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D L Thomas

Publications and source records attributed to D L Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2001

Racial differences in HLA class II associations with hepatitis C virus outcomes.

A broad, vigorous CD4 T cell response, mediated by class II human leukocyte antigens (HLAs), favors hepatitis C virus (HCV) clearance. HLA-DQB1*0301 has been associated with viral clearance in an ethnically homogeneous cohort. To validate this association and to identify other class II associations in an ethnically varied cohort, molecular class II HLA typing was performed on 200 HCV clearance and 374 matched persistently infected subjects. HLA-DQB1*0301 was weakly associated with viral clearance in combined ethnic groups (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.53-0.97) but was stronger in black subjects. In white subjects, viral clearance was associated with DRB1*0101 (OR, 0.32; 95% CI, 0.17-0.60) and its DQB1*0501 haplotype, whereas viral persistence was associated with DRB1*0301 (OR, 2.36; 95% CI, 1.23-4.52) and its DQB1*0201 haplotype. These results support a role for class II alleles in the immune response to HCV and underscore the importance of studying genetic associations in an ethnically diverse cohort.

Adult↗
PubMed2001

Multicenter evaluation of hepatitis C RNA levels among female injection drug users.

The purpose of this investigation was to identify factors that determine the blood level of hepatitis C virus (HCV) RNA. By use of a quantitative polymerase chain reaction assay, the level of HCV RNA was ascertained in stored serum samples from 676 women enrolled in a multicenter prospective investigation who were seropositive for anti-HCV antibodies. HCV RNA levels ranged from undetectable to 22.4x106 copies/mL in these women. Among the 520 women with detectable HCV RNA, levels were higher among those who were >41 years old and those who had human immunodeficiency virus (HIV) infection. After adjusting for age in a multivariate linear regression model, HCV RNA levels were more strongly associated with HIV RNA levels than with CD4(+) lymphocyte counts. However, <6% of person-to-person variance was explained by the factors evaluated. Additional research is needed to ascertain what determines the level of HCV RNA in blood.

Adolescent↗
PubMed2001

Simultaneous noninvasive measurement of CBF and CBV using double-echo FAIR (DEFAIR).

A new method for measuring cerebral blood flow (CBF) and cerebral blood volume (CBV) noninvasively using MRI is presented. The approach is based on the technique of arterial spin labelling (ASL), in which CBF-based contrast is generated by controlled modulation of the longitudinal magnetization of the blood. The proposed method also uses differences in T(2) between tissue and blood to differentiate the two compartments and allow assessment of the relative size of each. Two successive EPI images are acquired following spin preparation using either a slice-selective or global inversion pulse, and the technique is therefore referred to as double-echo FAIR (DEFAIR). DEFAIR is demonstrated in the normal gerbil brain and during hypothermia, where reductions of both CBF and CBV are known to occur. It is also shown theoretically that this method can be extended to include a measurement of oxygen extraction fraction. The main drawbacks of the technique are the long acquisition time and relatively low sensitivity to hemodynamic changes compared to conventional qualitative T2(*)-weighted BOLD contrast, which may limit its applicability and practical use in monitoring functional cerebral activation. However, the technique can be used repetitively in longer-term time course studies due to its noninvasive and quantitative nature.

Animals↗
PubMed2001

Cerebrovascular reactivity following focal brain ischemia in the rat: a functional magnetic resonance imaging study.

An essential goal of stroke research is to identify potentially salvageable regions of brain that may respond to therapy. However, current imaging methods are inadequate for this purpose. We therefore used dynamic magnetic resonance imaging of vascular reactivity following focal occlusion in the rat to determine whether measurement of perfusion reserve would help resolve this problem. We used the increase in blood-oxygen-level-dependent (BOLD) signal that occurs in normal brain following a CO2 challenge, to map vascular reactivity over the brain at 30-min intervals for 3.5 h after complete (CO) or partial (PO) focal ischemia. We assessed the regional correspondence between reactivity changes and areas of lowered apparent diffusion coefficient (ADC) and initial perfusion deficit. The area of lowered ADC was significantly smaller in the PO group compared to the CO group despite similar areas of perfusion deficit (P < 0.05). We identified four distinct areas within hypoperfused brain: a core area with low/absent reactivity and low ADC; borderzone areas with normal reactivity and either reduced ADC (CO group) or normal ADC (PO group); and an area with normal ADC and reduced/absent reactivity. In all ischemic regions, the BOLD peak arrival time in the brain was delayed or absent. There was a negative correlation between BOLD peak latency time and ADC (r = -0.42, P < 0.001), although latency alone did not differentiate individual ischemic regions. In conclusion, combining perfusion, ADC, and vascular reactivity mapping of the ischemic brain enables improved discrimination of core and borderzone regions.

Animals↗
PubMed2001

Hepatitis C. Epidemiologic quandaries.

Although many aspects of the transmission of HCV have been clarified, some important issues remain controversial, and the conventional wisdom may be based more on opinion than data (Table 2). HCV is transmitted by percutaneous exposure to contaminated blood, uncommonly from a mother to her infant and between sexual partners, and rarely during the provision of medical care in developed nations. Improved behavioral research instruments are needed to further the understanding of the practices that actually transmit infection. In addition, large, prospective studies are necessary to characterize the frequency [table: see text] of transmission between sexual partners and the potential role of cesarian section in reducing HCV transmission to infants.

Body Fluids↗
PubMed2001

High resolution MRI reveals global changes in brains of Cln3 mutant mice.

Batten disease, the juvenile-onset form of neuronal ceroid lipofuscinosis (NCL), is a progressive neurodegenerative disorder of childhood with an age of onset of 5-10 years of age. JNCL is caused by mutations in the CLN3 gene which encodes a membrane protein of unknown function. Magnetic resonance imaging of the brain of juvenile NCL patients has revealed changes in signal intensity and tissue atrophy, predominantly in the cortex and cerebellum. A mouse model for Batten disease was created by targeted disruption of the murine Cln3 gene in order to further understanding of the pathophysiology of Batten disease and to evaluate potential therapeutic approaches. Several features of the disease are displayed by Cln3 mice including accumulation of characteristic storage material in neurons. The aim of this work was to investigate neurodegeneration in the Cln3 mouse model using high resolution magnetic resonance imaging to measure signal intensity ratios in selected regions of interest. Global changes were observed in the brains of 12-month-old mutant mice that mirror those seen in juvenile NCL patients. There is a decrease in signal intensity ratio in grey matter regions including cortex, hippocampus and cerebellum, tissues where neuronal storage accumulation and cell loss have been seen in the mouse model. The alterations seen in Cln3 mutant mice support the validity of further imaging studies and suggest that this method will have application in assessment of therapeutic approaches in the study of mutant mouse models of NCL including the Cln3 mouse.

Animals↗
PubMed2001

Microbial rank.

Explore the source record for details and available documents.

Bacteria↗
PubMed2001

Several E4 region functions influence mammary tumorigenesis by human adenovirus type 9.

Among oncogenic adenoviruses, human adenovirus type 9 (Ad9) is unique in eliciting exclusively estrogen-dependent mammary tumors in rats and in not requiring viral E1 region transforming genes for tumorigenicity. Instead, studies with hybrid viruses generated between Ad9 and the closely related nontumorigenic virus Ad26 have roughly localized an Ad9 oncogenic determinant(s) to a segment of the viral E4 region containing open reading frame 1 (E4-ORF1), E4-ORF2, and part of E4-ORF3. Although subsequent findings have shown that E4-ORF1 codes for an oncoprotein essential for tumorigenesis by Ad9, it is not known whether other E4 region functions may similarly play a role in this process. We report here that new results with Ad9/Ad26 hybrid viruses demonstrated that the minimal essential Ad9 E4-region DNA sequences include portions of both E4-ORF1 and E4-ORF2. Investigations with Ad9 mutant viruses additionally showed that the E4-ORF1 protein and certain E4-ORF2 DNA sequences are necessary for Ad9-induced tumorigenesis, whereas the E4-ORF2 and E4-ORF3 proteins are not. In fact, the E4-ORF3 protein was found to antagonize this process. Also pertinent was that certain crucial nucleotide differences between Ad9 and Ad26 within E4-ORF1 and E4-ORF2 were found to be silent with respect to the amino acid sequences of the corresponding proteins. Furthermore, supporting a prominent role for the E4-ORF1 oncoprotein in Ad9-induced tumorigenesis, an E1 region-deficient Ad5 vector that expresses the Ad9 but not the Ad26 E4-ORF1 protein was tumorigenic in rats and, like Ad9, promoted solely mammary tumors. These findings argue that the E4-ORF1 oncoprotein is the major oncogenic determinant of Ad9 and that an undefined regulatory element(s) within the E4 region represents a previously unidentified second function likewise necessary for tumorigenesis by this virus.

Adenovirus E4 Proteins↗
PubMed2001

Detection of diverse hepatitis C virus (HCV)-specific cytotoxic T lymphocytes in peripheral blood of infected persons by screening for responses to all translated proteins of HCV.

Broadly directed hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) have been identified from liver-infiltrating lymphocytes but have been more difficult to assess in peripheral blood of infected persons. To enhance the detection of CTL from peripheral blood mononuclear cells (PBMC), we cocultured PBMC with autologous Epstein-Barr virus-transformed B-lymphoblastoid cell lines that had been infected with recombinant vaccinia virus constructs so that they expressed the entire translated polyprotein of HCV-H, a type 1a strain. These stimulated cells from HCV-infected as well as exposed seronegative persons were then cloned at limiting dilution and tested for HCV-specific CTL activity using a standard (51)Cr release assay. HCV-specific CTL were detected in PBMC from seven of nine persons with chronic hepatitis, including five of seven in whom CTL had previously been detected from liver biopsy specimens but not PBMC. In a single person with chronic HCV infection, CTL directed against as many as five different epitopes were detected in peripheral blood and were similar in specificity to those detected in liver tissue. This technique was used to evaluate eight subjects identified to be at high risk for HCV exposure due to continued injection drug abuse; no evidence of CTL in PBMC was found. We conclude that CTL can be detected in PBMC from the majority of persons with chronic HCV infection but are present at lower levels or absent in exposed but persistently seronegative persons. The high degree of concordance of HCV epitopes identified from liver and PBMC suggests that this strategy is a reasonable alternative to liver biopsy for characterizing the CTL response to HCV in chronically infected persons.

Biopsy↗
PubMed2001

Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies.

When chronic hepatitis C virus (HCV) infections are complicated by acquisition of human immunodeficiency virus (HIV), liver disease appears to accelerate and serum levels of HCV RNA may rise. We hypothesized that HIV might affect the HCV quasispecies by decreasing both complexity (if HIV-induced immunosuppression lessens pressure for selecting HCV substitutions) and the ratio of nonsynonymous (d(N)) to synonymous (d(S)) substitutions, because d(N) may be lower (if there is less selective pressure). To test this hypothesis, we studied the evolution of HCV sequences in 10 persons with chronic HCV infection who seroconverted to HIV and, over the next 3 years, had slow or rapid progression of HIV-associated disease. From each subject, four serum specimens were selected with reference to HIV seroconversion: (i) more than 2 years prior, (ii) less than 2 years prior, (iii) less than 2 years after, and (iv) more than 2 years after. The HCV quasispecies in these specimens was characterized by generating clones containing 1 kb of cDNA that spanned the E1 gene and the E2 hypervariable region 1 (HVR1), followed by analysis of clonal frequencies (via electrophoretic migration) and nucleotide sequences. We examined 1,320 cDNA clones (33 per time point) and 287 sequences (median of 7 per time point). We observed a trend toward lower d(N)/d(S) after HIV seroconversion in 7 of 10 subjects and lower d(N)/d(S) in those with rapid HIV disease progression. However, the magnitude of these differences was small. These results are consistent with the hypothesis that HIV infection alters the HCV quasispecies, but the number of subjects and observation time may be too low to characterize the full effect.

Adult↗
PubMed2001

Effect of weaning system on commercial milk production and lamb growth of East Friesian dairy sheep.

East Friesian crossbred ewes (n = 99) and their lambs (n = 232) were used to study the effects of three weaning systems on milk production and lamb growth. Prior to parturition, a ewe and her lambs were assigned to one of the following three treatments for the first 28 +/- 3 d of lactation: 1) ewes weaned from their lambs at 24 h postpartum, ewes machine milked twice daily, and their lambs raised artificially (DY1); or 2) beginning 24 h postpartum, ewes separated from their lambs for 15 h during the evening, ewes machine milked once daily in the morning, and their lambs allowed to suckle for 9 h during the day (MIX); or 3) ewes not machine milked and exclusively suckled by their lambs (DY30). After the treatment period, lambs were weaned from MIX and DY30 ewes, and all three groups were machine milked twice daily. Daily commercial milk yield and milk composition were recorded weekly or twice monthly, and lambs were weighed at weaning or at 28 d and at approximately 120 d of age. Average lactation length (suckling + milking period) was 183 +/- 5 d and was similar among weaning systems. Differences among weaning systems for milk yield, milk fat and protein percentages, and somatic cell count were highly significant prior to and around weaning, and became nonsignificant by 6 wk in lactation. Total commercial milk production was greatest for DY1 and MIX ewes (261 +/- 10 and 236 +/- 10 kg/ewe, respectively) and least for DY30 ewes (172 +/- 10 kg/ewe). Daily gain of lambs to 30 d and weight at 30 d were similar regardless of weaning system; however, by 120 d, DY30 lambs tended to be heaviest, MIX lambs intermediate, and DY1 lambs lightest (47.3 +/- 1.6, 45.9 +/- 1.8, and 43.7 +/- 1.2 kg, respectively). Overall financial returns for milk and lamb sales were greatest for the MIX system because of the increase in marketable milk during the first 30 d of lactation compared with the DY30 system and because of acceptable 120-d lamb weights without the expenses of artificial rearing compared with the DY1 system. A mixed system of suckling and milking during early lactation appears to be a valuable management tool for dairy sheep production.

Animals↗
PubMed2000

Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States.

BACKGROUND: Hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. This relationship has not been investigated at the population level, and its biological mechanism remains unknown. OBJECTIVE: To examine the prevalence of type 2 diabetes among persons with HCV infection in a representative sample of the general adult population of the United States. DESIGN: Cross-sectional national survey. SETTING: The Third National Health and Nutrition Examination Survey, 1988-1994. PARTICIPANTS: 9841 persons older than 20 years of age for whom data on HCV infection and diabetes were complete. MEASUREMENTS: The presence of diabetes was ascertained by using American Diabetes Association guidelines based on fasting plasma glucose measurement and medication history. Presence of HCV infection was assessed by testing for serum HCV-specific antibodies (anti-HCV). RESULTS: Of the 9841 persons evaluated, 8.4% had type 2 diabetes and 2.1% were anti-HCV positive. Type 2 diabetes occurred more often in persons who were older, were nonwhite, had a high body mass index, and had low socioeconomic status. Type 2 diabetes was less common in persons who acknowledged previous illicit drug use. After adjustment for these factors, persons 40 years of age or older with HCV infection were more than three times more likely than those without HCV infection to have type 2 diabetes (adjusted odds ratio, 3.77 [95% CI, 1.80 to 7.87]). None of the 19 persons with type 1 diabetes were anti-HCV positive. CONCLUSION: In the United States, type 2 diabetes occurs more often in persons with HCV infection who are older than 40 years of age.

Adult↗
PubMed2000

Genetic epidemiology of hepatitis C virus throughout egypt.

Hepatitis C virus (HCV) infection is a major health problem in Egypt, where the seroprevalence is 10-20-fold higher than that in the United States. To characterize the HCV genotype distribution and concordance of genotype assessments on the basis of multiple genomic regions, specimens were obtained from blood donors in 15 geographically diverse governorates throughout Egypt. The 5' noncoding, core/E1, and NS5B regions were amplified by reverse transcription-polymerase chain reaction and analyzed by both restriction fragment length polymorphism (RFLP) and phylogenetic tree construction. For the 5' noncoding region, 122 (64%) of 190 specimens were amplified and analyzed by RFLP: 111 (91%) were genotype 4, 1 (1%) was genotype 1a, 1 (1%) was genotype 1b, and 9 (7%) could not be typed. Phylogenetic analyses of the core/E1 and NS5B regions confirmed the genotype 4 preponderance and revealed evidence of 3 new subtypes. Analysis of genetic distance between isolates was consistent with the introduction of multiple virus strains 75-140 years ago, and no clustering was detected within geographic regions, suggesting widespread dispersion at some time since then.

Blood Donors↗
PubMed2000

HTLV-II and bacterial infections among injection drug users.

OBJECTIVE: To examine whether select bacterial infections are associated with HTLV-II infection among injection drug users, we conducted a nested case control study within an ongoing cohort study. METHOD: HTLV-II status was determined by enzyme-linked immunosorbent assay, immunofluorescent assay, and immunoblot. Diagnosis of bacterial pneumonia, infective endocarditis, and skin abscess was confirmed by standardized chart reviews. Three sets of cases were identified based on diagnosis of bacterial pneumonia, infective endocarditis validated by chart review, or self-reported skin abscess. Each case was matched to a minimum of 5 controls by age, HIV status, and study follow-up duration. Risk factors for each bacterial infection were analyzed separately by conditional logistic regression methods. RESULTS: Prevalence of HTLV-II infection ranged from 7% to 11% in cases and controls. The bivariate association of HTLV-II and bacterial pneumonia revealed an odds ratio (OR) of 1.1 (95% confidence interval [CI], 0.6-2.0); the association of infective endocarditis and HTLV-II revealed an OR of 1.7 (95% CI, 0. 7-3.9); and the association between HTLV-II and skin abscess revealed an OR of 1.3 (95% CI, 0.6-2.0). These ORs were unaltered by adjustment for other factors. CONCLUSION: Our results suggest that these three bacterial infections were not significantly associated with HTLV-II infection within a population of injection drug users. Additional associations between HTLV-II infection and disease outcomes merit further exploration.

Abscess↗
PubMed2000

The natural history of hepatitis C virus infection: host, viral, and environmental factors.

CONTEXT: Hepatitis C virus (HCV) infection may resolve (viral clearance), persist without complications, or cause end-stage liver disease (ESLD). The frequency and determinants of these outcomes are poorly understood. OBJECTIVE: To assess the incidence and determinants of viral clearance and ESLD among persons who acquired HCV infection from injection drug use. DESIGN AND SETTING: Community-based prospective cohort study with enrollment in 1988-1989 and a median follow-up of 8.8 years. SUBJECTS: A total of 1667 persons aged 17 years or older with a history of injection drug use and an HCV antibody-positive test result during follow-up. MAIN OUTCOME MEASURES: Viral clearance was assessed in a subset of 919 patients and defined as failure to detect HCV RNA in at least 2 consecutive samples collected 5 or more months apart. End-stage liver disease was assessed at semiannual visits and by review of medical records and death certificates and defined by the presence of ascites, esophageal varices, or hepatic encephalopathy, or when ESLD was stated as a cause of death. RESULTS: Viral clearance was observed in 90 persons who were compared with 722 with persistent viremia, while the viremia of 107 was not resolved. Viral clearance occurred more often in nonblacks (adjusted odds ratio [OR], 5.15; 95% confidence interval [CI], 2.60-10.17) and those not infected with human immunodeficiency virus (HIV) (adjusted OR, 2.19; 95% CI, 1.26-3.47). Forty cases of ESLD were observed throughout follow-up (incidence, 3.1 per 1000 person-years). In a multivariate model, risk of ESLD was higher for persons aged 38 years or older at enrollment (adjusted relative incidence, 3.67; 95% CI, 1.96-6.88) and who reported ingestion of more than 260 g of alcohol per week (adjusted relative incidence, 3.60; 95% CI, 1.73-7.52). Of 210 patients without ESLD randomly selected for biopsy, only 2 had cirrhosis. CONCLUSIONS: Our results indicate that although HCV infection can be self-limited or associated with ESLD, the majority of adults have persistent viremia without clinically demonstrable liver disease. Further research is needed to explain the less frequent clearance of HCV infection among black persons and to improve utilization of treatment for those infected in the context of injection drug use. JAMA. 2000;284:450-456

Adult↗