The legionnaires' outbreak in Barrow-in-Furness, summer 2002.
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Disaster Planning↗
Biomedical subjects
Andrew Smith
Publications and source records attributed to Andrew Smith.
English soccer teams' aggressive behavior when playing away from home.
Speculation about key factors affecting home advantage still exists. The present study investigated aggressive behavior amongst English Football Premiership (soccer) players and its relation to home advantage. The frequency of aggressive behaviour, identified by the award of a penalty or disciplinary card (yellow for caution or red for dismissal) was analysed over 2000-2003. Chi-square analyses assessed whether a greater frequency of aggressive behavior was performed by teams away from home. In decided matches, teams playing away received significantly more cautions (yellow cards) than home teams. A further analysis of tied matches indicated that away teams received significantly more cautions (yellow cards) than home teams. No significant differences between home and away teams were found for dismissals and penalties awarded. Reasons for these findings are considered.
Adult↗
Novel, potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
Many breast tumours are hormone-responsive and rely on estrogens for their sustained growth and development. The enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is primarily responsible for the conversion of estrone (E1) into the most potent of the human estrogens 17beta-estradiol (E2). Here we report the syntheses, inhibitory activities and docking studies for a novel series of pyrazole amides which have been discovered with the aim of probing the structure activity relationships (SAR) for such a template and of using this template to mimic the potent inhibitor 1 (Fig. 1). Amides containing an aromatic pyridyl moiety have been found to give the best inhibition, indicating that the pyridyl group interacts beneficially in the active site. This work has shown that extension from this position on the pyrazole template is well tolerated and the optimization of such systems is under investigation.
Amides↗
Benzothiazole derivatives as novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.
Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) have considerable potential as treatments for metabolic diseases, such as diabetes mellitus type 2 or obesity. Here, we report the discovery and synthesis of a series of novel benzothiazole derivatives and their inhibitory activities against 11beta-HSD1 from human hepatic microsomes measured using a radioimmunoassay (RIA) method. The benzothiazole derivatives 1 and 2 showed greater than 80% inhibition for 11beta-HSD1 at 10 microM and exhibited IC50 values in the low micromolar range. The preliminary SAR study suggested the introduction of a chlorine substituent at the 4 position of the benzothiazole ring greatly enhanced the inhibitory activities. Docking studies with the benzothiazole derivative 1 into the crystal structure of human 11beta-HSD1 revealed how the molecule may interact with the enzyme and cofactor.
11-beta-Hydroxysteroid Dehydrogenase Type 1↗
Correlates of daily caffeine consumption.
A study of 376 young British adults showed that estimated daily caffeine consumption increased with age, and was associated with smoking and greater alcohol consumption. Non-consumers of caffeine avoided tea and coffee (even the de-caffeinated form). Level of caffeine consumption was not associated with impulsivity, sociability, extraversion or trait anxiety.
Adult↗
E-ring modified steroids as novel potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are an important class of steroidogenic enzymes that regulate the bioavailability of active estrogens and androgens and are as yet a relatively unexploited therapeutic target. Based on our investigations and those of others, E-ring modified steroids were identified as a useful template for the design of inhibitors of 17beta-HSD type 1, an enzyme involved in the conversion of estrone into estradiol. The synthesis and biological evaluation of a new series of N- and C-substituted 1,3,5(10)-estratrien-[17,16-c]-pyrazoles and the corresponding SAR are discussed. Among the N-alkylated analogues, the most potent inhibitor was the 1'-methoxyethyl derivative, 41, with an IC(50) of 530 nM in T47-D human breast cancer cells. The X-ray crystal structure of the 1'-isobutyl derivative, was determined. Further optimization of the template using parallel synthesis resulted in a library of C5'-linked amides from which 73 emerged. This pyridylethyl amide had an IC(50) of 300 nM and its activity, with that of 41, suggests the importance of hydrogen bond acceptor groups in the pyrazole side chain. Both 41 and 73 displayed selectivity over 17beta-HSD type 2, and preliminary investigations showed 41 to be nonestrogenic in vitro in a luciferase reporter gene assay in contrast to the parent pyrazole 25. Molecular modeling studies, which support these findings, and a QSAR, the predictive power of which was demonstrated, are also presented.
17-Hydroxysteroid Dehydrogenases↗
Network security and data integrity in academia: an assessment and a proposal for large-scale archiving.
A direct impediment to the optimal use of online databases is the increasing prevalence, severity, and toll of computer and network security incidents. Funding agencies should set up working groups that can provide essential services such as universal backup, archival storage, and mirroring of community resources, consistent with the key goal of security in academia: to preserve data and results for posterity.
Archives↗
Pharmacy-based needle exchange in New Zealand: a review of services.
BACKGROUND: New Zealand has been offering needle exchange services since 1987. Over 170 community pharmacies are involved in the provision of this service. However, no recent detailed review of New Zealand's pharmacy-based needle exchange has been published. This study aimed to explore service provision, identify problems faced by pharmacists, and look for improvements to services. METHODS: The study used a cross-sectional survey of all needle exchange pharmacies. Postal questionnaires were used with postal and telephone follow-up. RESULTS: A response rate of 88% was obtained overall. Pharmacists had been providing the service for a mean of 6 years. Pharmacies had given out an average of 130 injecting units, in a mean of 62 transactions to a mean of 17 clients in the 4 weeks prior to completing the questionnaire. The majority had not incurred problems such as violence or intoxicated clients in the last 12 months, although almost one third had experienced shoplifting which they associated with service provision. Training and improving return rates were identified as potential areas for further development. CONCLUSION: New Zealand needle exchange pharmacies are providing services to a number of clients. The majority of service providers had been involved for a number of years, indicating the problems incurred had not caused them to withdraw their services--findings which echo those from the UK. Further training and support, including an exploration of improving return rates may be needed in the future.
Journal Article↗
A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes.
Cells such as fibroblasts and endothelial cells migrate through the coordinated responses of discrete integrin-containing focal adhesions and complexes. In contrast, little is known about the organization of integrins on the highly motile T lymphocyte. We have investigated the distribution, activity, and cytoskeletal linkage of the integrin lymphocyte function associated antigen-1 (LFA-1) on human T lymphocytes migrating on endothelial cells and on ligand intercellular adhesion molecule-1 (ICAM-1). The pattern of total LFA-1 varies from low expression in the lamellipodia to high expression in the uropod. However, high affinity, clustered LFA-1 is restricted to a mid-cell zone that remains stable over time and over a range of ICAM-1 densities. Talin is essential for the stability and formation of the LFA-1 zone. Disruption of the talin-integrin link leads to loss of zone integrity and a substantial decrease in speed of migration on ICAM-1. This adhesive structure, which differs from the previously described integrin-containing attachments displayed by many other cell types, we have termed the "focal zone."
Cell Adhesion↗
Importance of integrin LFA-1 deactivation for the generation of immune responses.
The dynamic regulation of ligand binding is considered crucial for integrin function. However, the importance of activity regulation for integrin function in vivo is largely unknown. Here, we have applied gene targeting to delete the GFFKR sequence of the lymphocyte function-associated antigen-1 (LFA-1) alpha(L) subunit cytoplasmic domain in mouse germline. Lymphocytes from Lfa-1(d/d) mutant mice showed constitutive activation of LFA-1-mediated cell adhesion and impaired de-adhesion from intercellular adhesion molecule-1 that resulted in defective cell migration. In contrast, signaling through LFA-1 was not affected in Lfa-1(d/d) cells. T cell activation by superantigen-loaded and allogeneic APCs, cytotoxic T cell activity, T-dependent humoral immune responses, and neutrophil recruitment during aseptic peritonitis were impaired in Lfa-1(d/d) mice. Thus, deactivation of LFA-1 and disassembly of LFA-1-mediated cell contacts seem to be vital for the generation of normal immune responses.
Animals↗
Analysis of ligation and DNA binding by Escherichia coli DNA ligase (LigA).
NAD(+)-dependent DNA ligases are essential enzymes in bacteria, with the most widely studied of this class of enzymes being LigA from Escherichia coli. NAD(+)-dependent DNA ligases comprise several discrete structural domains, including a BRCT domain at the C-terminus that is highly-conserved in this group of proteins. The over-expression and purification of various fragments of E. coli LigA allowed the investigation of the different domains in DNA-binding and ligation by this enzyme. Compared to the full-length protein, the deletion of the BRCT domain from LigA reduced in vitro ligation activity by 3-fold and also reduced DNA binding. Using an E. coli strain harbouring a temperature-sensitive mutation of ligA, the over-expression of protein with its BRCT domain deleted enabled growth at the non-permissive temperature. In gel-mobility shift experiments, the isolated BRCT domain bound DNA in a stable manner and to a wider range of DNA molecules compared to full LigA. Thus, the BRCT domain of E. coli LigA can bind DNA, but it is not essential for DNA nick-joining activity in vitro or in vivo.
Base Sequence↗
Novel and potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors.
Structure-based drug design using the crystal structure of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) led to the discovery of novel, selective, and the most potent inhibitors of 17beta-HSD1 reported to date. Compounds 1 and 2 contain a side chain with an m-pyridylmethyl-amide functionality extended from the 16beta position of a steroid scaffold. A mode of binding is proposed for these inhibitors, and 2 is a steroid-based 17beta-HSD1 inhibitor with the potential for further development.
17-Hydroxysteroid Dehydrogenases↗
Aortic pulse wave velocity and albuminuria in patients with type 2 diabetes.
Development of microalbuminuria increases the risk for cardiovascular disease (CVD) in type 2 diabetes. The nature of this relationship is unclear but may involve arterial stiffness, an independent risk marker for CVD mortality. Aortic pulse wave velocity (Ao-PWV) and albumin creatinine ratio (ACR) were measured in 134 consecutive patients with type 2 diabetes without overt renal impairment (serum creatinine <150 micromol/L). ACR ranged from 0.2 to 153 mg/mmol. Patients with raised ACR (>/=3 mg/mmol) had higher Ao-PWV, poorer diabetic control, and higher pulse pressure (PP) and systolic BP (SBP) (all P < 0.05) than those with normal ACR. The closest univariate associations of Ao-PWV were positively with age, duration of diabetes, SBP, PP, ACR, and insulin treatment and negatively with GFR and weight (all P < 0.01). In a multiple linear step-down regression analysis, the significant predictors of Ao-PWV were age, SBP or PP, duration of diabetes, gender, number of antihypertensive medications, and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which together explained 55% of the variance of Ao-PWV. When ACR was offered in place of arterial pressure to a separate model, ACR emerged as a significant predictor of Ao-PWV. After age adjustment, patients with lower, below median GFR had higher Ao-PWV than those with GFR above the median (P = 0.043). In patients with type 2 diabetes without overt renal impairment, raised ACR is associated with higher Ao-PWV, a relationship most likely mediated by raised BP. The association of Ao-PWV with reduced GFR suggests that even modest renal dysfunction may affect the viscoelastic properties of large arteries.
Adult↗
Impediments to database interoperation: legal issues and security concerns.
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Computational Biology↗
Effects of caffeine in non-withdrawn volunteers.
RATIONALE: Evidence for the behavioural effects of caffeine is prevalent in the literature. It is associated with increased subjective alertness, improved reaction time and enhanced encoding of new information. However, there is an on-going debate as to whether such changes are in fact improvements or merely a reversal of the negative effects of caffeine withdrawal. Using participants who had consumed their normal daily quota of caffeine this study alleviated this potential confound as all participants were not withdrawn at the time of testing. OBJECTIVES: To determine whether caffeine influenced the mood and performance of non-withdrawn volunteers. METHODS: Sixty eight volunteers, all of whom were regular caffeine consumers, consumed their normal amount of caffeine over the course of the day. Baseline measures of mood and performance were then carried out followed by double-blind administration of caffeine (2 mg/kg) or placebo. The test battery was repeated again 30 min after ingestion of the drink. RESULTS: Our findings showed improvements comparable to previous research. Mood was improved and performance on a number of cognitive measures was improved. The findings are discussed in relation to both noradrenergic and cholinergic neurotransmitter systems. CONCLUSIONS: This study provided evidence against the argument that behavioural changes due to caffeine are merely the reversal of negative withdrawal effects.
Activity Cycles↗
Fish consumption, advisory awareness, and hair mercury levels among women of childbearing age.
The Wisconsin Division of Public Health and the State of Maine Bureau of Health collaborated on a 12 state mercury awareness project. The primary goals of this initiative were to evaluate mercury sport fishing advisory awareness among women of childbearing age and assess the methylmercury exposure among this subpopulation. The project, which was conducted between December 1998 and December 1999, involved a randomized telephone survey of 3015 women of childbearing age and hair mercury analyses for a subset of 414 women. While 92% of these women had consumed fish or shellfish during the past year, less than one third (29%) of them had eaten any sport-caught fish. More than two thirds of the women who consumed sportfish were not aware that their state had issued fish consumption guidelines to protect against methylmercury exposure. Hair mercury levels ranged from 0.005 to 4.62 ppm and were positively correlated with recent fish consumption rates (P<0.0001). Women who ate sport-caught fish did not have significantly higher hair mercury levels than others (mean 0.51 vs. 0.48 ppm). Among women who ate sportfish, advisory awareness had no effect on their mercury exposure. Demographic indicators associated with higher hair mercury levels included residence in northeastern USA, marital status of married, college education, annual household income greater than $75,000, and Asian race.
Adolescent↗
Pancreas-sparing duodenectomy is effective management for familial adenomatous polyposis.
Duodenal adenocarcinoma remains the leading cause of cancer death in familial adenomatous polyposis patients following colectomy. Stratification based on Spigelman's criteria provides a means for determining therapy. Spigelman stage IV patients have been selected for pancreas-sparing duodenectomy. Twenty-one patients underwent resection between 1992 and 2004, with a mean age of 58 +/- 11 years. The mean time from colectomy to duodenectomy was 27 +/- 13 years. Invasive cancer was found in the distal duodenum in one patient. Operative time averaged 327 +/- 61 minutes with a mean blood loss of 503 +/- 266 ml. There was no mortality, and eight patients (38%) had 14 complications: six (29%) with delayed gastric emptying, four (19%) with biliary/pancreatic anastomotic leak, one with pancreatitis, and one with wound infection. There were two reoperations: one for delayed gastric emptying and one for an early biliary leak. Mean length of stay was 15 +/- 10 days. Two late complications occurred: a stomal ulcer and an intestinal obstruction at 48 and 24 months, respectively. Mean follow-up was 79 months (range, 3-152 months). Two patients developed polyps in the advanced jejunal limb and were endoscopically treated. Pancreas-sparing duodenectomy represents a definitive treatment for advanced duodenal polyposis and can obviate the need for pancreaticoduodenectomy.
Adenomatous Polyposis Coli↗
Comparative sensitivities between different plasma B-type natriuretic peptide assays in patients with minimally symptomatic heart failure.
Plasma B-type natriuretic peptide (BNP) assays have become widely used to diagnose and manage patients with heart failure. However, differences in assay characteristics may have important implications when BNP is used as a screening test for heart failure at a specific cutoff value. We performed a prospective comparison of 2 commercially available assays--one that is a laboratory-based, microparticle enzyme immunoassay (MEIA) that uses EDTA plasma specimens and one that is a point-of-care (POC), single-use fluorescence immunoassay that uses EDTA--anticoagulated whole blood or plasma specimens-in patients with heart failure and healthy controls. Despite the overall concordance between different SNP assays for the diagnosis of heart failure, their sensitivities may differ when compared at the approved diagnostic cutoff value of 100 pg/mL. At this cutoff value, the MEIA on AxSYM demonstrated greater sensitivity than POC Triage BNP assay in minimally symptomatic patients with heart failure. Therefore, for screening purposes, cutoff values for plasma BNP or N-terminal pro-BNP levels should be specific for each assay to optimize test performance. These findings suggest that there is a relationship between the decision statistics used in screening for left ventricular dysfunction and the type of diagnostic assay used.
Adult↗