Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update

The prevalence of hepatitis C virus (HCV) infection increases with advancing age, but the disease has been poorly studied in the elderly. A population-based study was therefore carried out to investigate the prevalence of HCV infection and the severity of HCV-related chronic liver disease in the elderly. One thousand and sixty-three people (> or = 60 years of age) were screened for antibodies to HCV (anti-HCV) and for possible abnormalities of common liver function tests. Positive subjects and sex and age-matched anti-HCV-negative controls were recalled 12 months later for measurements of liver enzymes, confirmatory testing of anti-HCV, HCV RNA analysis and HCV genotyping. All subjects answered a specific questionnaire concerning medical history and possible risk factors. Forty-four subjects were positive for anit-HCV, the prevalence being 4.1%. Thirty-five positive subjects and 35 controls were investigated further. Risk factors for acquiring HCV were found to be: blood transfusion, surgical intervention and the use of non-disposable syringes. Abnormal alanine aminotransferase levels were found in 13 patients (37.1%). HCV RNA genotyping showed type 1b in three (15.8%), type 2a in 13 (68.4%) and not classified in three (15.8%) patients. There was no relationship between abnormalities of serum aminotransferase, the rate of HCV RNA positivity and HCV genotypes. Ultrasound abnormalities were present in 13 (37.1%) patients. In this elderly population the relatively high prevalence of HCV infection was thought to be caused by previous parenteral exposure. The low incidence of liver disease could be related to the prevalence of HCV genotype 2a in the majority of these patients, and hints at the possibility of an HCV carrier state in elderly individuals.     

The risk of transmitting HCV, HBV or HIV by blood transfusion in Victoria

OBJECTIVE: To report the incidence rate of hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV in Victorian repeat blood donors and to derive the residual risk of transmission of the viruses by screened blood transfusion. DESIGN: The interval from the previous whole blood donation was extracted retrospectively from Victorian Red Cross Blood Bank records for each of the 358332 repeat donations given between March 1994 and December 1995. Records of repeat donors found positive for the viruses in this period were traced to the previous seronegative donation and accepted if screened by the same test. For each virus, the number of previous donations screened by the same test was calculated and the sum of all donation intervals used to derive the incidence of infection in the repeat donor population. Published intervals after infection (when a donation can be infective although seronegative) were used to calculate the risk of release of a seronegative unit which would be infective. PARTICIPANTS AND SETTING: Homologous blood donors at the Red Cross Blood Bank of Victoria. MAIN OUTCOME MEASURES: Incidence rate of HBV, HCV and HIV in regular blood donors and risk of infective donations being seronegative. RESULTS: The incidence of infection in repeat donors was: HBV: 1.67 per 100000 person-years; HCV: 1.89 per 100000 person-years; and HIV: 1.31 per 100000 person-years. The risk of a seronegative repeat donation being infective was: HBV: 2.71 per million donations (adjusted to 6.45 to account for viraemias which remain seronegative); HCV: 4.27 per million donations; and HIV: 0.79 per million donations. CONCLUSION: The risk of transmitting HCV, HBV or HIV by repeat blood donors is low and compares favourably with overseas data. Repeat donors have an incidence rate of HIV and HBV comparable to that of the general population, but the incidence rate of HCV is lower for repeat donors than in the general population.     

Vertical transmission of hepatitis C virus in New Zealand

AIMS: To investigate the transmission of hepatitis C virus from viraemic mothers to infants. METHODS: The study group comprised 54 hepatitis C ribonucleic acid (RNA) positive, human immunodeficiency virus (HIV) negative women attending antenatal clinic, their infants when born, 12 previous children and 44 children of 29 additional nonpregnant, viraemic women. During the study period there were 60 live births (1 set of twins, 5 sequential pregnancies). All infants were tested at birth for hepatitis C virus (HCV) RNA. Thirty infants were retested at 6 months or later. Breast milk from 30 mothers was tested for HCV RNA. The 56 other children were tested for antibody to HCV and HCV RNA. RESULTS: Of the 60 infants tested at birth, 30 failed to attend a 6 month or later followup, 2 infants were HCV viraemic by six months of age, 2 infants had one episode of possible HCV RNA positivity followed by loss of detectable HCV RNA and 26 have shown no evidence of HCV infection. Five of the 30 breast milk samples tested were positive for HCV RNA. Four older children of viraemic mothers were HCV RNA positive. CONCLUSIONS: In this study, 2 of 30 (6.6%) of infants born to HIV negative, HCV viraemic mothers acquired HCV infection. Breast milk remains a possible contributory source of infant HCV infection. Management of babies born to HCV viraemic mothers should include retesting of baby for HCV RNA at 3 to 6 months of age.     

Immunochemical study of incomplete platelet autoantibodies by the anti-globulin consumption test (AGCT) with specific anti-immunoglobulin sera

The indirect anti-globulin consumption test (AGCT) with specific immunoglobulin antisera (anti-IgG and anti-IgM) has been applied to the immunochemical characterization of incomplete platelet auto-antibodies in 33 patients with idiophatic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE) and autoimmune hemolytic anemia (AHA). In these cases indirect AGCT on platelets was positive with polyvalent gamma antiserum. The test with anti-IgG was positive in all cases except two, while always negative with anti-IgM, with no relation to the presence of complete platelet antibodies, the type of disease and the immunochemical type of erythrocyte autoantibodies in AHA patients. These results indicate that the incomplete platelets auto-antibodies were of the IgG class.     

Cardiovascular research support by the American Heart Association in Louisiana

The American Heart Association (AHA) was founded in 1924 by a group of physician-scientists to promote the exchange of research ideas in an era when the treatment of heart disease was extremely frustrating. The organization has evolved to include education and community service in its mission, but the support and promotion of quality research has remained at the AHA's core. Research support by the AHA has been responsible for major advances in cardiovascular medicine, including the development of diuretics, pacemakers, artificial heart valves, defibrillators, cardiopulmonary resuscitation, hypercholesterolemia therapy, and artificial surfactant. Working to ensure the efficient distribution of funds, the AHA has distributed nearly $1.4 billion in support of quality research for graduate and medical students, post-doctoral fellows, and beginning and established investigators. Such support has assisted in the career development of four Nobel Prize winners. While cardiovascular disease remains America's leading cause of death, the activities of the AHA continue to support advances in its diagnosis and treatment.     

Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection

A pathogenetic role of the hepatitis C virus (HCV) has been hypothesized for a subset of B-cell non-Hodgkin's lymphomas (NHLs). However, the preliminary characterization of B-cell NHLs in HCV-infected individuals has been poorly addressed. In the present study, we report detailed information on 35 consecutive patients with overt B-cell NHL of recent onset and HCV infection; all patients referred to a single oncological center in Northeast Italy. Histopathologic evaluation was performed by a single reference hemopathologist, and the link with the two relevant autoimmune diseases predisposing to B-cell NHL and in which HCV has been implied, ie, "essential" mixed cryoglobulinemia (EMC) and Sjogren's syndrome, was investigated. Control groups included 122 consecutive HCV-negative patients with B-cell NHL and 464 consecutive histopathologic cases of B-cell NHL referred to the same center, as well as 127 consecutive patients with HCV infection and without lymphoma referred to a different center in the same geographical area. B-cell NHLs in HCV-infected patients frequently presented at onset (1) an extranodal localization with peculiar target organs of HCV infection (ie, the liver and major salivary glands) being significantly overrepresented; (2) a diffuse large cell histotype without any prior history of low-grade B-cell malignancy or bone marrow involvement; and (3) a weak association with a full-blown predisposing autoimmune disease, although serum autoimmune features were common and cryoglobulins were always present. Therefore, the HCV-related B-cell NHLs in this oncological series presented distinctive features compared with B-cell NHLs in HCV-negative patients, and they differed from bone marrow low-grade NHLs frequently diagnosed in HCV-positive patients with EMC. Such novel information may be relevant for future research aimed at clarifying the possible link between HCV infection, autoimmunity, nonmalignant B-cell lymphoproliferation, and overt B-cell malignancy.     

Structure-activity relationship studies of 4-substituted-2-guanidinothiazoles: reversible inhibitors of gastric (H+/K+)-ATPase

To investigate the incidence of child's HCV infection in our area, 637 children with different background, including 65 posttransfusion cases, 419 hepatitis patients (250 cases of acute hepatitis A, 156 cases of chronic hepatitis B and 13 cases of non-A, non-B hepatitis), 50 infantile hepatitis syndrome (IHS) infants and 103 healthy day-cared children were tested for serum anti-HCV antibody (EIA) and HCV RNA (nested PCR). It was found that posttransfusion children had significantly higher anti-HCV positive rate (30.8%) and HCV infection incidence (43.1%) than hepatitis patients (4.3% and 5.3%), IHS infants (6.0% and 8.0%) and day-cared children (2.9% and 2.9%). 25 of 33 cases with posttransfusion hepatitis (PTH) developed hepatitis C, which was the leading cause of PTH (75.8%) and NANB PTH (25/30, 83.3%). The incidence of HCV infection in NANBH patients was 23.1% (3/13) which was apparently higher than that in day-cared children (P < 0.02) and lower than that in PTH patients (P < 0.001), but not statistically different from that in AHA and CHB patients (P > 0.05). Mother-infant paired study in IHS group showed that 4 pairs of mother-infant had HCV infection, one boy aged 8 months and his mother were anti-HCV positive, and another 3 pairs possessed HCV RNA in sera. 3 of 103 healthy day-cared children were found to have inapparent HCV infection, who were anti-HCV and HCV RNA positive.     

Comparative effects of central administration of naloxone and clonidine on the blood pressure and heart rate response to anterior and posterior hypothalamic stimulation

The purpose of this study was to examine the roles of brain opioid receptors, using the opioid receptor antagonist naloxone, and brain alpha 2 adrenergic and imidazole receptors, using their agonist clonidine, in the hypertension and tachycardia induced by electrical stimulation of the AHA and PHA area. Unanesthetized and unrestrained Wistar rats 300-400 g that had previously had catheters inserted into the lateral cerebral ventricle and femoral artery and electrodes in AHA or PHA areas received intracerebral (ICV) administration of naloxone or clonidine prior to hypothalamic stimulation. AHA and PHA stimulation with current strength from 0.5 to 2.0 mA produced a significant (p < 0.05) and dose dependent increase in BP and heart rate. Naloxone reduced the increase in BP with AHA stimulation at all but the highest stimulation current intensity. Clonidine also blunted the BP increase to AHA stimulation but to a lesser degree than naloxone. The combination of both naloxone and clonidine completely prevented the increase in BP even at high current intensities. Both naloxone and clonidine prevented the increase in heart rate with AHA stimulation. In contrast to AHA stimulation, naloxone did not alter the BP increase produced by PHA stimulation while clonidine prevented the effects of PHA stimulation. Heart rate did not increase with PHA stimulation. These data suggest that (i) the mechanisms involved in the hypertensive response to AHA are different from that of PHA. (ii) the endogenous opioid system is more operative in mediating the BP elevation produced by AHA but not PHA stimulation (iii) activation of the central alpha adrenergic or imidazole receptors can suppress hypertensive response to both AHA and PHA but is more effective for PHA than AHA stimulation.     

High prevalence of hepatitis G virus (HGV) infection in renal transplantation

INTRODUCTION: The newly discovered (1995) hepatitis G virus (HGV) is an RNA virus from the Flaviviridae family with 85% genomic homology to GB virus C (GBV-C). We studied the prevalence of HGV infection among a cohort of 398 renal transplant recipients (RTR), all of whom had previously received blood transfusions, been grafted between August 1984 and December 1991, and been treated by cyclosporin A (CsA) as the main immunosuppressant. SUBJECTS AND METHODS: According to hepatitis C virus (HCV) antibody status, and after exclusion of 28 HBs antigen-positive recipients, this cohort had previously been divided into an HCV +ve subgroup (106 RTR; 62 M vs 44 F; 29 French vs 77 non-French) and an HCV -ve subgroup (264 RTR; 181 M vs 83 F, 196 French vs 68 non-French). We randomly selected 27 RTR in the HCV+/HBV- subgroup (14 M vs 13 F, 10 French vs 17 Italians) and 27 RTR in the HCV-/HBV- subgroup (19 M vs 8 F, 18 French vs 9 Italians) for HGV screening. The detection of HGV RNA sequences in serum (viraemia) was done by double nested RT-PCR using specific primers chosen in the 5' non-coding genomic region. The serum detection of specific antibodies (anti E2) was done by ELISA test. All sera (at time of liver biopsy or at last follow-up) were tested in duplicate. RESULTS: The prevalence of HGV viraemia was 26% (14/54) in the whole group and in both HCV +ve and -ve subgroups (7/27). The prevalence of HGV infection (viraemia + and/or anti E2 antibodies +) was 44% (24/54) in the whole group and in both HCV +ve and -ve subgroups (12/27). In addition, the prevalence was similar in males vs females and in French vs foreigners recipients (mostly Italians). In the HCV +ve subgroup, the seven HGV viraemia-positive patients who previously had liver biopsies disclosed chronic active hepatitis in four (mean Knodell score 5.75) and normal livers in three, with only one case of elevated ALT (CAH 5). In the HCV- subgroup, none of the seven HGV+ viraemic patients had elevated ALT and liver biopsy was not performed. CONCLUSION: HGV infection prevalence is high (44%) in RTR, but clearly independent of HCV status and/or the geographical origin of the recipients. This data indicates a different epidemiology as compared to our HCVs previous experience.     

Costs and benefits of integrating information between the cerebral hemispheres: A computational perspective.

Because interaction of the cerebral hemispheres has been found to aid task performance under demanding conditions, the present study examined how this effect is moderated by computational complexity, the degree of lateralization for a task, and individual differences in asymmetric hemispheric activation (AHA). Computational complexity was manipulated across tasks either by increasing the number of inputs to be processed or by increasing the number of steps to a decision. Comparison of within- and across-hemisphere trials indicated that the size of the between-hemisphere advantage increased as a function of task complexity, except for a highly lateralized rhyme decision task that can only be performed by the left hemisphere. Measures of individual differences in AHA revealed that when task demands and an individual's AHA both load on the same hemisphere, the ability to divide the processing between the hemispheres is limited. Thus, interhemispheric division of processing improves performance at higher levels of computational complexity only when the required operations can be divided between the hemispheres. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of natural antioxidants, superoxide dismutase and hydrogen peroxide on capacitation of frozen-thawed bull spermatozoa

This study comprised 100 persons with antibodies to hepatitis C virus (HCV), including 77 intravenous drug users (IVDUs). They were tested with serological HCV typing assays (Murex HCV serotyping 1-6 assay; Chiron RIBA HCV Serotyping SIA). Patients with a positive polymerase chain reaction (PCR) for HCV (n = 66) were tested with genotyping molecular assays (Inno-Lipa HCV II test; Sorin GEN-ETI-K HCV typing assay). Comparison of the results of these tests showed that (a) 92% of samples could be typed by one test at least; 44% could be typed by all four tests; 88% could be typed by one serological test at least and 66% by one molecular test at least; (b) 81% of the samples successfully tested with both serological tests gave comparable results; 95% of the samples successfully tested with both molecular tests gave comparable results; (c) when serological and molecular tests yielded different results, sequences in the 5'-non-coding (5' NC) or E1 regions always confirmed the results of the molecular tests; (d) in case of discrepancy between the results of the molecular tests the E1 region sequences confirmed the Sorin test results. It is concluded that the molecular tests compared gave similar results. The fact that the Murex serological test gave comparable results in more than 80% of cases indicates that it is an alternative to the molecular tests for routine diagnosis. However, comparison of the results of this test with those obtained in patients consulting a hepatology department showed that it gave the best results in a population of patients not exposed repeatedly to HCV.     

Efficacy of interferon monotherapy in the treatment of relapsers and nonresponders with chronic hepatitis C infection

Results of numerous studies have demonstrated similar efficacy profiles for the interferons (IFNs) currently approved for the treatment of chronic hepatitis C virus (HCV) infection. Although it has been suggested that some IFNs are more efficacious in certain patient populations, the current data support an equivalent efficacy and safety profile for these agents. Among patients requiring retreatment, no single study has made a direct comparison of IFN alfa-2b (IFN-alpha 2b) and consensus IFN (CIFN) in patients who have relapsed or have not responded to previous IFN therapy. However, at least 11 studies using IFN-alpha 2b and 1 using CIFN have demonstrated efficacy in the relapsing and nonresponding patient populations. A review of these studies suggests that overall efficacy and tolerability are similar regardless of IFN-alpha subtype. Overall, up to 59% and 83% of relapsed patients retreated with IFN have shown sustained response rates, as measured by negative HCV RNA titer and normalization of alanine aminotransferase (ALT) levels, respectively. Up to 14% and 25% of patients who failed to respond to previous IFN therapy have shown sustained HCV RNA response and normalization of ALT, respectively, after retreatment.     

Prevalence and risk factors for hepatitis C virus infection in continuous ambulatory peritoneal dialysis patients

BACKGROUND: Studies on hepatitis C virus antibodies (Anti-HCV) in CAPD patients are scarce and include a small number of patients. Nevertheless, risk factors related to Anti-HCV in these patients are still subject to controversy. Purpose of the study. To analyse the incidence and risk factors associated with the presence of Anti-HCV in CAPD patients. METHODS: We studied 255 patients from five different treatment centres of our region. The analysis was repeated after excluding 161 patients who had previously received haemodialysis treatment at least once. Anti-HCV testing was made by the 2nd-generation ELISA: As a supplementary test we used RIBA-4 in three centers and INNOLIA in the other two. Risk factors were analysed using logistic regression model for multivariate analysis. RESULTS: In the whole group, 29 patients (11.4%) were anti-HCV positive. Logistic regression analysis determined the following variables as independent risk factors: hepatitis previous to CAPD (P<0.001, odds ratio (OR):44.9), Anti HBc positivity (P=0.019, OR:9. 24), blood transfusions previous to CAPD (P=0.015, OR:1.05) and CAPD duration were excluded, the prevalence of HCV antibodies was 8.5% (8/94). In this group multivariate analysis showed that Anti-HCV positivity correlated with hepatitis previous to CAPD (P<0.0003, OR: 126) and Anti HBc positivity (P=0.002, OR:41.9). CONCLUSIONS: Our prevalence of hepatitis C virus (HCV) infection in CAPD patients was lower than other renal replacement therapy modalities, and correlated to events occurring mainly before starting CAPD treatment. This technique could be considered as low risk for HCV infection.     

Involvement of a tyrosyl residue in the interaction of peanut lectin with lactose

The role of a tyrosyl residue in the binding of Arachis hypogaea (peanut) agglutinin, AHA, to lactose has been studied using two techniques, titration of the phenolic hydroxyl group of the tyrosine residue and chemical modification of the tyrosine with iodine. More than three tyrosyl residues per mol of AHA were masked when AHA was titrated in the presence of lactose. Lactose also protected some tyrosyl residues of AHA from the modification with iodine. Upon interaction with lactose, AHA iodinated in the presence of lactose gave a UV-difference spectrum with similar peaks to those of native AHA, while AHA iodinated in the absence of lactose gave a spectrum without such peaks. Though not only native AHA but also iodinated AHA was completely adsorbed on a column of lactamyl-Sepharose 6B, equilibrium dialysis showed that the binding constant and the number of binding sites of native AHA and iodinated AHA with lactose were 4.3 x 10(3) and 3.0 x 10(3) M-1, and 3.2 and 1.8, respectively. These results suggest that about two of four sugar binding sites have tyrosyl residues which induce the UV-difference spectra upon binding with lactose, and that the iodination of these tyrosyl residues results in a decrease of the number of binding sites on AHA.     

The natural history of chronic hepatitis C in haemophiliacs

Most haemophiliacs treated with non-virally-inactivated clotting factor concentrates have been infected with hepatitis C virus (HCV). We have studied the natural history of chronic HCV infection by following all 138 HCV-positive patients from our centre for periods of up to 28 years. As well as the clinical and biochemical characteristics, we studied 116 liver samples from 63 patients obtained at elective biopsy (n = 103) or autopsy (n = 13). 36 (26%) of the patients were HIV positive, and three were chronic carriers of hepatitis B. Evidence of previous exposure to hepatitis A and B was found in 37.2% and 48.1% respectively. Raised transaminase levels were found in 82.6% of patients. 11 of 15 patients with normal transaminases tested by PCR for HCV RNA were positive, indicating that most patients, even in this group, have chronic hepatitis C infection. Cirrhosis was diagnosed by liver histology in 19 patients, and nine patients developed liver failure. The incidence of cirrhosis rose rapidly 15 years after HCV infection to 15.6 per 1000 person-years. Multivariate analysis showed that HIV status, length of time since HCV infection and age at HCV infection were independently associated with both the development of cirrhosis and liver failure. Two patients developed hepatocellular carcinoma: one of these was exposed only to a single batch of FVIII concentrate 11 years earlier. Chronic hepatitis C is increasingly recognized as a major cause for morbidity and mortality in haemophiliacs, especially those who are HIV positive and who were infected at an older age.     

Transmission of hepatitis C in an isolated area in Japan: community-acquired infection. The South Kiso Hepatitis Study Group

BACKGROUND/AIMS: The spread of hepatitis C virus (HCV) infection not due to drug needle sharing or transfusion is largely unknown in communities. A search for risk factors for HCV infection in an endemic area might elucidate inapparent modes of transmission. METHODS: We conducted screening for hepatitis virus markers and parenteral exposures to blood among 435 inhabitants in an isolated area known for its endemicity for non-A, non-B hepatitis and in a nonendemic area with 1542 inhabitants. RESULTS: The prevalence of hepatitis B surface antigen was the same in both areas. The prevalence of antibody to HCV verified by the recombinant immunoblot assay was 32.4% in the highly endemic area and 2.3% in the nonendemic area (P < 0.001). Risk factors for HCV infection in the highly endemic area were complex but included folk remedies such as acupuncture and "vacuuming" for congested blood in muscle by the use of a warm glass bottle. CONCLUSIONS: Folk remedies such as acupuncture and cutting of the skin using nonsterilized knives should be considered as possible routes of HCV transmission not associated with blood transfusion or sharing of drug paraphernalia.