MRI of animal models of brain disease.
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Alzheimer Disease↗
Biomedical subjects
David L Thomas
Publications and source records attributed to David L Thomas.
Screening for depressive symptoms among HCV-infected injection drug users: examination of the utility of the CES-D and the Beck Depression Inventory.
The prevalence of depression is high among injection drug users (IDUs) and among those infected with the hepatitis C virus (HCV). Moreover, one of the drugs used in the standard treatment for HCV infection (interferon) has been known to exacerbate underlying psychiatric disorders such as depression and has been associated with the development of major depressive disorder among HCV-infected patients. For these reasons, the most recent National Institutes of Health consensus statement on the management of HCV infection recommends the identification and treatment of depression prior to the start of HCV treatment. This study aimed to examine the extent of current moderate/severe depressive symptoms in a cohort of HCV-infected IDUs as measured by two screening tools, the Center for Epidemiologic Studies Depression Scale (CES-D) and the Beck Depression Inventory (BDI). Subjects were participants in a multisite behavioral intervention trial among HCV-seropositive, human immunodeficiency virus-negative IDUs aged 18-35 years; the trial was designed to prevent secondary transmission of HCV and to enhance uptake of HCV treatment. Baseline data on demographics, risk behaviors, depression, alcohol use, and health care utilization were measured via audio computer-assisted self-interview. A factor analysis was conducted on each scale to examine the clustering of items used in each to measure depressive symptoms. Baseline depressive symptoms, as measured via the CES-D and the BDI, were also compared using Pearson's correlation coefficient. Of 193 HCV-infected individuals enrolled to date, 75.6% were male, and 65.3% were white. Median age was 25.8 years. Factor analyses revealed that these scales measured depression differently; a distinct somatic component was present in the BDI, but not the CES-D. Using cutoff scores of 23 for the CES-D and 19 for the BDI, 44.0% and 41.5% of the participants were identified as having moderate/severe depressive symptoms, respectively. Over half (56.0%) were identified as having depressive symptoms by either scale. However, there was only moderate agreement between the two scales (kappa=0.46). Depressive symptoms were highly prevalent in this cohort of HCV-infected IDUs. Results indicated that both scales should be used in tandem to have the most sensitive detection of depressive symptoms, thereby maximizing the potential for HCV treatment success.
Adolescent↗
Risk factors for hepatitis C virus infection among blood donors in northern Thailand.
BACKGROUND: The epidemiology, virology, and risk factors for hepatitis C virus (HCV) infection among blood donors in northern Thailand have not been extensively evaluated. STUDY DESIGN AND METHODS: We did a prospective matched case-control study of blood donors who tested positive for HCV and were confirmed by recombinant immunoblot assay or nucleic acid testing. Infected donors were matched with one to four HCV-uninfected donors for sex, age +/- 5 years, and donation at the same site within 15 days of the HCV-positive donor. Married donors were invited to bring their spouse for HCV testing. RESULTS: Among 166 matched sets, a history of intravenous drug use (IDU), reported by 58 HCV infected donors (35.5%) and 2 HCV-negative donors, was strongly associated with HCV infection (odds ratio [OR], 107.6; 95% confidence interval, 14.8-780.7). In multivariate analysis among donors without a history of IDU, significant risk factors included a history of a blood transfusion (OR, 28.8), immediate family with a history of hepatitis/jaundice (OR, 4.4), six or more lifetime sexual partners (OR, 2.7), and increased frequency of blood donation (OR, 0.9). Six of 45 spouses of HCV-infected donors, and none of 44 spouses of uninfected donors, were HCV positive (p = 0.005). CONCLUSION: Our data indicate that illicit IDU and a history of transfusion are important risk factors for HCV infection in Thailand. Also, our data suggest there may be some risk of transmission by sex or other close contact between spouses.
Analysis of Variance↗
Hepatitis C virus (HCV) core antigen assay to detect ongoing HCV infection in thai injection drug users.
We evaluated a quantitative enzyme immunoassay (trak-C) for hepatitis C virus core antigen (HCV core Ag) by testing serum specimens from 820 injection drug users in Thailand with anti-HCV antibodies. The HCV genotypes in this population include genotypes 3 and 6, which have not been extensively tested with this assay. Among these specimens, 629 (76.7%) yielded positive results, with HCV core Ag concentrations predominantly spanning (35.7%) or above (58.2%) the measurable range of 1.5 to 100 pg/ml. To assess reproducibility, we retested 30 specimens representing six core Ag ranges; the mean coefficient of variation for each range was < or = 9.7% (highest for 1.5 to 25 pg/ml). We also tested 204 specimens of the 820-specimen set for HCV RNA: while 146 (71.6%) were core Ag positive, 168 (82.4%) had detectable HCV RNA, of which 96% were typeable as genotype 3 (39%), 1 (31%), or 6 (26%) by nested reverse transcription-PCR. Among RNA-positive specimens, 86.9% had core Ag; 94% of the RNA negatives were core Ag negative. While there was no apparent bias for detecting core Ag representing the tested genotypes, median quantified results were higher for types 1a and 6 than for genotype 3 (P = 0.01); similarly, the median core Ag concentration was higher in HCV-human immunodeficiency virus-coinfected subjects than in HCV-monoinfected subjects. Our results demonstrated a good correlation between core Ag and HCV RNA in this population with high frequencies of genotypes 3 and 6. Because most core Ag concentrations were greater than those in the measurable range, we recommend a 10-fold dilution of the specimen before quantification. Reproducibility, low technical requirements, and high throughput should make this assay useful for clinical or research monitoring of HCV levels during active infection.
Adolescent↗
Accurate representation of the hepatitis C virus quasispecies in 5.2-kilobase amplicons.
Hepatitis C virus (HCV) exists as a swarm of genetically distinct but related variants, or a quasispecies, whose complexity and sequence evolution are critical to studies of viral pathogenesis. Because most studies of the HCV quasispecies have focused on a relatively small genomic segment, the first hypervariable region of the E2 gene, it is possible that viral complexity is occasionally underestimated (due to primer mismatch) and that sequence evolution is misperceived due to unrecognized covariation. This report describes a sensitive and reproducible method to amplify most of the HCV genome as a single 5.2-kb amplicon by using primers directed at relatively conserved genomic segments. Using 52 specimens obtained during acute infection over a range of viral RNA concentrations, the overall rate of successful amplification was 94% and varied in a concentration-dependent manner, with successful amplification in 26 of 26 (100%) specimens at greater than 10(5) IU/ml, 15 of 16 (94%) at 10(4) to 10(5) IU/ml, 6 of 7 (86%) at 10(3) to 10(4) IU/ml, and 2 of 3 (67%) at less than 10(3) IU/ml. Quasispecies complexity, determined by using this novel long-amplicon method followed by heteroduplex mobility assay combined with single-stranded conformational polymorphism (HDA+SSCP) analysis, was very high, even during acute HCV infection, when 10 to 21 (median, 16) different HDA+SSCP patterns were detected among 33 cDNA clones examined. Replicate analyses indicate that this diversity is not dominated by random errors generated during amplification. Therefore, the HCV quasispecies is highly complex even during acute infection and is accurately represented in amplicons representing more than half of the viral genome.
Amino Acid Sequence↗
Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory T-cell receptor expressed by activated and regulatory T cells. We hypothesized that single-nucleotide polymorphisms (SNPs) in the gene encoding CTLA-4 may affect the vigor of the T-cell response to hepatitis B virus (HBV) infection, thus influencing viral persistence. To test this hypothesis, we genotyped six CTLA4 SNPs, from which all frequent haplotypes can be determined, using a large, matched panel of subjects with known HBV outcomes. Haplotypes with these SNPs were constructed for each subject using PHASE software. The haplotype distribution differed between those with viral persistence and those with clearance. Two haplotypes were associated with clearance of HBV infection, which was most likely due to associations with the SNPs -1722C (odds ratio [OR] = 0.60, P = 0.06) and +49G (OR = 0.73, P = 0.02). The wild-type haplotype, which contains an SNP leading to a decreased T-cell response (+6230A), was associated with viral persistence (OR = 1.32, P = 0.04). These data suggest that CTLA4 influences recovery from HBV infection, which is consistent with the emerging role of T regulatory cells in the pathogenesis of disease.
Adult↗
Cross-genotype immunity to hepatitis C virus.
Recent studies in humans and chimpanzees suggest that immunity can be induced to diminish the incidence of chronic hepatitis C virus (HCV) infection. However, the immunity that promotes viral recovery is poorly understood, and whether the breadth of this adaptive immunity is sufficient to overcome the substantial intergenotype antigenic diversity represents a final obstacle to demonstrating the feasibility of vaccine development. Here we demonstrate that recovery from a genotype 1 HCV infection protects chimpanzees against infection with representatives of other genotypes that exhibit up to 30% divergence at the amino acid level, including challenges with genotype 4, a mixture of genotypes 2 and 3, and a complex inoculum containing genotypes 1, 2, 3, and 4. In each instance, the level and duration of viremia were markedly reduced in comparison to the primary infection in the same animal. The data indicate that epitopes conserved between genotypes must play an essential role in immunity. The inocula used in the rechallenge studies induced typical primary infection profiles in naïve chimpanzees. Rechallenge infections were associated with rapid increases in the intrahepatic transcripts of interferon-stimulated genes, even in animals exhibiting apparent sterilizing immunity. Protective immunity was often associated with an early increase in gamma interferon transcripts in the liver and increases in intrahepatic transcripts of Mig, a T-cell chemokine that is a gamma interferon response gene. These studies are the first to show that cross-genotype immunity can be induced to HCV, demonstrating the feasibility of developing a vaccine protective against all HCV strains.
Animals↗
Epistatic effects of immunoglobulin GM and KM allotypes on outcome of infection with hepatitis C virus.
Immunoglobulin GM and KM allotypes-genetic markers of gamma and kappa chains, respectively-are associated with immune responsiveness to several infectious pathogens and with survival in certain viral epidemics. We hypothesized that GM and KM allotypes affect the outcome of hepatitis C virus (HCV) infection. To test this hypothesis, we serologically allotyped 100 persons with well-documented clearance of HCV infection and 198 matched persistently infected persons. None of the GM or KM phenotypes by itself was associated with the clearance or persistence of HCV infection. Particular combinations of these phenotypes, however, were significantly associated with the outcome of HCV infection. Subjects with GM 1,17 5,13 and KM 1,3 phenotypes were over three times (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.44 to 8.87) as likely to clear the infection as the subjects who lacked these phenotypes. This GM phenotype had a similar association with clearance in the absence of KM 3 (OR, 2.75; 95% CI, 1.21 to 6.23). The presence of GM 1,3,17 23 5,13 phenotype (in the absence of KM 3) was associated with persistence (OR, 0.21; 95% CI, 0.06 to 0.77), while its absence (in the presence of KM 1,3) was associated with the clearance of infection (OR, 2.03; 95% CI, 1.16 to 3.54). These results show epistatic interactions of genes on chromosomes 14 (GM) and 2 (KM) in influencing the outcome of an HCV infection. Further investigations involving candidate genes (GM, KM, HLA, and Fcgamma receptors) and cellular and humoral immune responses to HCV epitopes are needed to understand the mechanisms underlying these associations.
Adult↗
The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons.
OBJECTIVE: To examine the prevalence and incidence of hyperglycemia among HIV-infected patients by hepatitis C virus (HCV) infection and type of highly active antiretroviral therapy (HAART). DESIGN Retrospective cohort analysis of 1230 persons on their first HAART regimen who had at least 1 random glucose measurement before and during antiretroviral therapy. METHODS: The prevalence of hyperglycemia and the incidence of hyperglycemia were compared among persons with and without HCV infection while on a protease inhibitor (PI)-containing HAART regimen, a nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen, or a regimen that contained both a PI and an NNRTI. Hyperglycemia was defined as either 2 random glucose levels > 11.1 mM (200 mg/dL) or documentation of the diagnosis of diabetes in the medical record. RESULTS: The prevalence of hyperglycemia was significantly higher in HCV-coinfected (5.9%) than HCV-uninfected persons (3.3%, P = 0.02). Among persons receiving HAART, both HCV coinfection (adjusted relative hazard [ARH], 2.28; 95% CI, 1.23-4.22) and PI use (ARH, 5.02; 95% CI, 1.39-18.16) were independent risk factors of developing hyperglycemia. The incidence of hyperglycemia was highest among HCV-coinfected persons receiving a PI (5.6 cases per 100-person years) and only 1 person who was neither HCV-infected nor receiving a PI developed hyperglycemia. CONCLUSION: In this urban HIV cohort, the risk of hyperglycemia was increased in HCV-coinfected patients and those prescribed a PI.
Adult↗
Association of hepatitis C virus infection with sexual exposure in southern India.
To determine the association between sexual exposure and hepatitis C virus (HCV) infection in urban Chennai, India, a random sample of adults who live in a slum community completed interviews and provided samples to test for HCV, herpes simplex virus type 2 (HSV-2), and other sexually transmitted infections (STIs). All analyses excluded recent and current injection drug users. HCV infection was not associated with the reported number of sex partners for men or women. Women were more likely to be HCV infected if they reported previous genital ulcer disease (adjusted odds ratio [AOR], 3.88; 95% confidence interval [95% CI], 0.94-16.0; marginally statistically significant). Men were more likely to be HCV infected if they were HSV-2 infected (AOR, 3.85; 95% CI, 1.18-12.6) or reported having had sex with men (AOR, 3.61; 95% CI, 1.00-13.1). Sexual transmission of HCV infection may be facilitated by ulcerative STIs and male-male sexual practices, but it appears to occur infrequently in this population.
Adult↗
The association of hepatitis C prevalence, activity, and genotype with HIV infection in a cohort of New York City drug users.
Factors associated with serum HCV antibody, HCV RNA level, and HCV genotype were assessed in 557 current and former drug users. Additional assays included HIV antibody, CD4+ lymphocyte counts, HIV viral loads, and hepatitis B markers. Seventy-five percent of subjects were anti-HCV positive, of whom 75% had detectable HCV RNA (median, 5.04 x 10(5) IU/mL; range, 1020-15.7 x 10(6)). On multivariate analysis HCV seropositivity was associated with history of drug injection, HIV seropositivity, and increased age and inversely with drug snorting. Among anti-HCV-positive persons, detectable HCV RNA was independently associated with HIV seropositivity, male gender, and history of injection and inversely associated with hepatitis B surface antigen positivity. Among persons with detectable HCV RNA, higher levels were independently associated with higher HIV viral load, increased age, and genotypes 2a and 2b. These findings demonstrate an association of HCV RNA level with HIV viral load, independent of the level of immunosuppression. However, a substantial degree of the person-to-person variability in the prevalence and level of detectable HCV RNA remains unexplained.
Adult↗
Risk factors for Kaposi's sarcoma-associated herpesvirus infection among HIV-1-infected pregnant women in the USA.
OBJECTIVES: We sought to identify risk factors for infection with the Kaposi's Sarcoma-associated herpesvirus (KSHV) among pregnant women and to examine a reported association of KSHV with injecting drug use (IDU) and hepatitis C virus (HCV) infection. DESIGN: Cross-sectional evaluation of questionnaire data and KSHV and HCV seroprevalence in the Women and Infants Transmission Study. METHODS: In sera collected from HIV-1-infected pregnant women (n = 887) and, at age 12 months, their offspring (n = 900) at six sites in the USA and Puerto Rico, KSHV and HCV antibodies were detected with sensitive and specific enzyme immunoassays. Risk of KSHV was estimated by the unadjusted and adjusted odds ratio (OR(adj)) and 95% confidence interval (CI). The geographic referent sites were Chicago and Boston. RESULTS: Forty-seven (5.3%) of the women and three (0.3%) of the infants were KSHV seropositive. In univariate and multivariate analyses, KSHV in the women was associated with enrollment in Puerto Rico, Houston or Brooklyn (OR(adj), 4.3; 95% CI, 1.8-10.4) or Manhattan (OR(adj), 9.8; 95% CI, 3.7-25.6); non-completion of high school (OR(adj), 1.8; 95% CI, 0.9-3.4); the number of sexually transmitted diseases (OR(adj), 1.4; 95% CI, 1.0-1.9 per disease); and especially with IDU and HCV infection (OR(adj), 3.5; 95% CI, 1.5-7.9). CONCLUSIONS: Transmission of KSHV by blood inoculation may be highly inefficient, but our data support the hypothesis that it does occur. Large formal studies to evaluate whether KSHV transmission occurs via transfusion are needed to inform decisions regarding screening volunteer blood donors to protect the blood supply.
AIDS-Related Opportunistic Infections↗
Hepatitis C in the HIV-Infected Person.
Because of shared routes of transmission, hepatitis C virus (HCV) infection is common in HIV-infected persons, who have been experiencing increasing HCV-related morbidity and mortality since the advent of effective antiretroviral therapy. Infection with HIV appears to adversely affect the outcome of hepatitis C, leading to increased viral persistence after acute infection, higher levels of viremia, and accelerated progression of HCV-related liver disease. In addition, hepatitis C may affect the course and management of HIV infection. The medical management of hepatitis C in HIV-infected persons is complicated by immune suppression, potential drug interactions and toxicities, and other forms of liver disease. In addition, there is little published experience with the safety and efficacy of the best available anti-HCV medications in HIV-infected persons. Thus, current efforts must be directed at preventing HCV and HIV infections and applying the principles learned in treating persons with either infection to manage those with both. Future efforts should include studies of the pathogenesis of HCV infection in HIV-infected persons and large, prospective studies that demonstrate the optimal management of persons co-infected with HIV and HCV. Such efforts will help to eliminate HCV-related liver disease as an emerging threat to HIV-infected persons.
Antiretroviral Therapy, Highly Active↗
Velocity-driven adiabatic fast passage for arterial spin labeling: results from a computer model.
Velocity-driven adiabatic fast passage (AFP) is commonly employed for perfusion imaging by continuous arterial spin labeling (CASL). The degree of inversion of protons in blood determines the sensitivity of CASL to perfusion. For this study, a computer model of the modified Bloch equations was developed to establish the optimum conditions for velocity-driven AFP. Natural variations in blood velocity over the course of the cardiac cycle were found to result in significant variations in the degree of inversion. However, the mean degree of inversion was similar to that for blood moving at a constant velocity, equal to the time-averaged mean, at peak velocities and heart rates within normal ranges. A train of RF pulses instead of a continuous RF pulse for labeling was found to result in a highly nonlinear dependence of the degree of inversion on RF duty cycle. This may have serious implications for the quantification of perfusion.
Animals↗
Hepatitis C in the HIV-infected patient.
Hepatitis C virus infection is common in people with HIV and represents an increasingly important public health problem. Thus, although there remains a considerable amount of uncertainty about whom to treat and the best way to treat, providers must use available information generated chiefly from patients without HIV to manage HCV infection in coinfected patients. Future efforts should include prospective studies that demonstrate the natural history and optimal management of HIV/HCV-coinfected patients, including the feasibility of liver transplantation.
AIDS-Related Opportunistic Infections↗
Hyperlactataemia syndromes associated with HIV therapy.
Hyperlactataemia is seen in 8-18.3% of HIV-infected patients taking nucleoside-analogue reverse transcriptase inhibitors (NRTIs). Recent epidemiological studies suggest that most episodes are transient and subclinical. However, symptomatic and occasionally life-threatening cases accompanied by metabolic acidosis and hepatic steatosis (ie, lactic acidosis syndrome) have also been described. Though yet to be fully elucidated, the proposed mechanism is NRTI-induced inhibition of mitochondrial DNA polymerase culminating in derangements in oxidative phosphorylation and lactate homeostasis. Signs and symptoms range from mild hyperlactataemia accompanied by nausea, abdominal discomfort, and weight loss to severe, intractable lactic acidosis complicated by coma and multi-organ failure. Significant progress has recently been made with regard to the natural history of NRTI-related hyperlactataemia. However, other important aspects of the disorder, such as its pathogenesis, predisposing conditions, and management, remain poorly understood. This article reviews the current published work on these issues, identifies areas of controversy, and addresses directions for future research.
Acidosis, Lactic↗
Hepatitis C virus infection and incident type 2 diabetes.
Although hepatitis C virus (HCV) infection is more common among adults with type 2 diabetes, it is uncertain whether HCV precedes the development of diabetes. Thus, we performed a prospective (case-cohort) analysis to examine if persons who acquired type 2 diabetes were more likely to have had antecedent HCV infection when enrolled in a community-based cohort of men and women between the ages of 44 and 65 in the United States (Atherosclerosis Risk in Communities Study [ARIC]). Among 1,084 adults free of diabetes at baseline, 548 developed diabetes over 9 years of follow-up evaluation. Incident cases of diabetes were identified by using fasting glucose and medical history and HCV antibodies were assessed at baseline. A priori, persons were categorized as low-risk or high-risk for diabetes based on their age and body mass index, factors that appeared to modify the type 2 diabetes-HCV infection incidence estimates. The overall prevalence of HCV in this population was 0.8%. Among those at high risk for diabetes, persons with HCV infection were more than 11 times as likely as those without HCV infection to develop diabetes (relative hazard, 11.58; 95% confidence interval, 1.39-96.6). Among those at low risk, no increased incidence of diabetes was detected among HCV-infected persons (relative hazard, 0.48; 95% confidence interval, 0.05-4.40). In conclusion, pre-existing HCV infection may increase the risk for type 2 diabetes in persons with recognized diabetes risk factors. Additional larger prospective evaluations are needed to confirm these preliminary findings.
Age Distribution↗
Comparative study of the FAIR technique of perfusion quantification with the hydrogen clearance method.
Arterial spin labeling magnetic resonance methods, including flow-sensitive alternating inversion recovery (FAIR), are becoming increasingly common for the noninvasive quantification of cerebral blood flow (CBF). This report compares the FAIR method with hydrogen clearance. The latter is an established, invasive technique for CBF measurement in animals. Paired readings of CBF were obtained in gerbils to maximize the degree of spatial and temporal correspondence between methods. Flow-sensitive alternating inversion recovery (50 averages, 6.7-minute measurement time) and hydrogen clearance measurements were made concurrently. Cerebral blood flow values measured by both techniques displayed an initial decrease because of the injurious effects of electrode insertion and subsequent recovery. Mixed model regression analysis, structural equations modeling, and a simple concordance correlation coefficient analysis were performed. No evidence of a marked systematic bias in the FAIR measurements was found; mixed model regression analysis yielded relative bias estimates of 0.4 (confidence interval: 3.0, 3.9) mL. 100 g-1. min-1 and -3.7 (-12.1, 4.7) mL. 100 g-1. min-1 at 20 and 100 mL. 100 g-1. min-1, respectively. The principal limitation of the FAIR technique was the magnitude of the random measurement error (imprecision), which had a standard deviation on the order of 10 mL. 100 g-1. min-1.
Animals↗