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Biomedical subjects

A Brown

Publications and source records attributed to A Brown.

At least 37 records · Page 2Linked to original sources
PubMed2005

Determining patient preferences for improved chemotoxicity during treatment for advanced bladder cancer.

Determining patient preferences for improved chemotoxicity during treatment for advanced bladder cancer Conventional treatment for advanced bladder cancer is methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC), with a median survival of 1 year but significant toxicity. The newer combination of gemcitabine plus cisplatin (GC) has demonstrated comparable survival and an improved toxicity profile (Von der Maase et al. 2000). At present, the importance to patients of the toxicity of chemotherapy has not been widely studied. An earlier study in bladder cancer indicated that toxicity was an important determinant of treatment preference (Davey et al. 2000). A study of preferences for advanced bladder cancer therapy in the UK was proposed.

Antimetabolites, Antineoplastic↗
PubMed2005

Nonatopic allergen-independent mast cell activation in parasitized eosinophilic athymic rats.

It is possible to induce eosinophilia in congenitally athymic rats by infection with the parasite Ascaris suum. Athymic bronchial eosinophilia is associated with increased expression of IL-5 and eotaxin mRNA, and with the presence of residual T cells and mast cells. Anamnestic mastocytosis is particularly pronounced and in this study we examine the relationship between mast cell degranulation and IgE production in athymic rats following infection. Incubation of peritoneal mast cells from athymic rats with anti-IgE induced dose-dependent degranulation, as measured by histamine release. However, the failure of mast cells from infected athymic rats to degranulate following incubation with all but one of the parasite antigens selected confirms the absence of a specific IgE response. In contrast, all agonists induced degranulation in euthymic rats. The only parasite-derived factor to induce histamine release in all mast cells was Ascaris body fluid, which contains an element capable of inducing IgE-independent degranulation. Furthermore, increased levels of rat mast cell protease II in athymic bronchoalveolar lavage fluid suggest degranulation of mast cells by IgE and allergen independent means in vivo. We believe that the development of eosinophilic lung inflammation in the absence of specific IgE makes this a prototype for investigating the immunological mechanisms underlying nonatopic asthma.

Animals↗
PubMed2004

Synergistic use of synchrotron radiation techniques for biological samples in solution: a case study on protein-ligand recognition by the peroxisomal import receptor Pex5p.

Circular dichroism spectropolarimetry and X-ray scattering data, obtained using synchrotron radiation, can yield information about the secondary and tertiary structure of proteins in solution. These techniques have been used to analyse the architecture and shape of a complex of two proteins in solution. The crystal structures of two separate proteins, the C-terminal domain of Pex5p and SCP2, are available but their complex has not previously been structurally characterized. Circular dichroism spectropolarimetry indicated that complex formation requires little secondary structure rearrangement. X-ray scattering data fit an elongated irregular 'shoe'-shaped particle of the complex of the two proteins, with dimensions of the order of 30 A x 40 A x 90 A. Comparison with the known crystal structures suggests that this 'shoe' shape requires a conformational change of the C-terminus of SCP2 to appropriately locate its peroxisomal targeting signal type-1 recognition motif into the binding pocket of the Pex5p receptor. Implications of the combined use of synchrotron-based circular dichroism spectropolarimetry and X-ray scattering in structural biology and proteomics are discussed.

Binding Sites↗
PubMed2004

Impaired response rates, but satisfying protection rates to influenza vaccination in dialysis patients.

Dialysis patients show impaired responses to several vaccines. Limited recent data are available on influenza vaccination in these patients. In the 1998-1999 influenza season, 44 dialysis patients received a standard trivalent vaccination followed by a booster two months later. The serum antibody responses in these patients were compared with those found in healthy subjects. A fourfold rise in serum hemagglutination inhibition titre was achieved in 23-58% of all patients. Protective titres were reached in 53-93% of the patients. Since protective antibody titers can be induced, it is recommended to vaccinate dialysis patients annually against influenza.

Aged↗
PubMed2004

DSIMS characterization of a drug-containing polymer-coated cardiovascular stent.

Dynamic Secondary Ion Mass Spectrometry (DSIMS) was used to study the release behavior of cytochalasin D, an actin polymerase inhibitor effective in the reduction of smooth muscle cell (SMC) proliferation, from a polymer-coated cardiovascular stent. High-performance liquid chromatography (HPLC) was used to determine the percentage of drug released as a function of time and showed the typical behavior of a drug-releasing system that is comprised of a core drug-polymer dispersion surrounded by a drug-free polymeric membrane: an initial burst of the drug followed by a gradual elution over time. DSIMS profiles, as a function of release time, indicated that depletion of the drug initially occurred only in the outer layers of the coating. As release progressed the DSIMS profile showed a gradual decrease of cytochalasin D with increasing depth. This study shows that DSIMS is a powerful tool for the determination of drug distributions in, and the release behavior from, thin polymer layers.

Cardiovascular Surgical Procedures↗
PubMed2004

Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22.

We performed a linkage analysis on 25 extended multiplex Portuguese families segregating for bipolar disorder, by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the GeneChip Human Mapping 10K Array (HMA10K). Of these families, 12 were used for a direct comparison of the HMA10K with the traditional 10-cM microsatellite marker set and the more dense 4-cM marker set. This comparative analysis indicated the presence of significant linkage peaks in the SNP assay in chromosomal regions characterized by poor coverage and low information content on the microsatellite assays. The HMA10K provided consistently high information and enhanced coverage throughout these regions. Across the entire genome, the HMA10K had an average information content of 0.842 with 0.21-Mb intermarker spacing. In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays. The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11.

Bipolar Disorder↗
PubMed2004

Serum amino acids in patients with mutations in the hepatocyte nuclear factor-1 alpha gene.

AIMS: Knockout mice lacking both copies of the hepatocyte nuclear factor 1 (HNF1) gene have altered serum levels of amino acids and generalized aminoaciduria. The aim of our study was to test whether alterations in serum amino acid levels were found in patients with mutations in the hepatocyte nuclear factor-1 alpha (HNF-1alpha) gene compared with controls. METHODS: Fasting serum from 20 patients with HNF-1alpha mutations and 20 age, sex and body mass index-matched controls was analysed for 16 amino acids. Means were compared between the two groups and Z scores calculated. RESULTS: There was no significant difference between patients with HNF-1alpha mutations and controls in serum levels of phenylalanine, arginine, citrulline or lysine as suggested by knockout mice models. Although serum levels of eight amino acids were different in the two groups, these were not significant after Bonferroni correction. CONCLUSIONS: The alterations in serum amino acid levels seen in mice models are not seen in patients with mutations in the HNF-1alpha gene. This suggests differences in mouse and man in the regulation of amino acid transport and has not provided us with a phenotypic marker to use before confirmatory genetic testing.

Amino Acids↗
PubMed2004

An assessment of the adequacy of suspension of insulin in pen injectors.

AIMS: To evaluate the completeness of insulin resuspension by users of neutral Hagedorn (NPH) insulin pens and premixed insulin pens and to relate this to how patients mix insulin before injecting. METHODS: Patients (n = 180) administering a medium duration or premixed insulin in cartridges in disposable pens were asked questions about mixing insulin, injection technique and storing insulin. They were also asked to demonstrate how they mixed their insulin and to send in a half-used pen. The cloudy component equates to the complexed insulin, while the clear component is the diluting fluid or soluble insulin, depending on the type of insulin used. The optical density, a simple way of measuring cloudiness, was measured in each cartridge or disposable pen and was compared with the range obtained from a series of unused control pens. The results for 146 pens containing the most commonly used insulin were included. The 21 patients whose residual pen insulins showed optical densities > 5 SD from the mean were re-interviewed and their medical records were examined in detail. Insulin in the pens was also measured by immunoassay to confirm the utility of optical density measurements. RESULTS: Only one patient mixed the insulin as the manufacturers recommended. In 58 out of 146 pens or cartridges (40%) the opacity of the insulin varied significantly from the expected value. CONCLUSIONS: Most patients in Kirkcaldy do not mix insulin adequately. This may result in their giving different incorrect doses of insulin during the use of each pen. More emphasis should be given to teaching patients to mix correctly.

Adolescent↗
PubMed2004

Hepatitis C virus among childbearing women in Scotland: prevalence, deprivation, and diagnosis.

OBJECTIVES: (A) To examine the prevalence and demographic characteristics of hepatitis C virus (HCV) infection among childbearing women in Scotland; and (B) to determine the extent of maternal HCV infection diagnosed prior to birth. METHODS: (A) Residual dried blood spot samples from routine neonatal screening, collected throughout Scotland during March-October 2000, were unlinked from identifiers and tested anonymously for HCV antibodies; and (B) electronic record linkage of Scotland's databases of births and diagnosed HCV infections was performed. RESULTS: (A) Of 30,259 samples, 121 were enzyme linked immunosorbent assay repeat reactive and 88 of these were confirmed as anti-HCV positive in the recombinant immunoblot assay, representing a seroprevalence of 0.29-0.40%. HCV seroprevalence was high among 25-29 year olds (0.4-0.57%), in high deprivation areas (0.92-1.07%), and in Greater Glasgow (0.83-0.96%) and Grampian (0.38-0.62%). Adjusted relative risk for HCV infection was highest among residents in high deprivation areas of Glasgow (7.2 (95% confidence interval 2.0-25.5)). (B) Of 121 HCV infections found among women at delivery, 24% and 46% were estimated to have been diagnosed prior to pregnancy and birth, respectively. CONCLUSIONS: HCV prevalence among Scottish childbearing women is consistent with that expected from injecting drug use. Based on reported rates of mother to child transmission, 8-11 paediatric infections are expected per annum. Diagnosis in only 24% of infected women prior to pregnancy indicates the extent to which HCV goes unrecognised in the injecting community. The current HCV screening approach-to test only those with a history of injecting drug use (or other risk factors for infection)-identifies approximately a quarter of previously undetected infections among pregnant women.

Adult↗
PubMed2004

Acetylated sialic acid residues and blood group antigens localise within the epithelium in microvillous atrophy indicating internal accumulation of the glycocalyx.

BACKGROUND: Microvillous atrophy, a disorder of intractable diarrhoea in infancy, is characterised by the intestinal epithelial cell abnormalities of abnormal accumulation of periodic acid-Schiff (PAS) positive secretory granules within the apical cytoplasm and the presence of microvillous inclusions. The identity of the PAS positive material is not known, and the aim of this paper was to further investigate its composition. METHODS: Formaldehyde fixed sections were stained with alcian blue/PAS to identify the acidic or neutral nature of the material, phenylhydrazine blocking was employed to stain specifically for sialic acid, and saponification determined the presence of sialic acid acetylation. The specificity of sialic acid staining was tested by digestion with mild sulphuric acid. Expression of blood group related antigens was tested immunochemically. RESULTS: Alcian blue/PAS staining identified a closely apposed layer of acidic material on the otherwise neutral (PAS positive) brush border in controls. In microvillous atrophy, a triple layer was seen with an outer acidic layer, an unstained brush border region, and accumulation within the epithelium of a neutral glycosubstance that contained acetylated sialic acid. Blood group antigens were detected on the brush border, in mucus, and within goblet cells in controls. In microvillous atrophy they were additionally expressed within the apical cytoplasm of epithelial cells mirroring the PAS abnormality. Immuno electron microscopy localised expression to secretory granules. CONCLUSIONS: A neutral, blood group antigen positive, glycosubstance that contains acetylated sialic acid accumulates in the epithelium in microvillous atrophy. Previous studies have demonstrated that the direct and indirect constitutive pathways are intact in this disorder and it is speculated that the abnormal staining pattern reflects accumulation of glycocalyx related material.

ABO Blood-Group System↗
PubMed2004

Hepatitis B and hepatitis C seroprevalence and risk behaviour among community-recruited drug injectors in North West Wales.

We estimated the prevalence of markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and injecting risk behaviour, among community-recruited injecting drug users (IDUs) in North West Wales in 2001 and 2002. Sample collection was undertaken by trained current and former IDUs. Oral fluid samples (n = 153) were tested as part of the Unlinked Anonymous Prevalence Monitoring Programme ongoing survey of IDUs. Approximately 12% of the sample reported that they were currently in a drug treatment programme. Of the 153 samples screened 27% (95% CI 20%-34%, 41/153) were anti-HBc positive, and 23% (95% CI 16%-30%, 35/153) were anti-HCV positive. Sixteen per cent (95% CI 10%-22%, 25/ 153) of the samples were positive for both anti-HBc and anti-HCV. Of the subjects 15% (95% CI 9%-20%) knew they had been vaccinated against hepatitis B. Direct sharing of needles and syringes in the 28 days prior to interview was reported by 44% (95% CI 35%-54%), and sharing of any equipment including that used for drug preparation prior to injection was reported by 66% (95% CI 57%-76%). In North West Wales, syringe sharing is a common practice, and a high proportion of IDUs have been exposed to bloodborne viruses. Hepatitis B vaccination coverage within this population appears to be low and needs to be increased. Further efforts are needed to improve the availability of clean injecting equipment.

Adult↗
PubMed2003

Influence of carbohydrate ingestion on immune changes after 2 h of intensive resistance training.

Thirty strength-trained subjects were randomized to carbohydrate (CHO) or placebo (Pla) groups and lifted weights for 2 h (10 exercises, 4 sets each, 10 repetitions, with 2- to 3-min rest intervals). Subjects received 10 ml x kg(-1) x h(-1) CHO (6%) or Pla beverages during the weight training bout. Blood, saliva, and vastus lateralis muscle biopsy samples were collected before and after exercise. Blood cell counts were determined, and plasma was analyzed for IL-6, IL-10, IL-1 receptor antagonist (IL-1ra), IL-8, and cortisol. Muscle was analyzed for glycogen content and relative gene expression of 13 cytokines (IL-1alpha, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, IFN-gamma, TNF-alpha) by use of real-time quantitative RT-PCR. Significant but modest increases were measured for plasma IL-6, IL-10, IL-1ra, and IL-8, but the pattern of increase did not differ between CHO and Pla groups. The rate of decrease in muscle glycogen content did not differ between CHO and Pla (P = 0.463). Muscle cytokine mRNA was detected preexercise for IL-1beta, IL-6, IL-15, IL-8, and TNF-alpha, and of these, IL-1beta, IL-6, IL-8, and TNF-alpha were significantly increased after the 2-h weight training bout. The increase in mRNA (fold difference from preexercise) did not differ between CHO and Pla groups. In summary, CHO vs. Pla ingestion did not alter modest increases measured for plasma IL-6, IL-10, IL-1ra, and IL-8, and muscle gene expression for IL-1beta, IL-6, IL-8, and TNF-alpha in strength-trained subjects lifting weights intensively for 2 h.

Administration, Oral↗
PubMed2003

Safety of community drinking-water and outbreaks of waterborne enteric disease: Israel, 1976-97.

Waterborne disease remains a major public health problem in many countries. We report findings on nearly three decades of waterborne disease in Israel and the part these diseases play in the total national burden of enteric disease. During the 1970s and 1980s, Israel's community water supplies were frequently of poor quality according to the microbiological standards at that time, and the country experienced many outbreaks of waterborne enteric disease. New regulations raised water quality standards and made chlorination of community water supplies mandatory, as well as imposing more stringent guidelines on maintaining water sources and distribution systems for both surface water and groundwater. This was followed by improved compliance and water quality, and a marked decline in the number of outbreaks of waterborne disease; no outbreaks were detected between 1992 and 1997. The incidence of waterborne salmonellosis, shigellosis, and typhoid declined markedly as proportions of the total burden of these diseases, but peaked during the time in which there were frequent outbreaks of waterborne disease (1980-85). Long-term trends in the total incidence of reported infectious enteric diseases from all sources, including typhoid, shigellosis, and viral hepatitis (all types) declined, while the total incidence of salmonellosis increased. Mandatory chlorination has had an important impact on improving water quality, in reducing outbreaks of waterborne disease in Israel, and reducing the total burden of enteric disease in the country.

Disease Outbreaks↗
PubMed2003

Comparative evaluation of the VITEK 2 Advanced Expert System (AES) in five UK hospitals.

OBJECTIVES: We carried out an evaluation of VITEK 2 in five UK laboratories, comparing results with 'gold standard' agar-dilution MIC data, assessing its ability to recognize resistant phenotypes and comparing results with those generated by routine antimicrobial susceptibility testing methods. METHODS: Laboratories tested a collection of 82 strains selected on the basis of their challenging and characterized resistance mechanisms. RESULTS: In comparison with the reference MIC method, VITEK 2 gave an essential agreement of 304/315 (enterococci), 1619/1674 (staphylococci) and 2937/3074 (Gram-negative bacilli): overall 96.0% agreement. Corresponding category (SIR) agreements with VITEK 2 were 247/252, 1496/1561 and 2478/2626 (overall 95.1%). Using five routine methodologies, category agreements ranged from 58/63 to 45/45; 222/232 to 174/174, and 333/372 to 250/259 for the three organism groups with an overall agreement of 95.0%. In contrast to VITEK 2 Advanced Expert System (AES), routine microbiology laboratories did not attempt to detect resistance mechanisms for every antibiotic studied. VITEK 2 AES detected all 19 resistance mechanisms in enterococci: where applicable, routine methods detected 14, 10 and 10. Of 30 resistance mechanisms in staphylococci, VITEK 2 AES detected 25 compared with 23, 20, 17 and 18 detected by routine methods. Finally, of 44 resistance mechanisms in Gram-negative bacilli, VITEK 2 AES detected 30 compared with 30, 23, 15 and 10 detected by routine methods. CONCLUSIONS: VITEK 2 performed susceptibility tests accurately and the AES detected and interpreted resistance mechanisms appropriately. Heavy inocula in a liquid medium possibly favour better expression of certain resistance determinants. Although certain routine microbiology methods performed adequately, VITEK 2 AES offers a rapid, standardized method suited to laboratories lacking experience of resistance mechanisms and/or those not testing an appropriate number, or range, of antibiotics to detect resistance phenotypes.

Bacteria↗
PubMed2003

Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3-h run.

Sixteen experienced marathoners ran on treadmills for 3 h at approximately 70% maximal oxygen consumption (Vo(2 max)) on two occasions while receiving 1 l/h carbohydrate (CHO) or placebo (Pla) beverages. Blood and vastus lateralis muscle biopsy samples were collected before and after exercise. Plasma was analyzed for IL-6, IL-10, IL-1 receptor agonist (IL-1ra), IL-8, cortisol, glucose, and insulin. Muscle was analyzed for glycogen content and relative gene expression of 13 cytokines by using real-time quantitative RT-PCR. Plasma glucose and insulin were higher, and cortisol, IL-6, IL-10, and IL-1ra, but not IL-8, were significantly lower postexercise in CHO vs. Pla. Change in muscle glycogen content did not differ between CHO and Pla (P = 0.246). Muscle cytokine mRNA content was detected preexercise for seven cytokines in this order (highest to lowest): IL-15, TNF-alpha, IL-8, IL-1beta, IL-12p35, IL-6, and IFN-gamma. After subjects ran for 3 h, gene expression above prerun levels was measured for five of these cytokines: IL-1beta, IL-6, and IL-8 (large increases), and IL-10 and TNF-alpha (small increases). The increase in mRNA (fold difference from preexercise) was attenuated in CHO (15.9-fold) compared with Pla (35.2-fold) for IL-6 (P = 0.071) and IL-8 (CHO, 7.8-fold; Pla, 23.3-fold; P = 0.063). CHO compared with Pla beverage ingestion attenuates the increase in plasma IL-6, IL-10, and IL-1ra and gene expression for IL-6 and IL-8 in athletes running 3 h at 70% Vo(2 max) despite no differences in muscle glycogen content.

Adult↗
PubMed2003

EphA/ephrin-A interactions regulate epileptogenesis and activity-dependent axonal sprouting in adult rats.

The Eph family of tyrosine kinase receptors and their ligands, ephrins, are distributed in gradients and serve as molecular guidance cues for axonal patterning during neuronal development. Most of these molecules are also expressed in mature brain. Thus, we examine here the potential roles of such molecules in plasticity and activity-dependent mossy fiber sprouting of adult CNS. We show that the ligand ephrin-A3 and the receptor EphA5 are expressed in complementary gradients in the adult rat mossy fiber system. Using the kindling model, we demonstrate that exogenous immunoadhesins that affect the interaction of endogenous EphA receptors and ephrin-A ligands modulate the development of kindling, one type of long-term plasticity, in mature rat brain. These immunoadhesins, combined with epileptogenic stimulations, alter both the extent and the pattern of collateral axonal sprouting in the mossy fiber pathway. Our results suggest that EphA receptors and ephrin-A ligands modify neuronal plasticity and may serve as spatial cues that modulate the development and pattern of activation-dependent axonal growth in adult CNS.

Animals↗