Biomedical subjects

D Brown

Publications and source records attributed to D Brown.

At least 55 records · Page 3Linked to original sources

PubMed2004

Estimation of parameters for a mathematical model of growth hormone secretion.

Here, we describe partial calibration of a parsimonious mathematical model of growth hormone (GH) secretion. From first principles, we derived a model of the effects on GH secretion from pituitary somatotrophs of stimulation by GH-releasing factor (GRF) or GH secretagogue, and of inhibition by somatostatin. We obtained a concise model by collapsing the many processes of the signal transduction cascade into a single step broadly reflecting the initial binding of GRF to its receptors. In the model, GH secretion is proportional to the rate of binding of GRF to activatable receptors. Desensitization occurs because of reduction of free receptors/available effector units, and resensitization occurs as those lost are replaced. This replacement is speeded up in the presence of somatostatin, which also inhibits GH secretion by reducing the constant of proportionality between the rate of GH secretion and the rate of GRF binding. We derived simple mathematical equations for the rate of GH secretion and cumulative secretion. Using these, we tested the model against data obtained from experiments performed in vitro, and made it quantitative using rigorous statistical approaches to optimize parameter estimates. The behaviour of the calibrated model matches experimental observations closely.

Algorithms↗

PubMed2004

Increased inflammation and altered macrophage chemotactic responses caused by two ultrafine particle types.

BACKGROUND: Ultrafine particles have been hypothesised to be an important contributing factor in the toxicity and adverse health effects of particulate air pollution (PM10) and nanoparticles are used increasingly in industrial processes. AIMS: To compare the ability of ultrafine and fine particles of titanium dioxide and carbon black to induce inflammation, cause epithelial injury, and affect the alveolar macrophage clearance functions of phagocytosis and chemotaxis in vivo. METHODS: Rats were instilled with fine and ultrafine carbon black and titanium dioxide. Inflammation was quantified by bronchoalveolar lavage; the ability of the macrophages to phagoytose indictor fluorescent beads and to migrate towards aC5a were determined. RESULTS: Ultrafine particles induced more PMN recruitment, epithelial damage, and cytotoxicity than their fine counterparts, exposed at equal mass. Both ultrafine and fine particles significantly impaired the phagocytic ability of alveolar macrophages. Only ultrafine particle treatment significantly enhanced the sensitivity of alveolar macrophages to chemotact towards C5a. CONCLUSIONS: Ultrafine particles of two very different materials induced inflammation and epithelial damage to a greater extent than their fine counterparts. In general, the effect of ultrafine carbon black was greater than ultrafine titanium dioxide, suggesting that there are differences in the likely harmfulness of different types of ultrafine particle. Epithelial injury and toxicity were associated with the development of inflammation after exposure to ultrafines. Increased sensitivity to a C5a chemotactic gradient could make the ultrafine exposed macrophages more likely to be retained in the lungs, so allowing dose to accumulate.

Air Pollutants↗

PubMed2004

The seroepidemiology of herpes simplex virus type 1 and 2 in Europe.

OBJECTIVES: To describe the seroepidemiology of herpes simplex virus (HSV) types 1 and 2 in the general populations of eight European countries to better understand recent reported changes in disease epidemiology. METHODS: Belgium, Bulgaria, Czech Republic, England and Wales, Finland, Germany, Netherlands, and Slovenia conducted national cross sectional serological surveys for HSV-1 and HSV-2 between 1989 and 2000. Survey sizes ranged from 3000 to 7166 sera. External quality control was ensured through reference panel testing. RESULTS: Large intercountry and intracountry differences in HSV-1 and HSV-2 seroprevalence were observed. Age standardised HSV-1 seroprevalence ranged from 52% in Finland, to 57% in the Netherlands, 67% in Belgium, 81% in Czech Republic, and 84% in Bulgaria. Age standardised (>12 years) HSV-2 seroprevalence ranged from 24% in Bulgaria, to 14% in Germany, 13% in Finland, 11% in Belgium, 9% in Netherlands, 6% in Czech Republic, and 4% in England and Wales. In all countries, probability of seropositivity for both infections increased with age. A large proportion of teenagers and young adults remain HSV-1 susceptible particularly in northern Europe. Women were significantly more likely to be HSV-2 seropositive in six of seven (p<0.05) countries and HSV-1 seropositive in four of seven (p<0.05) countries, particularly in northern Europe. No significant evidence of a protective role of HSV-1 for HSV-2 infection was found adjusting for age and sex (p<0.05). CONCLUSIONS: There is large variation in the seroepidemiology of HSV-1 and HSV-2 across Europe. The observation that a significant proportion of adolescents are now HSV-1 susceptible may have implications for transmission and clinical presentation of HSV-1 and HSV-2.

Adolescent↗

PubMed2004

Audit of rabies post-exposure prophylaxis in England and Wales in 1990 and 2000.

The objectives were to compare rabies post-exposure prophylaxis issued by the Public Health Laboratory Service (PHLS) in 1990 and in 2000, to evaluate their appropriateness, and to make recommendations for future issue of rabies post-exposure prophylaxis in England and Wales. The method was to review all rabies vaccine and immunoglobulin issues by PHLS in 1990 and 2000 with evaluation against Department of Health recommendations. The PHLS issued prophylaxis to 656 people in 1990 and 295 people in 2000. The fall is attributable to control measures in Western Europe leading to a lower risk of exposure in countries in the region. Vaccine was still issued for exposures in countries with a category of 'no risk' (15 individuals) including rabies immunoglobulin in six cases. Immunoglobulin was frequently not issued for exposures in high-risk countries but the reasons were not always evident from the information provided; in many cases treatment had probably been started abroad. Delay before contacting the PHLS fell between 1990 and 2000 (p = 0.003). Dogs continue to be the most common animal exposure reported, and their rabies status is generally unknown. The most frequent site of bite was the leg. Prophylaxis was issued for exposure to some animals which have never been known to transmit rabies. Successful control measures in Europe have reduced the need for rabies prophylaxis in UK residents who travel abroad. More detailed information should be collected in future on aspects such as pre-exposure vaccination and treatment started abroad to facilitate future audit of appropriateness of treatment. A repeat audit should be carried out to evaluate the impact of a death from European Bat Lyssavirus 2 infection in a UK bat handler in November 2002.

Adolescent↗

PubMed2003

Comparison of source images for protons, pi-'s, and lambda's in 6A GeV Au+Au collisions.

Source images are extracted from two-particle correlations constructed from strange and nonstrange hadrons produced in 6A GeV Au+Au collisions. Very different source images result from pp vs p Lambda vs pi(-)pi(-) correlations. Scaling by transverse mass can describe the apparent source size ratio for p/pi(-) but not for Lambda/pi(-) or Lambda/p. These observations suggest important differences in the space-time emission histories for protons, pions, and neutral strange baryons produced in the same events.

Journal Article↗

PubMed2003

Methicillin-resistant Staphylococcus aureus in children with cystic fibrosis: An eradication protocol.

A retrospective 12-year study (May 1988-July 2000) was undertaken in children with cystic fibrosis (CF) to evaluate 1) the magnitude of methicillin-resistant Staphylococcus aureus (MRSA) in these children; 2) the clinical impact of MRSA on CF; and 3) the efficacy of an MRSA protocol aimed at the eradication of the carrier state. The study maneuver comprised of 1) surveillance cultures of throat/rectum to detect the MRSA carrier state; 2) life-long cephradine rather than flucloxacillin to lift selection pressure; 3) topical application of oral and nebulized vancomycin for 5 days to clear the carriage of MRSA; and 4) a strict antistaphylococcal hygiene program, including handwashing and device policy. Fifteen children with CF (11 boys, with median age 117 months) positive for MRSA were enrolled. The current prevalence of MRSA among children with CF in our hospital is 6.5%. Of 15 children identified, only 12 (18 episodes of MRSA colonization) were treated according to protocol. Median age of MRSA acquisition was 73 months (interquartile range, 43-134 months). In 7 patients (55%), MRSA was eradicated. Of a total of 18 MRSA episodes, the protocol was successful in 10 episodes. The mean period of MRSA-free status was 12 months (range, 6-36 months). Pulmonary function (measured by FEV(1)) was not affected (68% of predicted before treatment, and 68% of predicted after treatment). All children were oropharyngeal carriers of both MRSA and ceftazidime-resistant P. aeruginosa. We believe that an effort has to be made to limit MRSA in CF clinics for the following reasons: 1) MRSA carriage in any individual is an abnormal condition; 2) limitation of systemic vancomycin use is desirable; 3) MRSA carriage may be a contraindication for lung transplantation; and 4) epidemiologically, a CF unit with a substantial MRSA problem functions as a source of dissemination for other patients.

Administration, Topical↗

PubMed2003

Effect of pramlintide on A1C and body weight in insulin-treated African Americans and Hispanics with type 2 diabetes: a pooled post hoc analysis.

An unresolved problem in the management of type 2 diabetes is that improvement of glycemic control with insulin, insulin secretagogues, and insulin sensitizers is often accompanied by undesired weight gain. This problem is of particular concern in ethnic groups with a high propensity for diabetes and obesity, such as African Americans and Hispanics. Two 1-year, randomized, double-blind, placebo-controlled clinical trials in insulin-treated patients with type 2 diabetes have shown that adjunctive therapy with pramlintide, an analog of the human beta-cell hormone amylin, reduces A(1C) with concomitant weight loss, rather than weight gain. To assess the effect of pramlintide in various ethnic groups with type 2 diabetes using insulin, we conducted a pooled post hoc analysis of the 2 trials, which included all Caucasian (n = 315), African American (n = 47), and Hispanic (n = 48) patients (age 57 years, A(1C) 9.1%, body mass index [BMI] 33 kg/m(2), mean values) who completed 52 weeks of treatment with either pramlintide (120 microg twice daily or 150 microg 3 times a day) or placebo. Primary endpoints included changes from baseline to week 52 in A(1C) and body weight. Collectively, pramlintide-treated patients achieved significant reductions from baseline in both A(1C) and body weight (placebo-corrected treatment effects at week 52: -0.5% and -2.6 kg, respectively, both P <.0001). The simultaneous reduction in A(1C) and body weight at week 52 was evident across all 3 ethnic groups and appeared to be most pronounced in African Americans (-0.7%, -4.1 kg), followed by Caucasians (-0.5%, -2.4 kg) and Hispanics (-0.3%, -2.3 kg). The glycemic improvement with pramlintide was not associated with an increased incidence of hypoglycemia over the entire study period (43% pramlintide v 40% placebo). Nausea, the most common adverse event associated with pramlintide treatment, was mostly mild and confined to the first 4 weeks of therapy (25% pramlintide v 16% placebo) with comparable patterns in the 3 ethnic groups. Thus, pending further experience, the combined improvement in glycemic and weight control with pramlintide treatment appears to be generalizable to a broad population of mixed ethnicity.

Black or African American↗

PubMed2003

Comparative effectiveness of full-length and B-domain deleted factor VIII for prophylaxis--a meta-analysis.

Recently reported data suggest the possibility of differences in clinical efficacy between full-length factor VIII (FL-FVIII) and B-domain deleted recombinant factor VIII (BDD-rFVIII). To address this question, we conducted a meta-analysis of studies reporting the incidence of bleeding under prophylaxis, as well as studies of FL-FVIII and BDD-rFVIII half-life. The pooled cumulative weekly prophylactic dose of BDD-rFVIII (81.3 +/- 13.8 IU kg(-1) week(-1)) was greater by 36% (P = 0.11) than that of FL-FVIII (60.0 +/- 5.9 IU kg(-1) week(-1)). The pooled incidence of bleeding in BDD-rFVIII recipients [16.8 bleeds per patient year; confidence interval (CI), 9.5-24.2 bleeds per patient year] was more than 2.5-fold larger (P < 0.0005) than that in patients receiving FL-FVIII (6.6 bleeds per patient year; CI, 4.7-8.5 bleeds per patient year). In a multivariate analysis, the incidence rate ratio was 2.10 (CI, 1.98-2.24), indicating that breakthrough bleeding under prophylaxis was more than twice as likely with BDD-rFVIII than FL-FVIII at equivalent doses and ages. The pooled half-life for plasma-derived FL-FVIII (13.7 h; CI, 12.8-14.6 h) was closely similar to that for recombinant FL-FVIII (14.3 h; CI, 13.3-15.4 h). By contrast, the pooled half-life for BDD-rFVIII (11.3 h; CI, 9.9-12.7 h) was shorter by approximately 3 h compared with FL-FVIII. Although the results of the meta-analysis need to be interpreted with caution, the pooled data suggest that breakthrough bleeding under prophylaxis may occur more frequently in patients receiving BDD-rFVIII than FL-FVIII and may at least partly reflect a more abbreviated half-life of BDD-rFVIII. Several biochemical differences between BDD-rFVIII and FL-FVIII may underlie the observed disparities in bleeding incidence and half-life. This meta-analysis should be confirmed by further studies.

Adolescent↗

PubMed2003

Comparison of three stool antigen tests for Helicobacter pylori detection.

BACKGROUND: Active Helicobacter pylori infection can be diagnosed by invasive (biopsy based) or non-invasive methods, such as stool antigen testing. AIMS: To compare three stool antigen enzyme immunoassay kits--Premier Platinum Hp SA, FemtoLab Cnx, and Hp Ag--with biopsy based methods for the detection of H pylori in previously undiagnosed patients. METHODS: One hundred and eleven adults with dyspepsia referred for endoscopy provided a stool sample for testing and had biopsies taken. Patients were considered H pylori positive if two out of three invasive tests were positive or if culture alone was positive. RESULTS: The sensitivities and specificities of the Premier Platinum Hp SA, FemtoLab Cnx, and Hp Ag stool antigen kits when compared with biopsy based diagnosis were, 63.6%, 88.0%, and 56.0% and 92.6%, 97.6%, and 97.6%, respectively. CONCLUSIONS: FemtoLab Cnx may be considered as an alternative to urea breath testing in the initial diagnosis of patients with dyspepsia who do not require immediate endoscopy. Stool testing has the potential advantages of being simple to perform, relatively cheap, and samples can be submitted directly from primary care.

Adult↗

PubMed2003

pp60c-Src Kinase mediates growth effects of the full-length precursor progastrin1-80 peptide on rat intestinal epithelial cells, in vitro.

Growth factor effects of precursor forms of gastrins have become evident in recent years. However, intracellular pathways that mediate growth effects of the precursor molecules are not known. In previous studies, we reported an increase in Tyr phosphorylation of pp60(c-Src) in intestinal epithelial cells (IEC) in response to the fully processed form of gastrin [gastrin(1-17) (G17)]. We have now examined whether c-Src kinase is similarly phosphorylated and activated in response to the full-length precursor molecule, progastrin (PG)(1-80), (recombinant human PG) in IEC cells. We found a significant increase in pp60(c-Src) kinase activity in response to both G17 and PG (0.1-1.0 nM), suggesting that growth effects of both the precursor and fully processed gastrin molecules may be mediated via similar pathways. On the other hand, pp62(c-Yes) was not phosphorylated or activated in response to either G17 or PG. To examine whether c-Src kinase mediates proliferative effects of PG, IEC cells were microinjected with anti-Src-IgG and (3)H-thymidine ((3)H-Tdr) uptake of the cells measured. Control cells received nonimmune IgG. The (3)H-Tdr uptake of cells stimulated with 1.0 nM PG was significantly reduced in cells microinjected with anti-c-Src-IgG; control IgG had no effect. In cells stimulated with 1.0% fetal calf serum, microinjection with c-Src-IgG had no effect on (3)H-Tdr uptake. The specificity of the effect was further confirmed by blocking the inhibitory effect of anti-c-Src-IgG with antigenic Src peptide. These results suggest that activation of c-Src kinase likely represents a critical step in mediating proliferative effects of both the precursor and fully processed forms of gastrins on IEC.

Animals↗

PubMed2002

Q2 evolution of the generalized Gerasimov-Drell-Hearn integral for the neutron using a 3He target.

We present data on the inclusive scattering of polarized electrons from a polarized 3He target at energies from 0.862 to 5.06 GeV, obtained at a scattering angle of 15.5 degrees. Our data include measurements from the quasielastic peak, through the nucleon resonance region, and beyond, and were used to determine the virtual photon cross-section difference sigma(1/2)-sigma(3/2). We extract the extended Gerasimov-Drell-Hearn integral for the neutron in the range of four-momentum transfer squared Q2 of 0.1-0.9 GeV2.

Journal Article↗

PubMed2002

Twenty years of mercury monitoring in dental surgeries.

From 1981 to 2001 disposable mercury monitors based on palladium chloride have been deployed in 3,568 dental surgeries throughout the United Kingdom. They have performed well as first-level indicators of high concentrations of mercury vapour in surgeries that had become contaminated by spillage of mercury or faulty equipment. Whilst accumulated data suggests that mercury hygiene practices have improved over the past 20 years, the move to the use of disposable capsules rather than automatic amalgamators does not appear to have been a major factor in this improvement.

Accidents, Occupational↗

PubMed2002

The genome sequence of Schizosaccharomyces pombe.

We have sequenced and annotated the genome of fission yeast (Schizosaccharomyces pombe), which contains the smallest number of protein-coding genes yet recorded for a eukaryote: 4,824. The centromeres are between 35 and 110 kilobases (kb) and contain related repeats including a highly conserved 1.8-kb element. Regions upstream of genes are longer than in budding yeast (Saccharomyces cerevisiae), possibly reflecting more-extended control regions. Some 43% of the genes contain introns, of which there are 4,730. Fifty genes have significant similarity with human disease genes; half of these are cancer related. We identify highly conserved genes important for eukaryotic cell organization including those required for the cytoskeleton, compartmentation, cell-cycle control, proteolysis, protein phosphorylation and RNA splicing. These genes may have originated with the appearance of eukaryotic life. Few similarly conserved genes that are important for multicellular organization were identified, suggesting that the transition from prokaryotes to eukaryotes required more new genes than did the transition from unicellular to multicellular organization.

Base Sequence↗

PubMed2002

A proposed 3D structure for crotamine based on homology building, molecular simulations and circular dichroism.

Crotamine, isolated from the venom of the South American rattlesnake Crotalus durissus terrificus is a strongly basic 42-amino acid polypeptide belonging to the small basic myotoxin family. As no tridimensional structure is available for this myotoxin subfamily, despite its important pharmacological interest, we propose in this paper a theoretical 3D model for crotamine. Starting from a homology modelling procedure, followed by intensive molecular dynamics (MD) simulations in water and complementary CD experiments, the designed 3D model is the first example of a tridimensional structure in this family of small basic myotoxins. Crotamine, therefore, belongs to a newly identified structural family presenting a common fold also found in beta-defensin and antopleurine-B. The proposed 3D model will be used for future calculations about crotamine aggregation and interaction with membranes.

Amino Acid Sequence↗

PubMed2002

Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin.

Cutaneous aging is a complex biological phenomenon affecting the different constituents of the skin. To compare the effects of intrinsic and extrinsic aging processes, a total of 83 biopsies were collected from sun-exposed and protected skin of healthy volunteers representing decades from the 1st to the 9th (6-84 years of age). Routine histopathology coupled with computer-assisted image analysis was used to assess epidermal changes. Immunoperoxidase techniques with antibodies against type I and type III collagens and elastin were used to quantitatively evaluate changes in collagen and elastic fibers and their ultrastructure was examined by transmission electron microscopy. Epidermal thickness was found to be constant in different decades in both sun-exposed and protected skin; however, it was significantly greater in sun-exposed skin (P = 0.0001). In protected skin, type I and III collagen staining was altered only after the 8th decade, while in sun-exposed skin the relative staining intensity significantly decreased from 82.5% and 80.4% in the 1st decade to 53.2% and 44.1% in the 9th decade, respectively (P = 0.0004 and 0.0008). In facial skin the collagen fiber architecture appeared disorganized after the 4th decade. The staining intensity of elastin in protected skin significantly decreased from 49.2% in the 1st decade to 30.4% in the 9th decade (P = 0.05), whereas in sun-exposed skin the intensity gradually increased from 56.5% in the 1st decade to 75.2% in the 9th decade (P = 0.001). The accumulated elastin in facial skin was morphologically abnormal and appeared to occupy the areas of lost collagen. Collectively, the aging processes, whether intrinsic or extrinsic, have both quantitative and qualitative effects on collagen and elastic fibers in the skin.

Adolescent↗

PubMed2002

In the prostatic epithelium, dietary isoflavones from red clover significantly increase estrogen receptor beta and E-cadherin expression but decrease transforming growth factor beta1.

In mice fed a diet supplemented with red clover isoflavones the prostatic epithelium displays a significant increase in the production of estrogen receptor beta and the adhesion protein E-cadherin but a decrease in transforming growth factor beta1. These proteins are estrogenically-induced markers of proliferation, maintenance of histological architecture, preservation of cell phenotype and reduction of the potential for neoplastic and metastatic transformation. This study suggests that red clover isoflavones represent a non-toxic dietary treatment for prostatic hyperplasia and a reduction in the potential for neoplastic transformation.

Animal Feed↗

PubMed2002

Immunoassays to detect the serum antibody response of cattle to infection with Salmonella Typhimurium definitive type 104 and following vaccination with Bovivac S.

AIMS: To use ELISA and immunoblotting assays to examine the serum antibody response of cattle infected with Salmonella Typhimurium DT104 and following vaccination with Bovivac S. METHODS AND RESULTS: Three hundred and twenty-nine cattle, including 16 shedding multiresistant Salmonella Typhimurium DT104, were screened for serum antibodies binding to O=1, 4, 5, 12 lipopolysaccharide (LPS) antigens before and after vaccination with Bovivac S. Sera with an ELISA reading of 0.9A405 or above were shown to contain antibodies, of the IgG-class only, to the LPS of Salmonella Typhimurium using immunoblotting. Prior to vaccination, only 11 cattle had serum IgG-class antibodies to the O=4, 5 LPS antigens, and of these one also had antibodies to outer membrane proteins and H=i flagellar antigens. Following vaccination, 87 out of 315 cattle developed serum antibodies to the LPS of Salmonella Typhimurium. CONCLUSIONS: Evidence of infection of cattle with Salmonella Typhimurium was readily obtained with an LPS-based ELISA in association with an immunoblotting procedure, supplementing existing bacteriological procedures. This enabled the detection of an increase in the number of cattle with serum antibodies to Salmonella Typhimurium LPS following vaccination with Bovivac S. SIGNIFICANCE AND IMPACT OF THE STUDY: The immunoassays described provided evidence of infection with Salmonella Typhimurium and served as a valuable adjunct to established bacteriology.

Animals↗

PubMed2002

Causes of morbilliform rash in a highly immunised English population.

AIMS: To determine the causes of morbilliform rash and fever in a population with high vaccination coverage for measles and rubella. METHODS: Comprehensive laboratory investigation additional to routine oral fluid testing of children presenting to primary care physicians in East Anglia, England. RESULTS: Laboratory confirmation of infection was obtained in 93 (48%) of 195 children: parvovirus B19 in 34 (17%); group A streptococcus in 30 (15%); human herpesvirus type 6 in 11 (6%); enterovirus in nine (5%); adenovirus in seven (4%); and group C streptococcus in six (3%) (four individuals tested positive for two agents). None had measles or rubella. CONCLUSIONS: Oral fluid testing to cover infections additional to measles and rubella aids clinical management and is likely to maintain uptake of testing, which is essential for measles and rubella surveillance in highly immunised low incidence populations.

Adenoviridae Infections↗