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Biomedical subjects

Michael Brown

Publications and source records attributed to Michael Brown.

At least 19 recordsLinked to original sources
PubMed2007

Echocardiographic evaluation of ventricular function in mice.

Ventricular dysfunction remains a hallmark of most cardiac disease. The mouse has become an essential model system for cardiovascular biology, and echocardiography an established tool in the study of normal and genetically altered mice. This review describes the measurement of ventricular function, most often left ventricular function, by echocardiographic methods in mice. Technical limitations related to the small size and rapid heart rate in the mouse initially argued for the performance of echocardiography under anesthesia. More recently, higher frame rates and smaller probes operating at higher frequencies have facilitated imaging of conscious mice in some, but not all, experimental protocols and conditions. Ventricular function may be qualitatively and quantitatively evaluated under both conditions. Particular detail is provided for measurement under conscious conditions, and measurement under conscious and sedated or anesthestized conditions are contrasted. Normal values for echocardiographic indices for the common C57BL/6 strain are provided. Diastolic dysfunction is a critical pathophysiologic component of many disease states, and progress in the echocardiographic evaluation of diastolic function is discussed. Finally, echocardiography exists among several competing imaging technologies, and these alternatives are compared.

Adrenergic Agents↗
PubMed2006

Evaluation of Goldmann applanation tonometry using a nonlinear finite element ocular model.

Goldmann applanation tonometry (GAT) is the internationally accepted standard for intra-ocular pressure (IOP) measurement, which is important for the diagnosis of glaucoma. The technique does not consider the effect of the natural variation in the corneal thickness, curvature and material properties. As these parameters affect the structural resistance of the cornea, their variation is expected to lead to inaccuracies in IOP determination. Numerical Analysis based on the finite element method has been used to simulate the loading conditions experienced in GAT and hence assess the effect of variation in corneal parameters on GAT IOP measurements. The analysis is highly nonlinear and considers the hyper-elastic J-shaped stress-strain properties of corneal tissue observed in laboratory tests. The results reveal a clear association between both the corneal thickness and material properties, and the measured IOP. Corneal curvature has a considerably lower effect. Similar trends have been found from analysis of clinical data involving 532 patients referred to the Glaucoma Unit at Moorfields Hospital, and from earlier mathematical analyses. Nonlinear modelling is shown to trace the behaviour of the cornea under both IOP and tonometric pressure, and to be able to provide additional, and potentially useful, information on the distribution of stress, strain, contact pressure and gap closure.

Biomedical Engineering↗
PubMed2006

Making sense of modernity's maladies: health and disease in the Industrial Revolution.

The industrialization and urbanization of Britain during the 19th century gave the medical profession something to think about. In particular, were the radical changes taking place in society responsible for the sudden rise in endemic and epidemic disease? This article (part of the Science in the Industrial Revolution series) examines the reactions of two key figures in the history of British public health, James Philips Kay and Thomas Southwood Smith, to this question. Their outlooks typify the tendency of Victorian medical practitioners to construct economies of health that saw disease as a consequence of the violation of natural laws and cycles rather than as a product of industrial modernity.

Disease Outbreaks↗
PubMed2006

T-cell recognition of a prostate specific antigen is not sufficient to induce prostate tissue destruction.

METHODS: The ability of CD8(+) T-cells to induce prostate inflammation was examined using a prostate ovalbumin expressing transgenic mouse (POET) and/or adoptive transfer of T-cell receptor (TCR) transgenic T-cells (OT-I) that specifically recognize ovalbumin. Localization of inflammatory cells to prostate tissue was examined following T-cell activation via endogenous prostatic antigen, recombinant type 5 adenovirus carrying the gene coding ovalbumin (Ad5-mOVA), or adoptive transfer of in vitro antigen stimulated OT-I cells. RESULTS: Ovalbumin specific OT-I cells were activated by autologous prostate antigen and trafficked to the prostate, but did not induce inflammation unless present in overwhelming numbers ( approximately 65% of CD8(+) T-cells). Activation of antigen specific CD8(+) T-cells in vitro (peptide pulsed antigen presenting cells) or in vivo (Ad5-mOVA) induced transitory prostate inflammation, without induction of prostate pathology, regardless of CD4(+) T-cell availability. Inflammation also was observed in OT-I x POET mice but again, pathological effects were not observed. CONCLUSIONS: T lymphocytes specific for a prostate antigen are capable of inducing inflammatory infiltration of prostatic tissue rapidly following activation, but do not produce pathological prostate injury.

Adoptive Transfer↗
PubMed2006

Secondary osteon and Haversian canal dimensions as behavioral indicators.

Variation in the size of structures within mature cortical bone is relevant to our understanding of apparent differences between human samples, and it is relevant to the development of histologically based age-estimation methods. It was proposed that variation may reflect effects of physical activity, through biomechanical and/or metabolic mechanisms. If these factors are local, femoral osteon area (On.Ar) should be more histologically variable than On.Ar in ribs. Ribs should show a higher variation in Haversian canal area (H.Ar) if they are sites of more remodeling activity and hence of arrested refilling of secondary osteons at time of death. This study compares On.Ar and H.Ar of secondary osteons from femora (15) and ribs (29) from 44 Holocene (Later Stone Age) foragers from South Africa (M = 19, F = 25) to values from paired femora and ribs from historic samples (Spitalfields and St. Thomas, 20 pairs from each). Fixed-effects analysis of variance demonstrates rib On.Ar to be significantly smaller than femur, but with no sex or age effects. The femur-to-rib On.Ar ratio is lower for the Holocene foragers than for the two modern samples because of relatively large rib On.Ar. Femora and ribs from the same skeleton normally show femoral On.Ar larger than rib On.Ar (37/44 pairs). Mean femoral values of On.Ar are more diverse than rib On.Ar values, but within-sample coefficients of variation are similar. Values for H.Ar are highly variable and do not reflect anatomical site, age, sex, or population effects. The patterning of osteon size does not appear to be linked to physical activity or to different rates of metabolic activity within the skeleton, at least not in a straightforward way.

Adolescent↗
PubMed2006

Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1.

The mTOR kinase controls cell growth, proliferation, and survival through two distinct multiprotein complexes, mTORC1 and mTORC2. mTOR and mLST8 are in both complexes, while raptor and rictor are part of only mTORC1 and mTORC2, respectively. To investigate mTORC1 and mTORC2 function in vivo, we generated mice deficient for raptor, rictor, or mLST8. Like mice null for mTOR, those lacking raptor die early in development. However, mLST8 null embryos survive until e10.5 and resemble embryos missing rictor. mLST8 is necessary to maintain the rictor-mTOR, but not the raptor-mTOR, interaction, and both mLST8 and rictor are required for the hydrophobic motif phosphorylation of Akt/PKB and PKCalpha, but not S6K1. Furthermore, insulin signaling to FOXO3, but not to TSC2 or GSK3beta, requires mLST8 and rictor. Thus, mTORC1 function is essential in early development, mLST8 is required only for mTORC2 signaling, and mTORC2 is a necessary component of the Akt-FOXO and PKCalpha pathways.

Animals↗
PubMed2006

A new research agenda: improving health care in general hospitals.

AIM AND OBJECTIVES: To set out the research required to improve the health of people with learning disabilities in general hospital settings. The objectives are: (i) to share service developments in a mapping exercise to provide a picture of current work in this area, and (ii) to identify practice issues and experiences that can contribute to a broader research agenda. BACKGROUND: It is recognized that people with learning disabilities are high users of all healthcare systems and have different pattern of health needs that often go unidentified, with some requiring general hospital care. The research evidence base in this area of practice needs to be developed to promote and improve health care. METHOD: A facilitated focus group design was employed at a conference event to identify areas for research in the future and determined that action is required on four broad research fronts. RESULTS: Research is required to establish core principles of care, service developments, practical care measures and influencing change in practice. CONCLUSION: Research collaborations need to be established to support activity in this area and requires action in the future. RELEVANCE TO CLINICAL PRACTICE: The evidence base and understanding of the high and differing pattern of health needs of people with learning disabilities continues to evolve and develop, with considerable scope to identify new areas for research. A conference approach was used to identify research questions to improve the care of this group in general hospital settings and offers a model that may be helpful in defining new areas of enquiry in the future.

Delivery of Health Care↗
PubMed2006

Schistosoma mansoni, nematode infections, and progression to active tuberculosis among HIV-1-infected Ugandans.

Rates of tuberculosis (TB) in Africa are highest among people infected with HIV. Searching for additional risk factors in a cohort of HIV-infected Ugandan adults, we previously found that a type 2 cytokine bias and eosinophilia were associated with progression to active TB. A possible role for helminth infection was assessed in this study. We analyzed TB incidence in 462 members of this cohort who were screened for filarial infections, gastrointestinal nematodes, and schistosomiasis. Progression to TB was not associated with gastrointestinal nematodes (rate ratio [RR], 1.18; confidence intervals [CIs], 0.66-2.10) or Mansonella perstans (RR, 0.42; CI, 0.13-1.34). A weak association between Schistosoma mansoni infection and TB was found (RR, 1.42; CI, 0.86-2.34); after adjusting for potential explanatory variables and using more stringent diagnostic criteria, the association was strengthened (RR, 2.31; 1.00-5.33). This analysis suggests an effect of S. mansoni infection on progression to active TB among HIV-1-infected Ugandans.

Adolescent↗
PubMed2006

Renin-angiotensin system genes and exercise training-induced changes in sodium excretion in African American hypertensives.

OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) and angiotensinogen (ACT) genotypes could predict changes in urinary sodium excretion in response to short-term aerobic exercise training (AEX). DESIGN: Longitudinal intervention. SETTING: The study was conducted at the University of Maryland at College Park and at Baltimore, and the University of Pittsburgh General Clinical Research Center. PARTICIPANTS: 31 (age 53 +/- 2 years) sedentary, hypertensive (146 +/- 2/88 +/- 2 mm Hg) African Americans. INTERVENTION: Aerobic exercise training (AEX) consisted of seven or eight consecutive days, 50 minutes per day, at 65% of heart rate reserve. Participants underwent a 24-hour period of ambulatory blood pressure (BP) monitoring and urine collection at baseline and 14-18 hours after the last exercise session. MAIN OUTCOME MEASURES: Angiotensiongen (AGT) M235T and ACE I/D genotype and sodium excretion and ambulatory BP. RESULTS: Average sodium excretion for the entire group independent of genotype increased after AEX (108 +/- 9 vs 143 +/- 12 mEq/day, P=.003). Sodium excretion significantly increased after exercise training in the ACE II (114 +/- 22 vs 169 +/- 39 mEq/day, P=.04), but not in the ID (100 +/- 8 vs 133 +/- 17 mEq/day, P=.12) or DD (113 +/- 18 vs 138 +/- 11 mEq/day, P=.13) genotype groups. In the II genotype group, the increase in sodium excretion was significantly and inversely correlated with decreases in 24-hour diastolic (r= -.88, P=.02) and mean (r= -.95, P=.004) BP. The ACT TT and MT+MM genotype groups similarly increased their sodium excretion by 34 +/- 16 (P=.05) and 37 +/- 17 (P=.05) mEq/day respectively. CONCLUSIONS: These results suggest that African American hypertensives with the ACE II genotype may be more susceptible to sodium balance and BP changes with exercise training compared with those with the ID and DD genotypes.

Black or African American↗
PubMed2006

Role of potassium excretion and percent body fat on ethnic differences in plasma aldosterone levels.

OBJECTIVE: To determine whether plasma aldosterone (PA) levels differed between African American and White prehypertensives and if so, could the difference be explained by ethnicity-related variability in urinary K+ and Na+ excretion, body mass index (BMI), and percent body fat. DESIGN: Ethnic comparison SETTING: The University of Maryland College Park and the University of Maryland School of Pharmacy. PARTICIPANTS: 61 (African American, n=28; White, n=33) prehypertensives (systolic blood pressure [SBP] 131 +/- 10 mm Hg, diastolic blood [DBP] 85 +/- 6 mm Hg). INTERVENTION: 6-week dietary stabilization and medication tapering period. MAIN OUTCOME MEASURES: PA levels, Na+ and K+ excretion, blood pressure, and percent body fat and BMI. RESULTS: We saw no differences in SBP (P=.36) and DBP (P=.54) between the two ethnic groups. PA levels were lower in African Americans compared to Whites (62 +/- 7 vs 107 +/- 12 pg/mL, P=.002). 24-hour K+ excretion was lower among African Americans compared to Whites (51 +/- 7 vs 70 +/- 4 mmol/day, P=.002). We saw no difference in percent body fat, BMI, SBP, or DBP between African Americans and Whites. After separately accounting for K+ excretion and Na+ excretion and BMI, plasma aldosterone levels remained significantly different between the two ethnic groups. After adjusting for percent body fat, PA levels were not significantly different between the two ethnic groups (P = .06). CONCLUSIONS: The findings of the current study indicate that PA levels differ between African American and White prehypertensives and this difference may partly be due to ethnic variability in K+ excretion and percent body fat.

Adiposity↗
PubMed2005

The differential effects of mutant p53 alleles on advanced murine lung cancer.

We report a direct comparison of the differential effects of individual p53 mutations on lung tumor growth and progression, and the creation of a murine model of spontaneous advanced lung adenocarcinoma that closely recapitulates several aspects of advanced human pulmonary adenocarcinoma. We generated compound conditional knock-in mice with mutations in K-ras combined with one of three p53 alleles: a contact mutant, a structural mutant, or a null allele. p53 loss strongly promoted the progression of K-ras-induced lung adenocarcinomas, yielding a mouse model that is strikingly reminiscent of advanced human lung adenocarcinoma. The influence of p53 loss on malignant progression was observed as early as 6 weeks after tumor initiation. Furthermore, we found that the contact mutant p53R270H, but not the structural mutant p53R172H, acted in a partially dominant-negative fashion to promote K-ras-initiated lung adenocarcinomas. However, for both mutants, loss-of-heterozygosity occurred uniformly in advanced tumors, highlighting a residual tumor-suppressive function conferred by the remaining wild-type allele of p53. Finally, a subset of mice also developed sinonasal adenocarcinomas. In contrast to the lung tumors, expression of the point-mutant p53 alleles strongly promoted the development of sinonasal adenocarcinomas compared with simple loss-of-function, suggesting a tissue-specific gain-of-function.

Adenocarcinoma↗
PubMed2005

Emergency care for people with learning disabilities: what all nurses and midwives need to know.

People with learning disabilities have high health needs and as a result will require access to all aspects of healthcare systems, including the emergency services. The evidence of the health needs experienced by this group is evolving and developing and they have a range of issues that will bring them into contact with general hospital and the emergency services. It is now apparent that they experience risks to their health when accessing general hospital care and action is required to identify and address their distinct health needs. Emergency services are often the first point of entry into the healthcare system and as a result they need to develop their knowledge and skills in meeting the health needs of this group. Partnership working with specialists in learning disability health and emergency care can help to improve care.

Clinical Competence↗
PubMed2005

Treatment of Schistosoma mansoni infection increases helminth-specific type 2 cytokine responses and HIV-1 loads in coinfected Ugandan adults.

BACKGROUND: Studies showing that helminths stimulate type 2 cytokine responses and influence responses to unrelated antigens suggest that helminths may accelerate human immunodeficiency virus type 1 (HIV-1) disease progression in coinfected individuals and that antihelminthic therapy may be beneficial. By the same logic, however, the increase in type 2 cytokines occurring immediately after antischistosomal treatment might increase viral replication and be detrimental. METHODS: To assess the effect of antischistosomal therapy on immune responses and HIV-1 replication, a cohort of 163 Ugandans coinfected with Schistosoma mansoni and HIV-1 was treated with praziquantel. CD4(+) T lymphocyte counts, eosinophil counts, and plasma HIV-1 RNA concentrations were measured before treatment and 1 month and 5 months after treatment. Schistosoma mansoni- and Mycobacterium tuberculosis-specific cytokine responses and serum interleukin (IL)-10 concentrations were analyzed. RESULTS: Transient increases in viral load and sustained decreases in CD4(+) T lymphocyte count were observed, especially in subjects with higher-intensity infections. Despite enhanced posttreatment S. mansoni-specific type 2 responses, no increase in eosinophils or in M. tuberculosis-specific type 2 responses nor any decline in M. tuberculosis-specific interferon (IFN)-gamma responses were seen. A significant decline in circulating IL-10 concentrations was observed. CONCLUSION: Although the mechanisms underlying the increase in viral load after treatment with praziquantel are unclear, these results do not support the hypothesis that treating schistosomiasis is beneficial in the management of HIV-1 disease in Africa.

Adult↗