Biomedical subjects
M Wood
Publications and source records attributed to M Wood.
Getting evidence into clinical practice: an organisational behaviour perspective.
OBJECTIVES: To study the relationship between research evidence and clinical behaviour change in the UK National Health Service (NHS) in the period 1995-1997 by examining the 'careers' of change issues designed to reshape clinical practice, the impact of such change efforts, and the factors shaping change outcomes. METHODS: Comparative case study methods were used. Four clinical change issues were studied using semi-structured interviews (n = 119) and documentary analysis in one English NHS region. For each issue, there was an overview semi-structured interview survey of the issue at regional level, followed by an intensive analysis of its impact at local level on the practice of specific clinical groups. RESULTS: There was a weak relationship between the evidence base and its diffusion. The diffusion and take-up of scientific evidence were shown to be socially constructed. Different forms of evidence were differentially accepted by individuals and groups. Specific organisational and social factors affected this pattern of impact. The general management hierarchy of the NHS played a very limited role in enabling evidence-based clinical change. CONCLUSIONS: The implementation of evidence-based medicine is a complex and contested process. The results of this study confirm a professional dominance model of clinical behaviour change and identify tacit expert knowledge as a key power resource in shaping the way research evidence influences clinical practice.
Evaluation of a nucleic acid-based cross-linking assay to screen for hereditary hemochromatosis in healthy blood donors.
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Site-specific splice variation of the human P2X4 receptor.
P2X4 receptors are expressed in specific brain areas. We now describe site-specific splice variations of the human P2X4 receptor subunit, occurring at residue [YVIG / WVFV(W)] near the end of the first predicted transmembrane domain. p2X4(b) is formed by the insertion of an additional 16 amino acids. p2X4(C) is formed by deleting a cassette of 130 amino acids, including six of the 10 conserved extracellular cysteine residues. Transfection of P2X4(a), but not p2x4(c), formed functional channels in Xenopus oocytes and human 1321N1 cells. After transfection of p2X4(b) small, inconsistent ATP-evoked responses were detected only in the human cells, but when co-expressed, p2x4(b) may alter the function of P2X4(a) in oocytes. The distribution of splice variant RNA within human brain suggests regionally-dependent expression. These data indicate that the functions of the human P2X4 receptor may be altered by alternative splicing.
A pilot study of exercise training to reduce trunk fat in adults with HIV-associated fat redistribution.
OBJECTIVE: Body fat redistribution ('lipodystrophy'), with gain in abdominal and trunk fat, and decline in facial and limb fat, is a newly recognized problem in patients with HIV infection that has been linked to use of HIV-1 protease inhibitors. Increased abdominal fat may predispose these patients to hypertension, diabetes, and coronary artery disease. At this time no effective treatment is available. We examined whether exercise training could reduce trunk fat in men with fat redistribution. DESIGN: Open-label pilot study. METHODS: Ten men with increasing abdominal girth participated in a 16 week pilot study of progressive resistance training with an aerobic component. They trained in a community health club three times per week. Total body lean and fat mass, and trunk fat mass, were assessed by dual-energy x-ray absorptiometry (DXA). RESULTS: After 16 weeks of exercise, strength increased for three of the four exercises tested (leg press + 13% [p < 0.02], leg extension + 19% [p < 0.03], seated row + 7% [p < 0.13], chest press + 18% [p < 0.0051). There was a significant decline in total body fat by 1.5 kg (= 2.1 percentage points, p < 0.01); most of the decline in body fat occurred in trunk fat, which decreased by 1.1 kg (p < 0.03). Weight, lean mass (+ 1.1 + 2.6 kg, p = 0.23), and bone mineral density measured by DXA did not change. No adverse effects were seen from the training. CONCLUSIONS: Exercise training may reduce trunk fat mass in HIV-positive men with fat redistribution. Controls trials of this approach are warranted.
Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiency virus.
BACKGROUND: To assess the efficacy of progressive resistance training (PRT) in increasing strength and lean body mass (LBM) in HIV-infected adults. METHODS: Twenty-five adults with HIV infection were trained using a highly intensive PRT regimen for 8 weeks, followed by an additional 8 weeks of observation under ad libitum physical activity conditions. RESULTS: Twenty-four of the 25 patients completed the first phase of the study. They had significant increases in strength on all four exercises tested (P < 0.0001), and an increase in LBM of 1.75 +/- 1.94 kg (mean +/- SD, P < 0.0002), with a concomitant decline in fat of 0.92 +/- 2.22 kg (P < 0.05), and no significant change in weight or bone mineral content. Twenty-one of the patients returned for follow-up 8 weeks after completing the PRT. Compared with their baseline values, their mean lean mass remained 1.40 +/- 1.8 kg higher (P < 0.003). Among those who continued to train to some extent, lean mass increased by a mean of 1.1 +/- 1.6 kg (n = 9, P < 0.05 versus end of PRT), whereas those who did no further training showed an increase in lean mass of 0.28 +/- 1.4 kg (n = 12, P = NS versus end of PRT). The difference between the two groups was not, however, significant (P = 0.25). Among six patients with AIDS wasting, the increase in LBM was larger than among non-wasted patients (2.8 versus 1.4 kg, P < 0.06), and there was an increase in both weight (+3.9 versus -0.2 kg, P < 0.002) and fat mass (+ 0.95 versus -1.5 kg, P < 0.002) at 8 weeks, which persisted at 16 weeks (weight: +4.0 versus -1.6 kg, P < 0.0002; fat: +1.6 versus -1.9 kg, P < 0.01). CONCLUSION: This preliminary study suggests that short-term, high intensity PRT can significantly increase LBM and strength in HIV infection, and may be used as an alternative or adjunct to pharmacological anabolic treatments in this disease.
Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status.
BACKGROUND: Cigarette smoking is among the few unequivocal risk factors for the development of pancreatic ductal adenocarcinoma (PDAC). Activating mutations in codon 12 of the K-ras protooncogene is a frequent and early molecular event in the pathogenesis of PDAC and a variety of nonmalignant ductal pancreatic lesions. The molecular epidemiologic relation between heavy cigarette smoking and mutational activation of K-ras in PDAC has been examined to a limited extent. The authors have examined the mutational status of K-ras in nonneoplastic pancreata in relation to cigarette smoking status. METHODS: Archival formalin fixed paraffin embedded specimens of nonneoplastic pancreata (n = 39) were obtained from the American Cancer Society and evaluated histopathologically. Specimens from age- and gender-matched individuals were stratified into three groups: 1) those who never smoked cigarettes (n = 16), 2) those who smoked 1-2 packs/day for more than 20 years (n = 10 cases), and 3) those who smoked more than 2 packs/day for 20 or more years (n = 13). Cases were preselected from 77 specimens based on the quality, suitability, and cellularity of the archival tissues for analyses. Furthermore, none of the patients died of primary PDAC or had evidence of pancreatic metastases from an extrapancreatic primary tumor. Tissue sections were microdissected and deparaffinized, and genomic DNA was purified by standard proteinase K-phenol-chloroform extraction techniques. Genomic DNA was analyzed for mutations in codon 12 of the K-ras protooncogene by two mutant-allele-enriched polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assays and by multiplex PCR-based ligase chain reaction (LCR) analyses. RESULTS: Analyses of multiple microdissected pancreata specimens from 39 cases revealed wild-type K-ras codon 12 sequences in both nonsmoking individuals and those who smoked 1-2 packs/day for 20 or more years. K-ras codon 12 mutations were confirmed by PCR-RFLP and PCR-LCR assays in 5 of 13 pancreata cases (39%) obtained from individuals who smoked more than 2 packs of cigarettes/day for 20 years or more (P < 0.005). The K-ras mutation spectra revealed two G-->T transversions, one G-->C transversion and two G-->A transitions. There was no clear relation between the incidence or spectra of mutations and pancreatic histopathology, as overtly normal pancreata as well as pancreata with squamous metaplasia, periductal fibrosis, and ductal atypia revealed reproducible K-ras alterations. Similarly, among those 34 cases in which a wild-type K-ras sequence was revealed by both approaches, a similar histopathologic profile was evident. CONCLUSIONS: Mutational activation of codon 12 of the K-ras protooncogene was confirmed reproducibly by mutant allele-enriched PCR-RFLP and multiplex PCR-LCR analyses in 39% (5 of 13) of archival nonneoplastic pancreata from age- and gender-matched individuals who smoked more than 2 packs of cigarettes/day for 20 or more years. The presence of a mutated or wild-type or K-ras was independent of the histopathologic profile of the 39 cases examined. The data provide further suggestive molecular epidemiologic evidence of an association between a major and unequivocal risk factor for PDAC (heavy cigarette smoking) and mutations in a molecular target (K-ras), the activation of which is an important and early event both in the pathogenesis of PDAC and in the development of a variety of nonneoplastic ductal pancreatic lesions.
Biologic model of bone transport distraction osteogenesis and vascular response.
We developed an experimental model in the rabbit of distraction osteogenesis through bone transport that closely corresponds to the clinical use of bone transport in humans. We also applied injection angiography to study the arterial response of a limb undergoing bone transport. This model includes a proximal osteotomy and bone transport to fill in a segmental tibial diaphyseal defect. Regenerate bone formed well in the gap that was created that trailed the transport segment, and slow healing at the docking site was observed, as seen in humans. The angiographic techniques clearly revealed, by radiography and anatomic dissection, the arterial response to bone transport. The results showed that the transport segment had an arterial supply after osteotomy and after transport. They also demonstrated an extensive increase in vessels in limbs that had undergone distraction osteogenesis, an observation made clinically in humans but not well demonstrated experimentally. Furthermore, angiography showed proximal stretching and distal kinking of the major artery of the leg. This model closely resembles distraction osteogenesis through bone transport in humans and definitively demonstrates that the transport segment can maintain blood supply and remain viable during the transport process. The results of this study provide a basis for further work on factors that enhance and interfere with successful bone transport in humans.
Promoting cancer screening among the first-degree relatives of breast and colorectal cancer patients: the design of two randomized trials.
BACKGROUND: In this paper two large nationwide trials are described, both of which will test a comparable telephone-based counseling intervention to promote cancer screening among the first-degree relatives (FDRs) of breast and colorectal cancer patients. The unit of randomization will be the family unit of eligible FDRs. Access to FDRs will be obtained from their relatives with cancer. Selected intervention and design issues are reviewed, including how both projects will respond to FDRs who exhibit significant levels of cancer-specific anxiety or distress and how potential high-risk cancer families will be accommodated. METHODS: Pursuant to the development of both studies, two feasibility surveys were conducted to determine whether patients would grant access to their FDRs and whether the FDRS identified by these patients would be receptive to the telephone intervention. RESULTS: Approximately 80% (106 of 132) of breast cancer patients agreed to provide access to their eligible FDRs when contacted on-site at participating hospitals and clinics. Of those subsequently selected for telephone follow-up (n = 95 or 90%), 80% (n = 76) were successfully contacted by telephone, and of these 97% (n = 74) provided the names and telephone numbers of their FDRs. Among colorectal cancer patients contacted on-site (n = 46), 96% (n = 44) agreed to provide access to their FDRs, and of those contacted by telephone (n = 33 or 75%), 91% (n = 30) provided the requested information about their FDRs. Once contacted, 95% of breast cancer FDRs (55 of 58) and 91% of colorectal cancer patients (51 of 56) endorsed the intervention strategy. CONCLUSIONS: It is argued that this intervention, if proven effective, could provide an exportable strategy for reaching large numbers of high-risk individuals to promote cancer screening.
Sips, Sops, and SPIs but not stn influence Salmonella enteropathogenesis.
The virulence factors influencing Salmonella-induced enteropathogenesis remain poorly characterised. The interactions of different serotypes of Salmonella with bovine ileal mucosa have been characterised in the ligated ileal loop model. In a quantitative intestinal invasion assay Salmonella dublin, S. choleraesuis, S. gallinarum, and S. abortusovis strains were all recovered from ileal mucosa, either with or without Peyer's patches in similar numbers. This observation suggests that the magnitude and route of intestinal invasion does not mediate Salmonella serotype host specificity. Despite being equally invasive there was a clear hierarchy in the enteropathogenicity of these serotypes. The magnitude of the enteropathogenic responses did not correlate to serotype host specificity. These observations implicate undefined serotype specific factors in influencing enteropathogenicity independently of intestinal invasion. Disruption of genes in Salmonella Pathogenicity Island (SPI) 1 of S. typhimurium and S. dublin blocked the secretion of Salmonella Invasion Proteins (Sips) and Salmonella Outer Proteins (Sops). These mutants were significantly less invasive and enteropathogenic then the wild type strain in ligated ileal loops. Disruption of sopB and sopD significantly reduced enteropathogenesis, but without influencing intestinal invasion. These two genes appear to act in concert. Surprisingly, disruption of stn, the Salmonella enterotoxin gene cloned on the basis of its homology to cholera toxin, did not influence enteropathogenesis. SopB was mapped to the 20 centisome of S. typhimurium and is flanked by 5 genes that are organised in a manner typical of a pathogenicity island, which we have termed SPI-5. Mutation of the other genes in SPI-5 also attenuated enteropathogenesis but not virulence for mice, suggesting SPI-5 is a key locus specifically influencing Salmonella enteropathogenesis.
Comparison of two methods for quantification of hepatitis B viral DNA.
BACKGROUND: Quantitation of serum hepatitis B virus (HBV) DNA has proven useful in assisting with patient management and treatment and several commercially available assays have been developed to quantify serum HBV-DNA levels. METHODS: The performance of the cross-linking assay and the branched-DNA signal amplification (bDNA) assay for the quantitative measurement of HBV-DNA was studied in 99 hepatitis B surface antigen-positive and viraemic patients. RESULTS: Of these samples, 82 (83%) were positive for HBV-DNA by both assays and four (4%) were below the cut-off for both assays. Of the remaining 13 samples, 10 contained measurable levels of HBV-DNA by the cross-linking assay alone and three other samples contained measurable levels of HBV-DNA by the bDNA assay alone. The sensitivity gain of the cross-linking assay relative to bDNA assay in this study population was 10/92 (11%). In addition, a linear regression analysis showed that the HBV-DNA levels obtained from both assays was significantly correlated (gamma=0.974, P< 0.0001). CONCLUSIONS: These findings suggest that the recently developed cross-linking assay is more sensitive than the bDNA assay for the quantitative determination of HBV-DNA.
Potassium-dependent changes in the conformation of the Kv2.1 potassium channel pore.
The voltage-gated K+ channel, Kv2.1, conducts Na+ in the absence of K+. External tetraethylammonium (TEAo) blocks K+ currents through Kv2.1 with an IC50 of 5 mM, but is completely without effect in the absence of K+. TEAo block can be titrated back upon addition of low [K+]. This suggested that the Kv2.1 pore undergoes a cation-dependent conformational rearrangement in the external vestibule. Individual mutation of lysine (Lys) 356 and 382 in the outer vestibule, to a glycine and a valine, respectively, increased TEAo potency for block of K+ currents by a half log unit. Mutation of Lys 356, which is located at the outer edge of the external vestibule, significantly restored TEAo block in the absence of K+ (IC50 = 21 mM). In contrast, mutation of Lys 382, which is located in the outer vestibule near the TEA binding site, resulted in very weak (extrapolated IC50 = approximately 265 mM) TEAo block in the absence of K+. These data suggest that the cation-dependent alteration in pore conformation that resulted in loss of TEA potency extended to the outer edge of the external vestibule, and primarily involved a repositioning of Lys 356 or a nearby amino acid in the conduction pathway. Block by internal TEA also completely disappeared in the absence of K+, and could be titrated back with low [K+]. Both internal and external TEA potencies were increased by the same low [K+] (30-100 microM) that blocked Na+ currents through the channel. In addition, experiments that combined block by internal and external TEA indicated that the site of K+ action was between the internal and external TEA binding sites. These data indicate that a K+-dependent conformational change also occurs internal to the selectivity filter, and that both internal and external conformational rearrangements resulted from differences in K+ occupancy of the selectivity filter. Kv2.1 inactivation rate was K+ dependent and correlated with TEAo potency; as [K+] was raised, TEAo became more potent and inactivation became faster. Both TEAo potency and inactivation rate saturated at the same [K+]. These results suggest that the rate of slow inactivation in Kv2.1 was influenced by the conformational rearrangements, either internal to the selectivity filter or near the outer edge of the external vestibule, that were associated with differences in TEA potency.
Albumin in the prevention of severe OHSS.
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Arginine vasopressin: old drug, new uses.
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Administrative support of programs for the prevention of poor perinatal outcomes.
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A four-shock Bayesian up-down estimator of the 80% effective defibrillation dose.
INTRODUCTION: New defibrillation techniques are often compared to standard approaches using the defibrillation threshold. However, inference from thresholding data necessitates extrapolation from reactions to relatively ineffective shocks, an error prone procedure requiring large sample sizes for hypothesis testing and large safety margins for defibrillator implantation. In contrast, this article presents a clinically validated statistical model of a minimum error, four-shock defibrillation testing protocol for estimating the 80% effective defibrillation strength for a given patient (ED80). METHODS AND RESULTS: A Bayesian statistical model was constructed assuming that the defibrillation dose-response curve is sigmoidal, and the ED80 is between 150 and 750 V. The model was used to design a minimum predicted error testing protocol and estimates. To prospectively validate the testing protocol and estimates, 170 patients received voltage-programmed biphasic testing. Four fibrillation episodes were induced and terminated in each patient according to the Bayesian up-down protocol. In addition, a validation attempt was made at the estimated ED80 rounded up to the nearest 50 V. In order to estimate the safety margin, in 136 patients, a defibrillation attempt was made at the rounded ED80 + 100 V. Of the 170 attempts at the rounded ED80, 143 (84%) attempts terminated fibrillation. Of the 136 attempts at the rounded ED80 + 100 V, 133 (98%) were effective. CONCLUSIONS: The four-shock Bayesian up-down protocol is the first clinical protocol to accurately predict an ED80 voltage. A 100 V increment above the ED80 provides an adequate safety margin. This simple and accurate method for estimating a highly effective defibrillation dose may be a valuable tool for population-based clinical hypothesis testing, as well as defibrillator implantation.
Some limits to evidence-based medicine: a case study from elective orthopaedics.
There has been growing interest in recent years in the application of the principles of evidence-based medicine (EBM), although implementation is complex. Scientific, organisational, and behavioural factors all combine to shape clinical behaviour change. Case study based qualitative data are presented which illuminate such processes within one clinical setting (elective orthopaedics), drawn from a larger study. It is suggested that (1) there are alternative models of what constitutes "evidence" in use; (2) scientific knowledge is in part socially constructed; and (3) clinical professionals retain a monopoly of technical knowledge. The implication is that there may be severe obstacles to the rapid or broad implementation of EBM.
The development of the Project NetWork administrative records database for policy evaluation.
This article describes the development of SSA's administrative records database for the Project NetWork return-to-work experiment targeting persons with disabilities. The article is part of a series of papers on the evaluation of the Project NetWork demonstration. In addition to 8,248 Project NetWork participants randomly assigned to receive case management services and a control group, the simulation identified 138,613 eligible nonparticipants in the demonstration areas. The output data files contain detailed monthly information on Supplemental Security Income (SSI) and Disability Insurance (DI) benefits, annual earnings, and a set of demographic and diagnostic variables. The data allow for the measurement of net outcomes and the analysis of factors affecting participation. The results suggest that it is feasible to simulate complex eligibility rules using administrative records, and create a clean and edited data file for a comprehensive and credible evaluation. The study shows that it is feasible to use administrative records data for selecting control or comparison groups in future demonstration evaluations.