Biomedical subjects
Publications and source records attributed to David Brown.
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Oral fluid (saliva) samples are increasingly used as a minimally invasive alternative to serum to detect antibody for viral diagnostics and population-based surveys of immunity to common infections. Postal collection of these samples is convenient, but it is uncertain how oral fluid antibody levels may deteriorate during transit. In this study multiple oral fluid samples, from a group of individuals, were collected and kept at two different temperatures (10 and 20 degrees C, simulating winter and summer conditions ) for periods of up to 7 days. They were then tested for total immunoglobulin G (IgG) and for rubella-specific IgG. Total IgG concentrations ranged from 2.0 to 48.6 mg/l but showed no significant decrease over the 7-day period. There was also no significant change in rubella-specific IgG measured using an antibody capture ELISA, but testing with an indirect rubella IgG ELISA revealed a significant decrease in absorbance values between day 1 and day 7 at 20 degrees C. The difference in the rubella assay results may reflect the different assay formats with the signal in the indirect procedure related to the concentration of rubella IgG in the oral fluid sample, rather than the proportion of virus-specific IgG measured with the antibody capture format. The study demonstrated that total and rubella specific IgG in oral fluid samples were stable for up to 7 days at differing temperatures and that an antibody capture assay format should be used for virus-specific testing to minimise inaccurate results due to low IgG concentrations in oral fluid samples.
Deletion, anergy, and a spectrum of functional impairments can affect virus-specific CD8 cells in chronic viral infections. Here we characterize a low frequency population of CD8 cells present in chronic hepatitis B virus (HBV) infection which survive in the face of a high quantity of viral antigen. Although they do not appear to exert immunological pressure in vivo, these CD8 cells are not classically "tolerant" since they proliferate, lyse, and produce antiviral cytokines in vitro. They are characterized by altered HLA/peptide tetramer reactivity, which is not explained by TCR down-regulation or reduced functional avidity and which can be reversed with repetitive stimulation. CD8 cells with altered tetramer binding appear to have a specificity restricted to envelope antigen and not to other HBV antigens, suggesting that mechanisms of CD8 cell dysfunction are differentially regulated according to the antigenic form and presentation of individual viral antigens.
Breast cancers in younger, premenopausal women are more likely to exhibit an adverse prognostic profile (including negative steroid hormone receptors and a high rate of cellular proliferation) and poor outcome than breast cancers in postmenopausal women. It has been hypothesized that this adverse prognostic profile is a result of the higher histologic grade of breast cancers in pre- compared with post-menopausal women. To assess the association of expression of steroid hormone receptors and indicators of proliferation while controlling for histologic grade, we identified 100 infiltrating ductal carcinomas from premenopausal women 45 years of age or younger and 100 from postmenopausal women 65 years of age or older. The carcinomas were selected so that the histologic grades (low versus high) were distributed equally between the 2 groups. Estrogen receptors (ER), progesterone receptors (PR), p27(Kip1) and Ki-67 (to measure rate of proliferation) were assessed by immunohistochemistry and compared between groups. Clinical information and survival data were also analyzed. ER content was lower and proliferation was higher in carcinomas in premenopausal women (p = 0.048 and p = 0.005, respectively). By univariate analysis, p27(Kip1) and PR were not different between the groups; however, in multivariate analysis, p27(Kip1) was higher in postmenopausal women, but only in a subgroup with highly proliferative carcinomas. Overall survival was similar in the pre- and postmenopausal women. Furthermore, low p27(Kip1) and African-American ethnicity predicted a poorer overall survival in the premenopausal, but not in the postmenopausal, women in our study. After controlling for histologic grade, a lower expression of ER and a higher proliferative index were detected in breast carcinomas in premenopausal women. Therefore, some prognostic indicators, such as ER and proliferative rate, may be more closely associated with menopausal status than histologic grade. Our data also suggest that some prognostic factors are not equally effective as predictors of survival in pre- and postmenopausal women.
OBJECTIVES: To quantify the association between prevalent or incident Herpes simplex virus type-2 (HSV2) infection and the incidence of HIV seroconversion among adults in the general population in rural Tanzania. STUDY POPULATION: Adults aged 15-54 years sampled randomly from 12 rural communities in Mwanza Region, Tanzania and recruited to a randomized trial of improved treatment of sexually transmitted diseases. STUDY DESIGN: Unmatched case-control study nested within trial cohort. METHODS: Participants included 127 cases who seroconverted to HIV during the 2-year follow-up period and 636 randomly selected controls who remained HIV negative. Subjects were tested for HSV2 serology at baseline and follow-up, and associations between HIV and HSV2 were analysed with adjustment for socio-demographic and behavioural factors. RESULTS: After adjusting for confounding factors, a strong association between HSV2 infection and HIV seroconversion was observed in men (test for trend: P < 0.001), with adjusted odds ratios (OR) of 6.12 [95% confidence interval (CI), 2.52-14.9] in those HSV2 positive at baseline, and 16.8 (95% CI, 6.06-46.3) in those acquiring HSV2 infection during follow-up. A weaker association was observed in women (tests for trend: P = 0.14), with adjusted OR of 1.32 (95% CI, 0.62-2.78) and 2.36 (95% CI, 0.81-6.84), respectively. Population attributable fractions of incident HIV infection due to HSV2 were estimated as 74% in men and 22% in women. CONCLUSIONS: The results suggest that HSV2 plays an important role in the transmission of HIV infection in this population. There is an urgent need to identify effective HSV2 control measures in order to reduce HIV incidence in Africa.
BACKGROUND: A highly sensitive PCR assay for early and rapid detection of enteroviral (EV) RNA in CSF is necessary to investigate the role of EV in acute neurological illnesses. OBJECTIVES: To evaluate and compare two PCR protocols (Titan one-tube RT-PCR and random primed RT-PCR) for detection of enteroviral RNA in CSF. STUDY DESIGN: The PCR protocols were evaluated for lower limit of input detection using log dilutions of five stock EV strains and an isolate of enterovirus-71 in minimum essential medium and three EV stock strains in CSF. The tests were also applied on 77 CSF samples, 46 from patients with suspected acute EV neurological illness and 31 from 'disease controls'. RESULTS: Even though in the initial virus titration assays there was no statistically significant difference in the limit of input detection by Titan system and the random primed two-step PCR, the latter had a higher positivity rate when used on CSF samples from patients (20/46 vs. 10/46, P<0.01). CONCLUSIONS: Random primed RT-PCR assay is superior to Titan one-tube RT-PCR for detection of EV RNA in CSF.
OBJECTIVES: To examine ways in which medicines information pharmacists approach ethical dilemmas encountered in information supply, to appreciate the factors affecting any observed variation in responses, and to identify and training deficits among medicines information (MI) pharmacists in this area. METHOD: A questionnaire was circulated to all medicines information pharmacists working in the hospital pharmacy service in the United Kingdom. The survey presented ten realistic scenarios involving requests for information on a variety of topics from 'lay' callers. MAIN OUTCOME MEASURES: Respondents were asked to identify any perceived ethical dilemmas presented by the scenarios and to indicate their preferred replies. Details on training given or received in this area were also requested. RESULTS: The overall response rate was 151 of 286 questionnaires mailed (52.8%), representing 137 discrete DI centres throughout the UK. Postgraduate clinical qualifications were possessed by 71% of respondents. Just 32 (21.2%) indicated that they gave training on ethical issues surrounding information supply while 57 (37.1%) said they had received such training. Over half (54.3%) had neither received nor delivered training on ethical issues. Of the 32 who said they gave training, 21 had received training themselves. Only 4 (2.6%) said they had a protocol in place for dealing with enquiries from members of the public. CONCLUSIONS: There was considerable variation in how respondents thought the scenarios might be resolved, emphasising the varying levels of appreciation of the issues and lack of a uniform approach to management. An interesting dichotomy emerged between liberal and conservative approaches. Liberal pharmacists clearly believed that all MI data is in the public domain and should be produced and evaluated on request because patients have a "right" to it. The conservative pharmacists had a more protective attitude toward the patient and believed that patients should not be given information by MI pharmacists directly; rather that it should be channelled through the patient's doctor. These two approaches are not incompatible, and may be adopted by the same pharmacist at different times. From their observations, the authors propose a basis of an ethical guideline for MI pharmacists.
AIM: To establish what is known about the clinical and economic impact of drug information (DI) services on patient outcome. METHOD: A systematic review and critical appraisal of world literature on work conducted by Drug Information Centres and UK Schools of Pharmacy. RESULTS: Six relevant published articles were recovered--three from the UK; two from the US and one from Canada; just one was prospective in design. Four were single-centre and two were multi-centre studies. Four studies relied heavily on questionnaire surveys of the enquirer to establish an effect; only one monitored patient outcome independently and used peer review to assess impact. CONCLUSION: The clinical and economic impact of drug information consultation and provision on patient care has not been investigated rigorously. A research methodology for such an investigation is suggested.
PURPOSE: Hypertension is an important risk factor for coronary artery disease. However, the impact of hypertension on the outcomes of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) is unknown. Our purpose was to evaluate the association between hypertension and adverse outcomes and repeat cardiac procedures during the 6-month period after PTCA. METHODS: We studied 791 patients who were enrolled in the Routine Versus Selective Exercise Treadmill Testing After Angioplasty (ROSETTA) registry. This registry is a prospective multicenter study examining the use of functional testing after a successful PTCA. RESULTS: We compared 411 hypertensive patients (mean age 60.1 +/- 10 years, 31.1% female) with 380 normotensive patients (mean age 59.1 +/- 12 years, 16.2% female). Patients with hypertension had a higher 6-month rate of composite clinical events (unstable angina, myocardial infarction, death) than did normotensive patients (16.5% vs 10.5%, P =.017). In addition, there was a trend for hypertensive patients to have higher rates of cardiac procedures (angiography, repeat PTCA, coronary artery bypass graft surgery) compared with normotensive patients (19.8% vs 14.9%, P =.074). However, functional testing after PTCA was lower among hypertensive subjects (44.4% vs 54.0%, P =.008). Among the 411 hypertensive patients, a regression analysis showed that several variables were independently associated with increased 6-month adverse event rates, including pre-PTCA Killip class III-IV (odds ratio [OR] 5.7, 95% CI 1.7-19.0), Canadian Cardiovascular Society angina class III-IV (OR 2.1, 95% CI 1.1-4.2), unstable angina as the reason for PTCA (OR 2.3, 95% CI 1.2-4.3), peripheral vascular disease (OR 3.2, 95% CI 1.5-6.4), PTCA of a bypass graft (OR 3.1, 95% CI 1.2-7.6), and calcium antagonist usage at admission for the index PTCA (OR 1.9, 95% CI 1.1-3.4). CONCLUSIONS: During the 6-month period after a successful PTCA, patients with hypertension have significantly higher adverse event rates than do those without hypertension. Several clinical variables may help identify which hypertensive patients are at higher risk for clinical events.
Ultrafine particles are a component of air pollution, derived from primary combustion sources, and so we have undertaken a programme of study on the mechanisms of lung injury caused by ultrafine particles. Ultrafine particles made of low-solubility, low-toxicity materials are more inflammogenic in the rat lung than fine respirable, particles made from the same material. Ultrafine particles can cause inflammation via processes independent of the release of transition metals, as shown by the fact that soluble products from ultrafine carbon black have no ability to cause inflammation. The property that drives the greater inflammogenicity of ultrafines is unknown but very likely relates to particle surface area and involves oxidative stress. Increases in intracellular Ca(++) may underlie the cellular effects of ultrafines, although the mechanism whereby ultrafines have this effect is not understood. However, increased influx of Ca(++) into macrophages occurs via the membrane Ca(++) channels following contact with ultrafine particles, and involves oxidative stress. Increased Ca(++) in macrophages exposed to ultrafines can lead to the transcription of key pro-inflammatory genes such as TNFalpha. Ultrafine particles can also impair the ability of macrophages to phagocytose and clear other particles, and this may be pro-inflammogenic.
The abnormal conditions to which blood is subjected during cardiopulmonary bypass (CPB) trigger an activation of the inflammatory response in all patients to varying degrees. Both complement activation and the release of cytokines characterize this response. Most inflammatory mediators have a molecular weight that is below the membrane pore size of commonly used ultrafilters, which should allow them to be freely filtered. However, some mediators have been shown to fail to cross through the membrane even though they are small enough to cross. The purpose of the present study was to determine whether certain inflammatory mediators could be removed by ultrafiltration when performed during the rewarming phase of CPB. Thirty adult patients undergoing a single, open-heart procedure were randomized to either control (no ultrafiltration) or to the zero-balance ultrafiltration (ZBUF) group. ZBUF was performed by removing 3 l/m2 blood using a 65-kDa ultrafilter with 1.3-m2 surface area. A volume of a balanced salt crystalloid solution (Plasmalyte) equal to the filtered blood volume was given to replace the fluid removed. Patient data was taken before CPB (T1), immediately following CPB (T2), and 12 h following the procedure (T3). The average volume of filtrate removed during ZBUF was 6405 ml, which was analyzed for the presence of interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-alpha), C3a, and C5a. The average concentrations of the mediators measured in the effluent were: IL-1, 0.17 pg/ml; IL-6, 0.64 pg/ml; TNF-alpha, 1.25 ng/ml; C3a, 782.6 ng/ml; C5a, 25.6 ng/ml. In every case except for IL-1, the amounts of mediators removed were significantly greater than zero. This study demonstrates that ultrafiltration is a strategy that can be used during CPB in the adult to remove significant amounts of inflammatory mediators.
OBJECTIVE: To determine the prevalence of and risk factors for reproductive tract infections among men and women in a rural community in Bangladesh. METHODS: In the Matlab area a systematic sample of married non-pregnant women aged 15-50 years was drawn from a comprehensive household registration system for married women. A systematic sample of married and unmarried men in the same age group was drawn from a census-derived demographic surveillance list. Private interviews were conducted with 804 women in a clinic, and cervical, vaginal, urinary and serological samples were collected. Urine and blood specimens were obtained from 969 men who were interviewed at home. FINDINGS: The prevalence of bacterial and viral reproductive tract infections was low to moderate. For example, fewer than 1% of the women had a cervical infection. No cases of human immunodeficiency virus (HIV) infection were found. However, among men there was a high level of reported risk behaviour and a low level of protection against infection. CONCLUSION: A low prevalence of reproductive tract infections, coupled with a high level of reported risk behaviour, indicated a need for primary programmes that would prevent an increase in the incidence of reproductive tract infections, sexually transmitted infections and HIV infection.
Project constraints often require social primates, such as macaques, to be housed individually. However, we believed the amount of time spent housed alone prior to renewed social exposure would effect an animal's behavior. We observed the behavior of adult male bonnet macaques (Macaca radiata) during time spent in an exercise pen with other adult males. We studied 2 groups (n = 3 males/group). Group one (group LT) was composed of males that had been housed alone for 24 months prior to the study, and the other group (group ST) consisted of male macaques that had been housed alone for 1 month prior to the study. One day each week for 8 weeks, members of each group were placed in an exercise pen containing items that would encourage foraging and object exploration. Seven 5-min focal observations were recorded for macaques during each session. The 2 most notable differences in social behavior were that macaques of group LT spent significantly (P = 0.003) more time alone than did macaques of group ST, whereas macaques of group ST spent significantly (P = 0.002) more time involved in social grooming than did macaques of group LT. Thus, prior duration of prior individual housing appeared to significantly affect social behavior.
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Explore the source record for details and available documents.
From an observation of efferent interspike intervals of a neuron, we consider how to decode the input temporal information. It is found that the integrate-and-fire model is blind in the temporal domain due to the fact that its efferent firing rate is independent of the input temporal frequency. The conclusion is then confirmed for the integrate-and-fire model with correlated inputs, with reversal potentials, with a nonlinear leakage and with a subthreshold oscillation. For the Hodgkin-Huxley model, however, in terms of efferent firing rates alone, it is possible to read out the input temporal information.
Postgraduate general dentistry programs are facing critical problems with funding, resident recruitment and viability. Recent federal actions reduced and eliminated graduate medical education (GME) support for some programs, and rising student debt and increasingly lucrative private practice opportunities reduce the value of postgraduate general dentistry experiences. Faced with these complex and interlinked challenges, the University of Nebraska Medical Center College of Dentistry General Practice Residency implemented a gainshare plan. The first 12 months of the plan produced a 44% increase in production and a concomitant 42% increase in actual collections resulting in enough funds to provide remuneration over base salary for residents, staff and faculty. The plan also compensated the Dean, the host department and the College of Dentistry while also funding the development of a reserve account for program enhancement and future stipend support. Gainshare concepts, rationale and details of the pilot plan are presented along with a discussion of key outcomes and experiences.
BACKGROUND: It is generally agreed that randomized controlled trials should be powered to detect small but clinically significant treatment effects. Toward these ends, minimal important difference (MID) was proposed as a benchmark for designing trials and for interpreting health-related quality-of-life instrument scores. MID was defined in 1989 as "the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troubling side effects and excessive cost, a change in the patient's management." OBJECTIVE: 1) To expand the idea of minimal clinically important difference so as to take into account harms as well as benefits. 2) To propose concepts and methods with which to do so. SUMMARY: The authors define sufficiently important difference (SID) as the smallest amount of patient-valued benefit that an intervention would require to justify associated costs, risks, and other harms. As a means toward estimation of SID, the authors propose benefit-harm tradeoff methods, in which domains of benefit and harm are systematically traded off against each other and assessed in relation to the global decision of whether a treatment choice is worthwhile. Specific SID estimates can be used to power and interpret clinical trials or to inform health services research and/or public health policy. This article briefly describes the evolution of the important difference concept and outlines similarities and differences between MID and SID.