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Biomedical subjects

P Miller

Publications and source records attributed to P Miller.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of BMD precision for Prodigy and Delphi spine and femur scans.

INTRODUCTION: Precision error in bone mineral density (BMD) measurement can be affected by patient positioning, variations in scan analysis, automation of software, and both short- and long-term fluctuations of the densitometry equipment. Minimization and characterization of these errors is essential for reliable assessment of BMD change over time. METHODS: We compared the short-term precision error of two dual-energy X-ray absorptiometry (DXA) devices: the Lunar Prodigy (GE Healthcare) and the Delphi (Hologic). Both are fan-beam DXA devices predominantly used to measure BMD of the spine and proximal femur. In this study, 87 women (mean age 61.6+/-8.9 years) were measured in duplicate, with repositioning, on both systems, at one of three clinical centers. The technologists were International Society for Clinical Densitometry (ISCD) certified and followed manufacturer-recommended procedures. All scans were acquired using 30-s scan modes. Precision error was calculated as the root-mean-square standard deviation (RMS-SD) and coefficient of variation (RMS-%CV) for the repeated measurements. Right and left femora were evaluated individually and as a combined dual femur precision. Precision error of Prodigy and Delphi measurements at each measurement region was compared using an F test to determine significance of any observed differences. RESULTS: While precision errors for both systems were low, Prodigy precision errors were significantly lower than Delphi at L1-L4 spine (1.0% vs 1.2%), total femur (0.9% vs 1.3%), femoral neck (1.5% vs 1.9%), and dual total femur (0.6% vs 0.9%). Dual femur modes decreased precision errors by approximately 25% compared with single femur results. CONCLUSIONS: This study suggests that short-term BMD precision errors are skeletal-site and manufacturer specific. In clinical practice, precision should be considered when determining: (a) the minimum time interval between baseline and follow-up scans and (b) whether a statistically significant change in the patient's BMD has occurred.

Absorptiometry, Photon↗
PubMed2006

Gene profiling study of G3139- and Bcl-2-targeting siRNAs identifies a unique G3139 molecular signature.

G3139 is a phosphorothioate oligodeoxyribonucleotide that is targeted to the initiation codon region of the Bcl-2 mRNA, which downregulates Bcl-2 protein and mRNA expression via an antisense mechanism. In previous work, we have demonstrated that the phenotype observed in several prostate and melanoma cell lines after treatment with G3139 appears to be Bcl-2 independent. In contrast, downregulation of Bcl-2 expression by a small interfering RNA (siRNA) produced little or no phenotype change. In the present work, we performed an Agilent oligonucleotide microarray assay on mRNA isolated from PC3 prostate cancer cells that were treated with two different oligonucleotide gene-silencing reagents. G3139 and a Bcl-2-targeting siRNA both downregulate Bcl-2 expression, but via different mechanisms. A side-by-side comparative analysis showed that the expression profile generated by these molecules differs substantially. The study revealed upregulation of the expression of stress-inducible genes in PC3 cells at 1 and 3 days after a 5-h transfection with G3139 complexed with Lipofectamine 2000. In contrast, only a very diminished stress response was seen 1 and 3 days after a 24-h transfection of siRNA/Lipofectamine 2000 complexes. These results highlight the profound differences in off-target effects in cells treated with the phosphorothioate oligonucleotide G3139 and with an siRNA targeted to the same gene, and provide further evidence that the mechanism of action of G3139 is not related to Bcl-2 silencing.

Cell Line, Tumor↗
PubMed2005

Oral ibandronate significantly reduces the risk of vertebral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis.

In a recent multinational, double-blind, placebo-controlled, randomized, phase III study (BONE: IBandronate Osteoporosis Vertebral Fracture trial in North America and Europe), oral daily ibandronate (2.5 mg) significantly and substantially reduced the risk of new vertebral fractures by 62% relative to placebo after 3 years of treatment. The objective of the present study was to retrospectively analyze data from the BONE study to examine the efficacy of oral ibandronate in preventing incident vertebral fractures of greater severity. This analysis was conducted on the placebo and oral daily ibandronate (2.5 mg) arms of the BONE study, comprising a total of 1964 women (aged 55-80 years, >or=5 years postmenopause) with osteoporosis. Vertebral fractures on annual lateral radiographs of the spine were graded as mild, moderate, or severe, using criteria derived from an established semiquantitative technique. The findings demonstrate that in addition to being effective in significantly reducing the risk of new vertebral fractures of all severities, oral daily ibandronate has a pronounced effect on the more severe, most clinically relevant, vertebral fractures: a significant and sustained reduction of 59% in the relative risk of combined new moderate and severe vertebral fractures was observed at years 1 (P = 0.0164), 2 (P = 0.0004), and 3 (P < 0.0001).

Administration, Oral↗
PubMed2005

Structural requirements for O2 sensing by the human tandem-P domain channel, hTREK1.

TREK1 is a member of the tandem-P domain K+ channel family which is expressed almost exclusively in the nervous system. It is modulated by a number of important factors including arachidonic acid and cell swelling. Since both factors are associated with brain ischemia, it has been suggested that activation of TREK1 may confer neuroprotection. However, it has been reported that the stably expressed human homologue of TREK1 is inhibited by hypoxia, calling into question its neuroprotective role in ischemia. Here, using transient transfection of HEK 293 cells with several hTREK1 mutations and whole-cell patch-clamp, we show that: hypoxic inhibition: (a) requires the C-terminal domain of the channel; (b) does not involve redox modulation of the C-terminal domain cysteine residues C365 and C399; and (c) is critically dependent on the glutamate residue at position 306. These data suggest strongly that neuroprotection is unlikely to be provided by this channel in low O2 environments and continue to cast a shadow of doubt over the precise role that TREK may have during hypoxic episodes.

Cell Line↗
PubMed2005

Cost effectiveness of a two-year home exercise program for the treatment of knee pain.

OBJECTIVE: To assess the cost effectiveness of a 2-year home exercise program for the treatment of knee pain. METHODS: A total of 759 adults aged > or = 45 years were randomized to receive exercise therapy, monthly telephone contact, exercise therapy and telephone contact, or no intervention. Efficacy was measured using self-reported knee pain at 2 years. Costs to both the National Health Service and to the patient were included. RESULTS: Exercise therapy was associated with higher costs and better effectiveness. Direct costs for the interventions were pound 112 for the exercise program and pound 61 for the monthly telephone support. Participants allocated to receive exercise therapy were significantly more likely to incur higher medical costs than those in the no-exercise groups (mean difference pound 225; 95% confidence interval pound 218, pound 232; P < 0.001). CONCLUSION: Exercise therapy is associated with improvements in knee pain, but the cost of delivering the exercise program is unlikely to be offset by any reduction in medical resource use.

Cost-Benefit Analysis↗
PubMed2005

Staged surgical management of hypoplastic left heart syndrome: a single institution 12 year experience.

OBJECTIVE: To describe a 12 year experience with staged surgical management of the hypoplastic left heart syndrome (HLHS) and to identify the factors that influenced outcome. METHODS: Between December 1992 and June 2004, 333 patients with HLHS underwent a Norwood procedure (median age 4 days, range 0-217 days). Subsequently 203 patients underwent a bidirectional Glenn procedure (stage II) and 81 patients underwent a modified Fontan procedure (stage III). Follow up was complete (median interval 3.7 years, range 32 days to 11.3 years). RESULTS: Early mortality after the Norwood procedure was 29% (n = 95); this decreased from 46% (first year) to 16% (last year; p < 0.05). Between stages, 49 patients died, 27 before stage II and 22 between stages II and III. There were one early and three late deaths after stage III. Actuarial survival (SEM) was 58% (3%) at one year and 50% (3%) at five and 10 years. On multivariable analysis, five factors influenced early mortality after the Norwood procedure (p < 0.05). Pulmonary blood flow supplied by a right ventricle to pulmonary artery (RV-PA) conduit, arch reconstruction with pulmonary homograft patch, and increased operative weight improved early mortality. Increased periods of cardiopulmonary bypass and deep hypothermic circulatory arrest increased early mortality. Similar factors also influenced actuarial survival after the Norwood procedure. CONCLUSION: This study identified an improvement in outcome after staged surgical management of HLHS, which was primarily attributable to changes in surgical technique. The RV-PA conduit, in particular, was associated with a notable and independent improvement in early and actuarial survival.

Cardiopulmonary Bypass↗
PubMed2005

Economic analysis of an early discharge rehabilitation service for older people.

OBJECTIVE: to measure the cost-effectiveness of an early discharge and rehabilitation service (EDRS) in Nottingham, UK. DESIGN: data were collected during a randomised controlled trial. METHODS: cost and cost-effectiveness analyses were conducted from the perspective of service providers (health and social services) over a period of 12 months. Resource variables included were the EDRS intervention, the initial acute hospital admission (from randomisation), readmission to hospital, hospital outpatient visits, stays in nursing and residential homes, general practitioner contact, community health services and social services. The effectiveness measure was the EuroQol EQ-5D score, from which quality-adjusted life years (QALY) were calculated. Cost-effectiveness was calculated as cost per QALY gained. RESULTS: at 12 months the mean untransformed total cost for the EDRS was 8,361 pound sterling compared to 10,088 pound sterling for usual care, a saving of 1,727 pound sterling (P = 0.05). Cost-effectiveness acceptability curves showed a high probability that the EDRS was cost effective across a range of monetary values for a QALY. CONCLUSIONS: the Nottingham EDRS was likely to be more cost effective than usual care.

Aged↗
PubMed2005

Upper gastrointestinal tolerability of once weekly alendronate 70 mg with concomitant non-steroidal anti-inflammatory drug use.

BACKGROUND: Both oral bisphosphonates and non-steroidal anti-inflammatory drugs have the potential to irritate the upper gastrointestinal mucosa, and are frequently used by the same patient population. AIM: To determine the rate of upper gastrointestinal adverse events with once weekly alendronate 70 mg and concomitant non-steroidal anti-inflammatory drug use. METHODS: A post hoc analysis was performed on 222 patients who received both medications concomitantly during a 3-month placebo-controlled study. A total of 450 (224 alendronate; 226 placebo) postmenopausal women and men with osteoporosis were randomized. Concomitant non-steroidal anti-inflammatory drug users were defined as patients who received > or =7 continuous days of any dose of a dual cyclo-oxygenase-1 and cyclo-oxygenase-2 inhibiting non-steroidal anti-inflammatory drug, a selective cyclo-oxygenase-2 inhibitor, or aspirin. A survival analysis was performed, and significance assessed. Logistic regression was used to assess consistency of treatment effect on rate of upper gastrointestinal adverse events across non-steroidal anti-inflammatory drug subgroups. RESULTS: Similar percentages of alendronate (52.7%) and placebo (46.0%) patients used non-steroidal anti-inflammatory drugs regularly. Among concomitant non-steroidal anti-inflammatory drug users, 11 alendronate and 11 placebo patients experienced upper gastrointestinal adverse events (9.3% and 10.8%, respectively, P = 0.744). Logistic regression revealed no significant interaction (P = 0.722) between alendronate and concomitant non-steroidal anti-inflammatory drug use. CONCLUSION: Based on this subgroup analysis, once weekly alendronate 70 mg used concomitantly with non-steroidal anti-inflammatory drugs, did not increase upper gastrointestinal adverse events relative to placebo over 3-months.

Aged↗
PubMed2005

Towards consensus in the long-term management of relapse prevention in schizophrenia.

APPROACH TO DEVELOPING GUIDANCE: When developing guidance for the long-term management of schizophrenia, one approach is to adopt a proactive strategy that sets out clear treatment goals and strategies. This should involve a broad view being taken, embracing overall mental and physical well-being rather than simply the absence of illness. Although relapse prevention is an important goal of any long-term management strategy, there are other aspects that need to be considered, such as reintegration into society, regaining independence and quality of life. CURRENT TREATMENT: To help achieve these goals, a range of interventions can be incorporated into long-term management strategies for schizophrenia, including pharmacological interventions, psychosocial therapies and alliance-building initiatives. The current UK National Institute for Clinical Excellence guidelines already recommend that continuous therapy should be practised using an atypical (second-generation) antipsychotic drug, whenever possible, in preference to older typical drugs. The launch of the first long-acting atypical antipsychotic is an interesting new advance that may benefit many patients with schizophrenia. Psychosocial interventions, particularly family-based therapies, as well as cognitive behavioural and compliance therapies, when used alongside antipsychotics, have been shown to reduce relapse rates dramatically and to assist in social reintegration. In addition, forging collaborative alliances with patients and their carers can help to demystify schizophrenia and empower patients to take responsibility for their illness. CONSENSUS STATEMENT: This article outlines a consensus reached by a panel of leading UK healthcare professionals working with schizophrenia brought together to discuss long-term management strategies.

Antipsychotic Agents↗
PubMed2003

Acute hypoxia occludes hTREK-1 modulation: re-evaluation of the potential role of tandem P domain K+ channels in central neuroprotection.

The human tandem P domain K+ channel hTREK-1 (KCNK2) is distributed widely through the CNS. Here, whole-cell patch clamp recordings were employed to investigate the effects of hypoxia on hTREK-1 channels stably expressed in human embryonic kidney cells. Acute hypoxia caused a rapid and reversible inhibition of whole-cell K+ current amplitudes; this was PO2 dependent with a maximal inhibition achieved at 60 mmHg and below. In accordance with previous studies, hTREK-1 current amplitudes were enhanced by arachidonic acid. This effect was concentration dependent, with maximal enhancement observed at a concentration of 10 microM. Membrane deformation by the crenator trinitrophenol (to mimic cell swelling) or the cup former chlorpromazine (to mimic cell shrinkage) caused robust activation and inhibition of currents, respectively. However, current augmentation by either arachidonic acid or trinitrophenol was completely prevented during hypoxia; conversely, hypoxia blunted the inhibitory action of chlorpromazine. The abilities of arachidonic acid to augment currents and of hypoxia to completely abrogate this effect were also observed in cell-attached patches. Our data indicate that hypoxia interacts with hTREK-1, and occludes its modulation by arachidonic acid and membrane deformation. These findings also suggest that the potential neuroprotective role of TREK channels, which has recently been proposed, requires reconsideration since hTREK-1 activation is unlikely when ambient PO2 is below 60 mmHg - a situation which normally pertains in the CNS even during systemic normoxia.

Arachidonic Acid↗
PubMed2003

Summary of the 2001-02 Pennsylvania H7N2 low pathogenicity avian influenza outbreak in meat type chickens.

H7N2 low-pathogenicity (LP) avian influenza (AI) virus was isolated from chickens submitted to the Pennsylvania Animal Diagnostic Laboratory System on December 4 and 5, 2001. The cases were from two broiler breeder flocks in central Pennsylvania that had clinical signs of an acute, rapidly spreading respiratory disease. Seroconversion to AI virus was detected on follow-up sampling. Subsequently, H7N2 LPAI virus was isolated in five different broiler flock cases submitted between December 14, 2001, and January 3, 2002. Clinical signs and lesions in broilers, when present, were compatible with multicausal respiratory disease. With the exception of one broiler flock that was processed, birds from all of the virus positive flocks were euthanatized in-house within 11 days of the original case submission date. Increased surveillance of poultry flocks within 10-mile radius zones centered at the foci of the positive farms continued until March 1, 2002. No additional cases were detected.

Animals↗
PubMed2003

XX male: a rare cause of short stature, infertility, gynaecomastia and carcinoma of the breast.

We present a case of an XX male with carcinoma of the breast and primary infertility. He was admitted to hospital with recurrent chest pains, but a history of surgery for breast carcinoma, gynaecomastia and the finding of bilaterally atrophied testes, coupled with the fact that he had never fathered children, necessitated further investigations. Chromosomal analysis showed a 46, XX male genotype with a normal X chromosome and an abnormal X chromosome formed by translocation between the short arm of one X chromosome and the Y chromosome. By using fluorescence in situ hybridisation, the patient proved to be SRY positive, the sex-determining region of the Y chromosome. In this rare genetic abnormality, males retain normal phenotype but they are generally of short stature, have gynaecomastia, and may have genital anomalies. They are infertile and at increased risk of developing carcinoma of the breast. This seems to be the first documented case of carcinoma of the breast in an SRY positive XX male. This particular case illustrates the need for all cases of male breast cancer to undergo full endocrinological assessment, especially in the presence of genital anomaly or infertility.

Aged↗
PubMed2002

Suppression of the "Quasiclassical" proximity gap in correlated-metal--superconductor structures.

We study the energy and spatial dependence of the local density of states in a superconductor--correlated-metal--superconductor Josephson junction, where the correlated metal is a non-Fermi liquid (described by the Falicov-Kimball model). Many-body correlations are treated with dynamical mean-field theory, extended to inhomogeneous systems. While quasiclassical theories predict a minigap in the spectrum of a disordered Fermi liquid which is proximity-coupled within a mesoscopic junction, we find that increasing electron correlations destroy any minigap that might be opened in the absence of many-body correlations.

Journal Article↗
PubMed2002

Sustained attention in young people at high risk for schizophrenia.

BACKGROUND: Sustained attention has been found to be impaired in individuals suffering from schizophrenia and their close relatives. This has led to the hypothesis that impaired sustained attention is an indicator of vulnerability to schizophrenia. METHODS: The Edinburgh High Risk Study used the Continuous Performance Test-Identical Pairs version (CPT-IP) to assess sustained attention in 127 high risk participants, 30 controls and 15 first-episode schizophrenic patients. A second assessment was completed by 59 high risk and 18 control participants 18 months to 2 years after the first. RESULTS: No differences in attentional capacity were found between the high risk and control groups and there was no association between genetic liability to schizophrenia and poor performance on the CPT-IP. Additionally, no association between occurrence of psychotic symptoms in the high risk group and impaired attentional capacity was found. CONCLUSIONS: The results suggest that deficits in sustained attention are not indicative of a genetic vulnerability to schizophrenia, and are not associated with the occurrence of psychotic symptoms.

Adult↗
PubMed2002

Demonstrating the economic value of occupational health services.

Many large companies operate some form of occupational health service (OHS). More companies now require specific evaluative information to justify the continued provision of an in-house OHS. This is in the face of increased pressure to control costs, combined with an awareness that the service itself can induce activity (supplier-induced demand) and could be substituted with health care provided or even funded outside the company. The lack of routinely collected data and the conceptual difficulty in defining and measuring the outcomes of an OHS provide challenges for economic evaluation. A purely human capital approach, where people are valued by their wage rates, is likely to be insufficient, since OHSs have multiple objectives. These objectives include fulfilling statutory obligations, contributing to the creation of a culture of partnership, reduction of potential costs to the company (sickness benefit, production loss, poor performance, litigation, insurance) and providing a suitable environment for the cost-effective reduction of the social and health service costs of illness at work. Evidence is needed to quantify some of these arguments and demonstrate to decision makers the value generated by OHSs. The aim of this paper is to consider the practicality of different economic evaluation methodologies, specifically cost models, contingent valuation (willingness-to-pay) and development of OHS-specific outcome measures. In considering different approaches, we present the results of our research in two UK companies.

Cost-Benefit Analysis↗