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Biomedical subjects

D O'Connor

Publications and source records attributed to D O'Connor.

At least 19 recordsLinked to original sources
PubMed2006

Screening for prostate cancer.

BACKGROUND: Any form of screening aims to reduce mortality and increase a person's quality of life. Screening for prostate cancer has generated considerable debate within the medical community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. Much of this debate is due to the limited availability of high quality research and the influence of false-positive or false-negative results generated by use of the diagnostic techniques such as the digital rectal examination (DRE) and prostate specific antigen (PSA) blood test. OBJECTIVES: To determine whether screening for prostate cancer reduces prostate cancer mortality and has an impact on quality of life. SEARCH STRATEGY: Electronic databases (PROSTATE register, CENTRAL the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT and the NHS EED) were searched electronically in addition to hand searching of specific journals and bibliographies in an effort to identify both published and unpublished trials. SELECTION CRITERIA: All randomised controlled trials of screening versus no screening or routine care for prostate cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The search identified 99 potentially relevant articles that were selected for full text review. From these 99 citations, two randomised controlled trials were identified as meeting the review's inclusion criteria. Data from the trials were independently extracted by two authors. MAIN RESULTS: Two randomised controlled trials with a total of 55,512 participants were included; however, both trials had methodological weaknesses. Re-analysis using intention-to-screen and meta-analysis of results from the two randomised controlled trials indicated no statistically significant difference in prostate cancer mortality between men randomised for prostate cancer screening and controls (RR 1.01, 95% CI: 0.80-1.29). Neither study assessed the effect of prostate cancer screening on quality of life, all-cause mortality or cost effectiveness. AUTHORS' CONCLUSIONS: Given that only two randomised controlled trials were included, and the high risk of bias of both trials, there is insufficient evidence to either support or refute the routine use of mass, selective or opportunistic screening compared to no screening for reducing prostate cancer mortality. Currently, no robust evidence from randomised controlled trials is available regarding the impact of screening on quality of life, harms of screening, or its economic value. Results from two ongoing large scale multicentre randomised controlled trials that will be available in the next several years are required to make evidence-based decisions regarding prostate cancer screening.

Humans↗
PubMed2006

Aldehyde oxidase and its contribution to the metabolism of a structurally novel, functionally selective GABAA alpha5-subtype inverse agonist.

(3-Tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d] [1,2,4]triazine was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5-containing receptors, which enhances performance in animal models of cognition. The routes of metabolism of this compound in rat, dog, rhesus monkey and human in vitro systems, and in vivo in rat, dog and rhesus monkey have been characterized. The current study demonstrates that both a cytosolic oxidative reaction and cytochrome P450 play important roles in the metabolism of the compound. Chemical inhibition studies showed the oxidation in human cytosol to be catalysed predominantly by aldehyde oxidase rather than the related enzyme, xanthine oxidase. The aldehyde oxidase-mediated metabolites were present in vitro and in vivo in both rat and rhesus monkey, and also in vitro in man. They were absent both in vitro and in vivo in dog.

Aldehyde Oxidase↗
PubMed2005

A clinical audit of the quality of care of hypertension in general practice.

Clinical audits monitor the use of particular interventions, or the care received by patients, against agreed standards. Any departures from "best practice" can then be examined, and causes can be determined and acted upon. The Ministry of Health (MOH), Jamaica, has recently published standards of care for hypertension. The medical records of a convenience sample of 125 hypertensive patients being managed by five current family medicine residents in their respective primary care practices were audited Initial results showed limited adherence to the MOH recommended hypertension management guidelines. The same practices were re-audited after an interval of six months, during which time the physicians were sensitized to the results of the preliminary audit. Marked improvements were noted in the second audit. Assessment for co-risk factors for hypertension-related diseases improved: nutritional advice (33% to 74%), smoking and alcohol intake history (40% to 65%) and history taking of physical activity (30% to 47%). Assessment for target organ damage also improved: fundoscopy done (11% to 54%), foot examination done (30% to 58%) and yearly electrolytes done (28% to 62%). There are clear gaps between current practice and standards that exist internationally and locally for management of hypertension. The MOH needs to disseminate and educate general practitioners about the standards of care guidelines.

Adult↗
PubMed2005

A survey of the causes of sudden cardiac death in the under 35-year-age group.

CRY (Cardiac Risk in the Young) is a registered Irish charity established by parents who are bereaved as a result of sudden cardiac death. The aim of this study is to establish the incidence and causes of sudden cardiac death in Dublin city in the 10-year period from 1st January 1993 to 31st December 2002. All sudden cardiac deaths in the under 35-year age group which were reported to the city coroner in the study period were examined. Details regarding age, sex, previous symptoms, investigations, circumstances of death and main pathological finding were recorded in each case. A total of 72 cases of sudden cardiac death in the under-35 year age group were reported. 52 were men. The median age was 26.5 years (range 12-34 years). The cause of death in 20 cases was reported as atherosclerotic Coronary Artery Disease. The second commonest cause of death (24% cases) was Hypertrophic Cardiomyopathy. Hypertrophic Cardiomyopathy was the commonest cause of death under the age of 25 years. Overall atherosclerotic coronary artery disease was the commonest cause of death in this group. The importance of Hypertrophic Cardiomyopathy is highlighted by the fact it was the commonest cause of death in the under 25-year age group. Screening those at high risk of sudden cardiac death especially the relatives of those affected by Hypertrophic Cardiomyopathy need to be discussed and implemented.

Adolescent↗
PubMed2003

Non-surgical treatment (other than steroid injection) for carpal tunnel syndrome.

BACKGROUND: Non-surgical treatment for carpal tunnel syndrome is frequently offered to those with mild to moderate symptoms. The effectiveness and duration of benefit from non-surgical treatment for carpal tunnel syndrome remain unknown. OBJECTIVES: To evaluate the effectiveness of non-surgical treatment (other than steroid injection) for carpal tunnel syndrome versus a placebo or other non-surgical, control interventions in improving clinical outcome. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised register (searched March 2002), MEDLINE (searched January 1966 to February 7 2001), EMBASE (searched January 1980 to March 2002), CINAHL (searched January 1983 to December 2001), AMED (searched 1984 to January 2002), Current Contents (January 1993 to March 2002), PEDro and reference lists of articles. SELECTION CRITERIA: Randomised or quasi-randomised studies in any language of participants with the diagnosis of carpal tunnel syndrome who had not previously undergone surgical release. We considered all non-surgical treatments apart from local steroid injection. The primary outcome measure was improvement in clinical symptoms after at least three months following the end of treatment. DATA COLLECTION AND ANALYSIS: Three reviewers independently selected the trials to be included. Two reviewers independently extracted data. Studies were rated for their overall quality. Relative risks and weighted mean differences with 95% confidence intervals were calculated for the primary and secondary outcomes in each trial. Results of clinically and statistically homogeneous trials were pooled to provide estimates of the efficacy of non-surgical treatments. MAIN RESULTS: Twenty-one trials involving 884 people were included. A hand brace significantly improved symptoms after four weeks (weighted mean difference (WMD) -1.07; 95% confidence interval (CI) -1.29 to -0.85) and function (WMD -0.55; 95% CI -0.82 to -0.28). In an analysis of pooled data from two trials (63 participants) ultrasound treatment for two weeks was not significantly beneficial. However one trial showed significant symptom improvement after seven weeks of ultrasound (WMD -0.99; 95% CI -1.77 to - 0.21) which was maintained at six months (WMD -1.86; 95% CI -2.67 to -1.05). Four trials involving 193 people examined various oral medications (steroids, diuretics, nonsteroidal anti-inflammatory drugs) versus placebo. Compared to placebo, pooled data for two-week oral steroid treatment demonstrated a significant improvement in symptoms (WMD -7.23; 95% CI -10.31 to -4.14). One trial also showed improvement after four weeks (WMD -10.8; 95% CI -15.26 to -6.34). Compared to placebo, diuretics or nonsteroidal anti-inflammatory drugs did not demonstrate significant benefit. In two trials involving 50 people, vitamin B6 did not significantly improve overall symptoms. In one trial involving 51 people yoga significantly reduced pain after eight weeks (WMD -1.40; 95% CI -2.73 to -0.07) compared with wrist splinting. In one trial involving 21 people carpal bone mobilisation significantly improved symptoms after three weeks (WMD -1.43; 95% CI -2.19 to -0.67) compared to no treatment. In one trial involving 50 people with diabetes, steroid and insulin injections significantly improved symptoms over eight weeks compared with steroid and placebo injections. Two trials involving 105 people compared ergonomic keyboards versus control and demonstrated equivocal results for pain and function. Trials of magnet therapy, laser acupuncture, exercise or chiropractic care did not demonstrate symptom benefit when compared to placebo or control. REVIEWER'S CONCLUSIONS: Current evidence shows significant short-term benefit from oral steroids, splinting, ultrasound, yoga and carpal bone mobilisation. Other non-surgical treatments do not produce significant benefit. More trials are needed to compare treatments and ascertain the duration of benefit.

Administration, Oral↗
PubMed2003

Lizards in 'nuclear families': a novel reptilian social system in Egernia saxatilis (Scincidae).

Recent research has revealed unsuspected complexity in social organization among squamate reptiles. In particular, large Australian scincid lizards of the genus Egernia have been reported to occur in large aggregations of closely related individuals. However, the 'nuclear family' structure found in many other 'social' organisms (especially birds) has not been reported from reptiles. Our field studies on black rock skinks (Egernia saxatilis) in southeastern Australia document exactly this pattern. We quantified group composition using behavioural observations at regular intervals over three field seasons, and took tissue samples for parentage analysis. On the focal rock outcrop 72% of lizards were typically found as part of a stable social grouping, with individuals physically associated with other group members in a third of observations. Eighty-five per cent of juveniles lived in social groups, 65% in family groups with at least one of their parents (including 39% with both parents as revealed by parentage analysis of five microsatellite loci). Broader sampling in surrounding areas revealed similar patterns of group size, composition and relatedness. Overall, of the groups that contained more than one adult, 83% contained a single adult pair. Long-term monogamy and group stability were evident from our genetic data, with up to three annual cohorts of full-sib offspring living with their biological parents. Our data expand the range of social systems known for reptiles, and reveal strong convergence towards 'nuclear family' systems in distantly related vertebrates.

Animals↗
PubMed2003

Minimally displaced Colles' fractures: a prospective randomized trial of treatment with a wrist splint or a plaster cast.

Sixty-six adult patients with minimally displaced distal radial fractures were randomly assigned to treatment with either a plaster cast or a lightweight removable wrist splint. Outcome assessment was by clinical and radiological evaluation and an independent physiotherapy assessment. There were significant differences between the treatments for cast satisfaction, cast problems and the functional assessment score at 6 weeks, with the removable splint scoring better in all cases.

Activities of Daily Living↗
PubMed2003

Aftercare attendance and post-treatment functioning of severely substance dependent residential treatment clients.

The present study evaluated the impact of a structured aftercare programme following residential treatment for severe alcohol and/or heroin dependent clients. Over 17 months, 77 participants were recruited to the study and allocated randomly to either a structured aftercare (SA) programme or to unstructured aftercare (UA) of crisis counselling on request. Independent clinicians interviewed participants and collaterals, at 4-month (median) intervals, for 12 months following residential treatment. SA compared to UA was associated with a fourfold increase in aftercare attendance and one-third the rate of uncontrolled principal substance use at follow-up. Participants who attended either type of aftercare relapsed a median of 134 days later than those who attended no aftercare. Overall, 23% of monitored participants remained abstinent throughout, 21% maintained controlled substance use and 56% relapsed, within a median of 36 days following residential treatment. The only significant predictor of days to relapse, controlling for age, was pretreatment use of additional substances. Participants with pretreatment additional substance use relapsed a median of 192 days earlier than those who had used no other substances. The degree of agreement between participant self-reports and collateral reports was fair-to-moderate and moderate among collaterals. Intention-to-treat analyses revealed significant and clinically meaningful reductions in substance use in this sample of severely dependent residential treatment clients. The generalizability of these results is limited because of significant differences in age and presenting substance between the study sample and other clients admitted to the service during the study. This latter group of younger, male, heroin-dependent clients with polydrug use who refuse opioid pharmacotherapy, are more likely to drop out of treatment or relapse early following treatment and continue to present a challenge to treatment services.

Adult↗
PubMed2003

P-Glycoprotein efflux reduces the brain concentration of the substance P (NK1 receptor) antagonists SR140333 and GR205171: a comparative study using mdr1a-/- and mdr1a+/+ mice.

Investigation of the antidepressant-like actions of substance P (NK1 receptor) antagonists has been hindered by the few available compounds that bind with high affinity to the rat and mouse NK1 receptor, as these are the most commonly used preclinical species. The best available compounds for such studies are SR140333 and GR205171. However, SR140333 does not penetrate the central nervous system (CNS) after systemic administration, and GR205171 is active only at high doses, where unspecific pharmacological effects occur, so that changes in behaviour cannot be attributed to selective NK1 receptor blockade. These compounds may be substrates for P-glycoprotein (P-gp) and hence are actively excluded from the brain. The present studies used mdr1a-/- mice, a spontaneously occurring mutant that is deficient in P-gp, to examine the CNS penetration of SR140333 and GR205171. Following systemic administration of SR140333 and GR205171 (0.01-10 mg/kg i.v.), considerably higher drug concentrations were achieved in the brains of mdr1a-/- than in mdr1a+/+ mice, and this corresponded with a greater ability to inhibit NK1-agonist-induced behaviours in the mdr1a-/- mutants. Moreover, an NK1-receptor-specific inhibition of aggressive behaviour by GR205171 (10 mg/kg) could be demonstrated in mdr1a-/-, but not mdr1a+/+, mice. These findings suggest that P-gp deficient mice may have useful applications in behavioural pharmacology studies, especially when highly brain-penetrant compounds are not yet available.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Functional outcome study of patients after surgical decompression for lumbar spinal stenosis: effects of concomitant pathology.

The aim of this study is to identify factors associated with poor outcome in the medium (2-5 years) postoperative period following lumbar stenosis surgery. Fifty-six consecutive patients who underwent decompression for lumbar spinal stenosis were retrospectively analyzed using chart and radiologic review, questionnaire using American Association of Orthopaedic Surgeon's MODEM questionnaire containing disability, symptoms, and illness rating, as well as Short Form-36 questionnaires. Postoperatively, there was 98% partial or total relief in leg pain, 85% had partial or total relief in back pain, and 69% had partial or total recovery of neurologic deficit. Functional outcome according to the Short Form-36 was comparable with the age-adjusted population when other comorbidities were taken into account. We found a direct relationship between poor outcome and coexisting medical conditions (p <0.001). Accompanying comorbid conditions have a significant impact on outcome after surgical decompression for lumbar spinal stenosis.

Activities of Daily Living↗
PubMed2001

Vaccination with CTL epitopes that escape: an alternative approach to HIV vaccine development?

This article describes a novel approach to HIV vaccine design that is, as yet, unproven and still in preliminary development. In rhesus macaques infected with simian immunodeficiency virus (SIV), we have identified particular cellular immune responses that select for viral variants during primary infection. We speculate that the detection of viral variants with altered amino acids in CTL epitopes implies the successful clearance of cells harboring wild-type virus. Here, we present our rationale suggesting why such potent early CTL responses that exert an antiviral effect may be particularly attractive targets for induction by candidate vaccines. Conventional wisdom suggests that regions of the virus that are structurally and functionally important will generally be well-conserved both among clades and within an infected host. Amino acid replacements within these well-conserved regions should be difficult for the virus to accommodate. Therefore, these regions are traditionally considered ideal targets for vaccine induced immune responses because they are refractory to CTL escape mutations. Many examples of these regions have been identified in both HIV-1 and SIV(mac) (J. Immunol. 162 (1999) 3727; J. Virol. 67 (1993) 438) and have been included in candidate vaccine formulations. Human clinical trials testing these vaccines are currently underway. Our proposed method of vaccination with CTL epitopes that escape explores an alternative hypothesis. Rather than engendering responses to regions of the virus that do not escape, we reason that vaccination needs to accelerate the development of the initial immune responses that effectively select for amino acid variants during acute infection. By examining CTL escape during the acute phase, we will identify CTL responses that the virus cannot tolerate and incorporate these responses into vaccines.

AIDS Vaccines↗
PubMed2001

Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.

CONTEXT: Incidence of end-stage renal disease due to hypertension has increased in recent decades, but the optimal strategy for treatment of hypertension to prevent renal failure is unknown, especially among African Americans. OBJECTIVE: To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression. DESIGN, SETTING, AND PARTICIPANTS: Interim analysis of a randomized, double-blind, 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m(2)) enrolled between February 1995 and September 1998. This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000. INTERVENTIONS: Participants were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441), with other agents added to achieve 1 of 2 blood pressure goals. MAIN OUTCOME MEASURES: The primary outcome measure was the rate of change in GFR; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50% or 25 mL/min per 1.73 m(2), end-stage renal disease, or death. RESULTS: Among participants with a urinary protein to creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/d), the ramipril group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m(2)/y) slower mean decline in GFR over 3 years (P =.006) and a 48% reduced risk of the clinical end points vs the amlodipine group (95% confidence interval [CI], 20%-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (P =.38). However, compared with the amlodipine group, after adjustment for baseline covariates the ramipril group had a 38% reduced risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in GFR after 3 months (P =.002), and less proteinuria (P<.001). CONCLUSION: Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria.

Adrenergic beta-Antagonists↗
PubMed2001

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT(2A) receptor antagonists.

The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT(2A) receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT(2A) receptors, with bioavailability of 80% and half-life of 12 h in rats.

Animals↗
PubMed2001

Understanding cytotoxic T-lymphocyte escape during simian immunodeficiency virus infection.

Infection of rhesus macaques with simian immunodeficiency virus (SIV) is an excellent model system for studying viral adaptation to immune responses. In this review, we discuss how the SIV-infected macaque has provided unequivocal evidence for cytotoxic T-lymphocyte (CTL) selection of viral escape variants. This improved understanding of CTL escape may influence human immunodeficiency virus (HIV) vaccine design as well as our understanding of HIV pathogenesis.

AIDS Vaccines↗
PubMed2001

Comparison of cross-sectional renal function measurements in African Americans with hypertensive nephrosclerosis and of primary formulas to estimate glomerular filtration rate.

Renal function measurements were obtained in 1,703 African Americans with presumed hypertensive nephrosclerosis who were screened for entry into the African-American Study of Hypertension and Kidney Disease (AASK). We examined the effect of race on relationships involving renal variables by comparing African Americans enrolled into the AASK with non-African Americans enrolled into the Modification of Diet in Renal Disease (MDRD) study. We examined the effect of gender on renal variables by comparing African American men and women. We compared various methods for estimating glomerular filtration rate (GFR) with iodine 125-labeled ((125)I)-iothalamate GFR. AASK data were also used to derive a new formula for estimating GFR in African Americans. After adjusting for age, sex, and baseline GFR, African American patients on the AASK study were heavier and had larger body surface areas and body mass indices than either MDRD African Americans or non-African Americans. African Americans had greater serum creatinine levels and urinary creatinine excretions for any given level of GFR. Mean GFR was greater in African American men than African American women (59.7 versus 51.7 mL/min/1.73 m(2)), although serum creatinine levels were also greater in men (1.91 versus 1.73 mg/dL). Seventy-eight percent of women with serum creatinine levels between 1.2 and 1.5 mg/dL had GFRs less than 65 mL/min/1.73 m(2). For African Americans in the AASK, GFR was overestimated by the 24-hour creatinine clearance and underestimated by the Cockcroft-Gault formula. A prediction formula developed in the MDRD study more accurately predicted GFR in AASK patients than these measurements. AASK data were also used to derive a new five-term formula for estimating GFR that was slightly more accurate in the African Americans in the AASK than the MDRD formula (median percentage of error, 12.4% for the MDRD formula versus 12.1% for the AASK formula). Important differences exist in renal variables between African Americans and non-African Americans and between African American men and African American women. Formulas using demographic data and readily measured serum values estimate (125)I-iothalamate GFR.

Adolescent↗