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Biomedical subjects

David Brown

Publications and source records attributed to David Brown.

At least 55 records · Page 3Linked to original sources
PubMed2004

New estimates of herpes simplex virus type 2 seroprevalence in England: 'high' but stable seroprevalence over the last decade.

OBJECTIVES: There have been few recent population-based herpes simplex virus type 2 (HSV-2) seroprevalence studies in England, but reports from the United States have indicated a 30% rise in HSV-2 seroprevalence between 1976 and 1994. This study aimed to ascertain trends in HSV-2 infection in England between 1991 and 2000. STUDY DESIGN: Anonymized serum residues collected through public health laboratories across England from individuals aged 16 to 64 years seeking health care through the National Health Service in 1991 (n = 2259) and 2000 (n = 3646) were tested for anti-HSV-2 IgG using the HerpeSelect 2 enzyme-linked immunosorbent assay IgG (Focus). RESULTS: In 9 sites across England, the age- and sex-standardized HSV-2 seroprevalence was 9.7% (95% confidence interval, 8.4-11.0%). Data from 4 sites common to both study years indicated no change in HSV-2 seroprevalence between 1991 and 2000. CONCLUSIONS: After adjustment for age, sex, and geographic location, there was no evidence of a change in seroprevalence between 1991 and 2000.

Adolescent↗
PubMed2004

Transfection with 4-hydroxynonenal-metabolizing glutathione S-transferase isozymes leads to phenotypic transformation and immortalization of adherent cells.

4-Hydroxy-2-trans-nonenal (4-HNE), one of the major end products of lipid peroxidation, has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. We show for the first time that incorporation of 4-HNE-metabolizing glutathione S-transferase (GST) isozyme, hGSTA4-4, into adherent cell lines HLE B-3 and CCL-75, by either cDNA transfection or microinjection of active enzyme, leads to their transformation. The dramatic phenotypic changes due to the incorporation of hGSTA4-4 include rounding of cells and anchorage-independent rapid proliferation of immortalized, rounded, and smaller cells. Incorporation of the inactive mutant of hGSTA4-4 (Y212F) in cells by either microinjection or transfection does not cause transformation, suggesting that the activity of hGSTA4-4 toward 4-HNE is required for transformation. This is further confirmed by the fact that mouse and Drosophila GST isozymes (mGSTA4-4 and DmGSTD1-1), which have high activity toward 4-HNE and subsequent depletion of 4-HNE, cause transformation whereas human GST isozymes hGSTP1-1 and hGSTA1-1, with minimal activity toward 4-HNE, do not cause transformation. In cells overexpressing active hGSTA4-4, expression of transforming growth factor beta1, cyclin-dependent kinase 2, protein kinase C betaII and extracellular signal regulated kinase is upregulated, whereas expression of p53 is downregulated. These studies suggest that alterations in 4-HNE homeostasis can profoundly affect cell-cycle signaling events.

Aldehydes↗
PubMed2004

Characterization of G10P[11] rotaviruses causing acute gastroenteritis in neonates and infants in Vellore, India.

Rotavirus G10P[11] strains, which are commonly found in cattle, have frequently been associated with asymptomatic neonatal infections in India. We report the finding of G10P[11] strains associated with severe disease in neonates in Vellore, southern India. Rotavirus strains from 43 fecal samples collected from neonates with or without gastrointestinal symptoms between 1999 and 2000 were genotyped by reverse transcription-PCR. Forty-one neonates (95%) were infected with G10P[11] rotavirus strains, and 63% of the infections were in children who had gastrointestinal symptoms, including acute watery diarrhea. G10P[11] strains were also seen infecting older children with dehydrating gastroenteritis in Vellore. Characterization of the genes encoding VP7, VP4, VP6, and NSP4 of these strains revealed high sequence homology with the corresponding genes of the asymptomatic neonatal strain I321, which in turn is very closely related to bovine G10P[11] strains circulating in India. No significant differences were seen in the sequences obtained from strains infecting symptomatic neonates or children and asymptomatic neonates.

Acute Disease↗
PubMed2004

Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy.

The cytotoxic T-cell response in chronic hepatitis B virus (HBV) infection has been described as weak and mono- or oligospecific in comparison to the more robust virus-specific T-cell response present in resolved infection. However, chronic hepatitis B is a heterogeneous disease with markedly variable levels of virus replication and liver disease activity. Here we analyzed (both directly ex vivo and after in vitro stimulation) the HBV-specific CD8 T-cell responses against structural and nonstructural HBV proteins longitudinally in patients with different patterns of chronic infections. We found that the profiles of virus-specific CD8(+)-T-cell responses during chronic infections are highly heterogeneous and influenced more by the level of HBV replication than by the activity of liver disease. An HBV DNA load of <10(7) copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8(+) T cells are consistently detected. Furthermore, CD8(+) T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8(+) T cells are associated with viral control, while CD8(+) T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (>10(7) copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.

Adult↗
PubMed2004

Regulation of LPS-mediated inflammation in vivo and in vitro by the thiol antioxidant Nacystelyn.

Increased levels of proinflammatory cytokines are present in bronchoalveolar lavage fluid in various lung diseases. Redox-sensitive transcription factors such as NF-kappaB regulate gene transcription for these cytokines. We therefore studied the effect of a new thiol antioxidant compound, Nacystelyn (NAL), on IL-8 regulation in a human macrophage-derived cell line (THP-1). LPS (10 microg/ml) increased IL-8 release compared with control levels. This LPS activation was inhibited by coincubation with NAL (1 and 5 mM). Pretreatment with cycloheximide or okadaic acid, protein synthesis, and serine/threonine phosphatase inhibitors, respectively, did not modify inhibition of IL-8 release caused by NAL. NF-kappaB and C/EBP DNA binding were increased after LPS treatment compared with control, an effect inhibited by cotreatment with NAL. Activator protein (AP)-1 DNA binding was unaffected. The enhanced neutrophil chemotaxis produced by conditioned media from LPS-treated cells was inhibited when cells were cotreated with NAL. The selectivity of NAL inhibition upon IL-8 expression was studied. LPS-treated THP-1 cells also had higher levels of TNF-alpha, transforming growth factor (TGF)-beta1 and -3, MIP-1alpha and -beta, and RANTES gene expression. However, only LPS-induced IL-8 and TGF-beta1 expressions were inhibited by NAL. An anti-inflammatory effect of NAL was confirmed in vivo as shown by a reduction in LPS-induced neutrophil recruitment to the lungs following instillation of NAL into the lungs. Our studies demonstrate that NAL has anti-inflammatory properties in vitro and in vivo, may therefore have a therapeutic role in lung inflammation, and has the advantage over other antioxidant agents in that it may be administrated by inhalation.

Acetylcysteine↗
PubMed2004

The efficacy of a brief alcohol intervention combined with %CDT feedback in patients being treated for type 2 diabetes and/or hypertension.

OBJECTIVE: Alcohol biomarkers are being developed to improve a physician's ability to identify and intervene with patients with chronic medical problems adversely affected by heavy alcohol use. This article reports the findings of a brief intervention trial which included feedback to patients of their carbohydrate-deficient transferrin (CDT) test results. METHOD: A pilot study was conducted to test the efficacy of brief clinician advice to reduce alcohol use and improve health status in a sample of 151 patients being treated for Type 2 diabetes and hypertension. The intervention included informing patients of their CDT levels. The patients were randomized to a usual care or brief intervention group. RESULTS: There were no significant differences at baseline between the two groups in alcohol use, CDT levels, addiction rates, age, gender, socioeconomic status or health status measures. Following brief intervention, significant differences were observed in the intervention group in alcohol use and CDT: The proportion of heavy drinkers at the 12-month follow-up compared with baseline decreased from 35.8% to 24.7% in the intervention group, with no change in the control group (p < .044). CDT levels decreased as well from 2.79% to 2.41% (16% change) in the control group and 3.05% to 2.35% (28% change) in the intervention group, with significantly more intervention-group patients reducing their CDT level by at least 25% (p < .006). CONCLUSIONS: The study provides new information suggesting brief intervention, combined with feedback on CDT levels, can reduce alcohol use and %CDT in a sample of primary care patients being treated for Type 2 diabetes and hypertension.

Adult↗
PubMed2004

Learning to work together: developing academic and community research partnerships.

BACKGROUND: Community-based participatory research (CBPR) has been promoted as an important collaborative methodology for addressing local health concerns. However, academic physicians and researchers usually are not trained to work with communities as partners. METHODS: Key characteristics of effective community-academic partnerships are examined based on experiences with 2 CBPR projects in Wisconsin. RESULTS: These 2 projects increasingly have involved the respective communities and researchers in a collaboration. The steps they have taken illustrate the qualities of successful CBPR partnerships: ongoing development of joint community and researcher analysis, communication, and mobilization to search for relevant solutions to important community health problems. To sustain this kind of partnership, it is critical for researchers using the CBPR approach to understand how their academic-scientific perspective differs as well as converges with the community members' practical-experiential perspective. CONCLUSIONS: Health care researchers can effectively make use of partnerships with communities by following defined CBPR steps for developing mutually agreed upon research agendas, timelines, and goals. This, in turn, builds the capacity of communities to initiate and engage in future collaborative research projects concerning health issues.

Academic Medical Centers↗
PubMed2004

Rubella serosurveys at three Aravind Eye Hospitals in Tamil Nadu, India.

OBJECTIVE: To determine the susceptibility of female eye hospital staff to rubella infection and the potential risk for hospital-based rubella outbreaks. METHODS: A prospective cohort study on the seroprevalence of rubella IgG antibodies was conducted at three large eye hospitals in Coimbatore, Madurai and Tirunelveli, Tamil Nadu, India, where young children with eye abnormalities attributable to congenital rubella are treated. A total of 1000 female hospital employees aged 18-40 years agreed to participate and gave written informed consent. FINDINGS: The proportions of rubella-seronegative women were: 11.7% at Coimbatore, with a 95% confidence interval (CI) of 8.1-16.5; 15% at Madurai (95% CI = 12.3-18.1), and 20.8 at Tirunelveli (95% CI = 14.7-28.6). For the entire cohort the proportion seronegative was significantly higher among married women (21.5%) than among single women (14.0%) (P = 0.02). Rates of seronegativity were highest among physicians and lowest among housekeepers. All 150 seronegative women in the study sample accepted a dose of rubella vaccine. CONCLUSION: These are the first rubella serosurveys to have been reported from eye hospitals in any country. The relatively high rate of susceptibility indicated a risk of a rubella outbreak, and this was reduced by vaccinating all seronegative women. A policy has been established at all three hospitals for the provision of rubella vaccine to new employees. Other hospitals, especially eye hospitals and hospitals in countries without routine rubella immunization, should consider the rubella susceptibility of staff and the risk of hospital-based rubella outbreaks.

Adolescent↗
PubMed2003

Rediscovering the sweet spot in drug discovery.

Advances over the past decade in drug discovery technologies have not yet led to an increase in productivity. We analyzed the reasons that have led to this juncture and identify the selection of the right target and the right lead as crucial. New approaches are required to take full advantage of the genomics revolution. For targets, methods are becoming available for high-throughput proteome analysis and pathway characterization that synergize with studies of disease association and differential expression. For leads, methods are being developed that 'reverse' the high-throughput screening paradigm by mapping drugs and drug-like compounds back onto the proteome. The synergy between pathway mapping and compound mapping could allow the pharmaceutical and biotechnology industries to rediscover the sweet spot of research productivity.

Biotechnology↗
PubMed2003

Evidence of aryl hydrocarbon receptor ligands in Presque Isle Bay of Lake Erie.

The purpose of the present studies was to use a biomarker approach to examine xenobiotic exposure of brown bullhead in Presque Isle Bay, Lake Erie (USA). In particular, the presence of compounds that act through the aryl hydrocarbon receptor (AhR) was of interest due to its central role in gene regulation and carcinogenesis of dioxins and certain polycyclic aromatic hydrocarbons (PAHs). Initial screening of Presque Isle Bay sediment samples by gene expression microarray in mouse hepatocytes revealed prototypical dioxin-response genes such as cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1). The presence of AhR ligands in sediment samples was confirmed and quantified using an in vitro assay, the Chemical Activated Luciferase Expression (CALUX) assay. The CALUX assay system, by using different incubation times, allows for determination of total dioxin induction equivalents (IEQ) for less persistent compounds such as PAHs as well as for stable compounds such as polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and certain polychlorinated biphenyls (PCBs). Parts of Presque Isle Bay have significant concentrations of AhR ligands in sediment ranging from 200 to 1400 parts per trillion (ppt) dioxin IEQ equivalents (dry weight). This is much higher than levels of dioxin equivalents found in similar sediment samples (approximately 10 ppt). Cascade Creek appears to be a major source of dioxin-like contaminants as IEQs in sediments taken from various regions of this tributary ranged from 1300 to 42000 ppt IEQ. In addition, the CALUX assay indicated that the majority of the IEQs (>90%) in PIB samples were in fact derived from less stable compounds. To determine if brown bullhead are exposed and respond to these high levels of AhR ligands, CYP1A cDNA was cloned from this species and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine mRNA levels. The CYP1A mRNA concentration was lower and less variable in fish taken from Presque Isle Bay than from a body of water with much lower AhR ligand concentration. Taken together, these studies show that sediment in Presque Isle Bay is highly contaminated with AhR ligands including dioxins and PAHs, but the brown bullhead are either not exposed or are non-responsive to these carcinogenic compounds.

Amino Acid Sequence↗
PubMed2003

The elimination of indigenous measles transmission in England and Wales.

Following a school-based measles-rubella vaccination campaign in November 1994, enhanced surveillance of measles, including IgM antibody testing of oral fluid from clinically diagnosed case-patients, was introduced in England and Wales. Between 1995 and 2001, 665 cases of measles were confirmed, including 371 (56%) confirmed only by IgM detection in oral fluid. Two hundred thirty-nine cases (36%) were sporadic and 426 (64%) were associated with 61 clusters. Fifty-four (23%) of the 239 sporadic cases and 26 (43%) of the 61 clusters were associated with a probable or possible importation of infection from overseas, and a wide variety of genotypes were identified in each calendar year. The effective reproduction number for measles over the period was estimated to be below 0.7. These data suggest that most measles in the UK is acquired following limited transmission from an imported infection, and they confirm that measles elimination has been achieved and sustained over this period.

Adolescent↗
PubMed2003

Immunogenicity of measles and rubella vaccines in Oman: a prospective clinical trial.

A prospective immunogenicity trial of measles and rubella vaccines was conducted in Oman. Children received measles vaccine at age 9 months and measles-rubella vaccine at age 15 months. Serum specimens were tested for measles-specific IgG and rubella-specific IgG. Of 1025 eligible infants, 881 (86.0%) returned for all five visits and had adequate serum samples for testing. Seroconversion to measles after vaccination at 9 months was 98.1%. At 15 months, 47 (5.3%) of the 881 children were seronegative for measles; of these, 44 (93.6%) seroconverted. At 16 months, 99% of the children seronegative at age 9 months seroconverted after receiving two doses of measles vaccine. At age 15 months, 684 (77.6%) children were seronegative for rubella. Of these, 676 (98.8%) seroconverted by age 16 months. One dose of measles vaccine at age 9 months was highly immunogenic. One dose of measles-rubella vaccine at age 15 months closed the remaining measles immunogenicity gap and resulted in a high rate of rubella seroconversion.

Antibodies, Viral↗
PubMed2003

Development of the Global Measles Laboratory Network.

The routine reporting of suspected measles cases and laboratory testing of samples from these cases is the backbone of measles surveillance. The Global Measles Laboratory Network (GMLN) has developed standards for laboratory confirmation of measles and provides training resources for staff of network laboratories, reference materials and expertise for the development and quality control of testing procedures, and accurate information for the Measles Mortality Reduction and Regional Elimination Initiative. The GMLN was developed along the lines of the successful Global Polio Laboratory Network, and much of the polio laboratory infrastructure was utilized for measles. The GMLN has developed as countries focus on measles control activities following successful eradication of polio. Currently more than 100 laboratories are part of the global network and follow standardized testing and reporting procedures. A comprehensive laboratory accreditation process will be introduced in 2002 with six quality assurance and performance indicators.

Clinical Laboratory Techniques↗
PubMed2003

Dendrodendritic inhibition and simulated odor responses in a detailed olfactory bulb network model.

In the olfactory bulb, both the spatial distribution and the temporal structure of neuronal activity appear to be important for processing odor information, but it is currently impossible to measure both of these simultaneously with high resolution and in all layers of the bulb. We have developed a biologically realistic model of the mammalian olfactory bulb, incorporating the mitral and granule cells and the dendrodendritic synapses between them, which allows us to observe the network behavior in detail. The cell models were based on previously published work. The attributes of the synapses were obtained from the literature. The pattern of synaptic connections was based on the limited experimental data in the literature on the statistics of connections between neurons in the bulb. The results of simulation experiments with electrical stimulation agree closely in most details with published experimental data. This gives confidence that the model is capturing features of network interactions in the real olfactory bulb. The model predicts that the time course of dendrodendritic inhibition is dependent on the network connectivity as well as on the intrinsic parameters of the synapses. In response to simulated odor stimulation, strongly activated mitral cells tend to suppress neighboring cells, the mitral cells readily synchronize their firing, and increasing the stimulus intensity increases the degree of synchronization. Preliminary experiments suggest that slow temporal changes in the degree of synchronization are more useful in distinguishing between very similar odorants than is the spatial distribution of mean firing rate.

Dendrites↗
PubMed2003

Phenoxodiol--an isoflavone analog--induces apoptosis in chemoresistant ovarian cancer cells.

Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. In this study we characterize the cytotoxic effect of phenoxodiol, a synthetic anticancer drug analog of genestein, and demonstrate the mechanism of action by which phenoxodiol affects the components of the Fas apoptotic pathway on ovarian cancer cells. Primary ovarian cancer cells, isolated from ascitic fluids of ovarian cancer patients, resistant to conventional chemotherapy, undergo apoptosis following phenoxodiol treatment. This effect is dependent upon the activation of the caspase system, inhibiting XIAP, an inhibitor of apoptosis, and disrupting FLICE inhibitory protein (FLIP) expression through the Akt signal transduction pathway. We suggest that phenoxodiol is an efficient inducer of cell death in ovarian cancer cells and sensitizes the cancer cells to Fas-mediated apoptosis. We identified FLIP and XIAP signalling pathways as key factors regulating the survival of ovarian cancer cells. These findings demonstrate a novel nontoxic drug that controls FLIP/XIAP function and has the potential to eliminate tumor cells through Fas-mediated apoptosis.

Antineoplastic Agents↗
PubMed2003

Improving the care of patients with regard to chemotherapy-induced nausea and emesis: the effect of feedback to clinicians on adherence to antiemetic prescribing guidelines.

PURPOSE: To evaluate the effect of performance and outcomes feedback on adherence to clinical practice guidelines regarding chemotherapy-induced nausea and emesis (CINE). METHODS: Institutional CINE clinical practice guidelines were developed based on American Society of Clinical Oncology guidelines. Consecutive administrations of moderately/highly emetogenic chemotherapy were assessed for errors. Baseline statistical process control (SPC) charts were created and mean errors per administration were calculated. Prospective SPC charts were used to measure the effect of guideline development and distribution, a visiting lecturer, and ongoing feedback regarding compliance with guidelines employing SPC charts. Patients were surveyed regarding the extent and severity of CINE for 5 days postadministration. These outcomes were then shared with physicians. RESULTS: Baseline compliance was poor (mean, 0.87 omissions per chemotherapy administration), largely because of inadequate adherence to recommendations for delayed CINE management. Most patients experienced delayed nausea, particularly on day 3 postchemotherapy. Physician prescribing performance did not undergo sustained improvement despite guideline development or distribution, a lecture by a visiting expert, or sharing of adherence data with clinicians. Once patient outcomes were shared, physicians accepted the need for compliance and instituted nurse practitioner antiemetic prescribing, with almost complete compliance and concurrent measurable reduction in day 3 nausea. SPC charts documented improvements in both outcomes. CONCLUSIONS: SPC charts effectively monitor ongoing compliance and patient symptoms and represent appropriate outcome measurement and change facilitation tools. However, physician participation in guideline development and evidence of poor compliance alone did not improve prescribing performance. Only evidence of patient CINE experience coupled with noncompliance improved results.

Adolescent↗