis G virus in serum of patients with sporadic fulminant and subfulminant hepatitis of unknown etiology.

Excluding acute hepatic failure caused by drugs, the etiology of fulminant hepatitis (FH) remains unknown in many patients. There are conflicting data about a possible pathogenic role for the hepatitis G virus (HGV) in patients with cryptogenic fulminant hepatitis (non-A-E FH). We investigated the presence of circulating HGV in 36 patients with well-documented non-A-E fulminant and 5 patients with subfulminant hepatitis from 3 geographic locations in the United States. Serum HGV RNA was determined by reverse transcriptase-polymerase chain reaction using primers from the NS5 region of the HGV genome. HGV RNA was also measured before and after liver transplantation in 5 patients and at different time points in 7 patients. Serum samples were recoded and reanalyzed for HGV RNA using different primer sets to assess the validity of the HGV RNA assay. HGV was present in serum of 14 of the 36 patients (38.8%) with non-A-E fulminant hepatitis. Twenty percent of patients from the Northeast, 11% of the patients from the Southeast, and 50% from the Mid-Atlantic regions of the United States had circulating HGV RNA. The use of therapeutic blood products was significantly associated with the presence of serum HGV RNA (P <.02). Retesting for HGV RNA with different primers was positive in all but 1 case. HGV RNA is not causally related to non-A-E fulminant hepatitis. The finding of HGV RNA in serum from these patients is likely related to the administration of blood product transfusion after the onset of fulminant hepatitis.

Adolescent↗
PubMed1999

Multiscale analysis of blood pressure signals.

We describe the multiresolution wavelet analysis of blood pressure waves in vasovagal syncope-affected patients compared with those in healthy people, using Haar and Gaussian bases. A comparison between scale-dependent and scale-independent measures discriminating the two classes of subjects is made. What emerges is a sort of equivalence between these two methodological approaches, that is, both methods reach the same statistical significance of separation between the two classes.

Biophysical Phenomena↗
PubMed1998

Naturally occurring mutations define a novel function of the hepatitis B virus core promoter in core protein expression.

Functional analysis of naturally occurring hepatitis B virus (HBV) mutations is crucial in understanding their impact on disease. We have recently identified two mutations in the HBV core promoter of an HBV strain associated with fulminant hepatitis leading to highly (15-fold) enhanced replication as a result of increased viral encapsidation of pregenomic RNA into the core particles (T. F. Baumert et al., J. Clin. Invest. 98:2268-2276, 1996). Functional studies in an encapsidation assay had demonstrated that the increase in encapsidation was largely independent of pregenomic RNA transcription. In this study, we define the molecular mechanism whereby the two core promoter mutations (C to T at nucleotide [nt] 1768 and T to A at nt 1770) result in enhanced viral encapsidation and replication. The effect of these mutations leading to increased encapsidation is mediated through enhanced core protein synthesis (15-fold) by the mutant virus. The marked increase in core protein synthesis is largely a result of posttranscriptional or translational effect of the mutations because the mutations resulted in only a twofold increase in pregenomic RNA transcription. In addition, this effect appears to be selective for core expression since reverse transcriptase-polymerase expression was increased only twofold. trans-complementation analyses of HBV replication demonstrated that enhanced replication occurred only when the mutations were provided together with the core protein in trans, confirming the functional association of the core promoter mutations and core protein expression. In addition, the effect of the mutations appears to be quantitatively dependent on the strain background to which the mutations were introduced. Our study suggests that the HBV core promoter regulates core protein expression at both transcriptional and posttranscriptional levels.

Gene Expression Regulation, Viral↗
PubMed1997

Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications.

Two missense mutations were uncovered in the UGT1A6 (HLUG P1) cDNA which codes for a human phenol-metabolizing UDP-glucuronosyltransferase. The mutant and a wild-type UGT1A6 cDNAs were isolated from a custom synthesized human liver lambda Zap cDNA library. Both an A to G transition at nucleotide 541 (T181 A) and an A to C transversion at nucleotide 552 (R184S) occurred in exon 1 of the UGT1A6 (UGT1F) gene at the UGT1 locus. The two mutations on a single allele created a heterozygous genotype. Newly created BsmI and BsoFI sites at the T181 A and R184S locations, respectively, were confirmed by endonuclease treatment of PCR-generated DNA using the donor-liver genomic DNA as template. Screens with endonuclease treatment showed that 33/98 DNA samples were heterozygous with both mutations on one allele. One other individual also carried the R184S mutation on the second allele. Wild-type UGT1A6 generated a broad plateau of activity from pH 5.0 to pH 8.0 with certain experimental phenols, while activity was 1.3-2.5-fold higher at pH 6.4 than at pH 7.2 for others. UGT1A6*2 (181 A+ and 184S+) metabolized 4-nitrophenol, 4-tert-butylphenol, 3-ethylphenol/4-ethylphenol, 4-hydroxycoumarin, butylated hydroxy anisole and butylated hydroxy toluene, with the pH 6.4 preference, at only 27-75% of the rate of the wild-type isozyme whereas 1-naphthol, 3-iodophenol, 7-hydroxycoumarin, and 7-hydroxy-4-methylcoumarin were metabolized at essentially the normal level. Furthermore, UGT1A6*2 metabolized 3-O-methyl-dopa and methyl salicylate at 41-74% of that of the wild-type, and a series of beta-blockers at 28-69% of the normal level. This evidence suggests that the UGT1A6 enzyme activity is affected by different amino acids depending upon the substrate selection.

Alleles↗
PubMed1997

Serum hepatitis G virus RNA in patients with chronic viral hepatitis.

OBJECTIVES: The hepatitis G virus (HGV) is a newly described flavivirus that affects a high proportion of patients with chronic viral hepatitis: our objective was to determine what role HGV might play in the course of disease. METHODS: We evaluated stored serum samples from 108 patients with chronic hepatitis B and 99 patients with chronic hepatitis C who participated in trials of alpha-interferon or ribavirin for the presence of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA by branched DNA and for the presence of HGV RNA by polymerase chain reaction (PCR), using primers from the NS5 region of the genome. RESULTS: Initially, 20 (19%) patients with hepatitis B and 11 (11%) with hepatitis C had HGV RNA in their serum. Patients with and without HGV infection were similar with regard to clinical features, laboratory tests, and hepatic histology. HGV RNA levels fell during interferon therapy and became undetectable in those receiving the highest doses; however, HGV RNA levels returned to pretreatment values when therapy was stopped. With ribavirin therapy, HGV RNA levels did not change. Two- to 12-yr follow-up serum samples were available from 17 initially HGV RNA-positive patients, of whom only 10 (59%) were still positive. CONCLUSIONS: HGV infection is common among patients with chronic hepatitis B and C but has little effect on the short-term course of disease or response to therapy. HGV RNA levels are suppressed but not eradicated by alpha-interferon and are unaffected by ribavirin treatment. Spontaneous loss of HGV RNA occurs over time in a proportion of patients.

Adult↗
PubMed1996

Genetic heterogeneity of hepatitis C virus. The clinical significance of genotypes and quasispecies behavior.

Knowledge of the molecular biology of the hepatitis C virus (HCV) has increased exponentially since its identification in 1989. Paradoxically, the understanding of many clinical aspects of HCV pathobiology has lagged behind, partly because of lack of suitable models of disease. The genomic variability of HCV is central to viral pathogenesis. This article briefly reviews some clinical and laboratory aspects of HCV variability, such as investigatory method, pitfalls in data interpretation, and possible directions for future research. The profound implications of stable quasispecies behavior, conserved genotype replication, and the unexpectedly low frequency of infection with multiple genotypes in susceptible individuals are discussed.

DNA-Directed RNA Polymerases↗
PubMed1994

Treatment of chronic hepatitis B in children with prednisone followed by alfa-interferon: a controlled randomized study.

The efficacy and safety of sequential treatment with prednisone and interferon was evaluated in a randomized, controlled study on 43 children with biopsy proven HBsAg/HBeAg/hepatitis B virus-DNA positive, anti-delta negative, chronic hepatitis (34 chronic persistent hepatitis, 9 chronic active hepatitis). Patients received either a 1-month course of prednisone (0.6 to 0.3 mg/kg per day) followed by interferon alfa-2a (3 MU/m2, thrice weekly, for 12 months; 22 patients) or no treatment (21 patients). At the end of the study (20 months), clearance of hepatitis B virus-DNA and HBeAg seroconversion were observed in nine (41%) of the patients treated with prednisone and interferon and in two (9.5%) of the untreated controls (p = 0.020). Two of the treated patients who lost HBeAg, also cleared HBsAg. In the treated group, 13 (59%) patients had stable normal levels of alanine aminotransferase on their last examination. The baseline serum level of hepatitis B virus-DNA was an important predictor of response. In fact, HBeAg clearance was observed in 75% of patients with a baseline hepatitis B virus-DNA level lower than 100 pg/ml and in none with a level above 100 pg/ml. We suggest that combined treatment with prednisone followed by alfa-interferon may be safe and effective in inducing a stable clearance of HBeAg and, in some cases, of HBsAg in children with chronic hepatitis B and with a low level of viral replication. For children with high levels of viral replication, this regimen seems to be ineffective.

Adolescent↗