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Biomedical subjects

A M MacLeod

Publications and source records attributed to A M MacLeod.

At least 19 recordsLinked to original sources
PubMed2006

Haemodiafiltration, haemofiltration and haemodialysis for end-stage kidney disease.

BACKGROUND: Renal replacement therapy (RRT) for end-stage kidney disease (ESKD) can be achieved by several interventions including haemodialysis (HD), peritoneal dialysis (PD) and kidney transplantation. HD, haemofiltration (HF), haemodiafiltration (HDF) and acetate-free biofiltration (AFB) are extracorporeal RRT methods. It has been suggested that HF and HDF may reduce the frequency and severity of intradialytic and post-dialytic adverse symptoms and may be more effective than HD in the removal of high molecular weight molecules. OBJECTIVES: To compare convective modes of extracorporeal RRT (HF, HDF or AFB) with HD and to establish if any of these techniques is superior to each other in patients with ESKD. SEARCH STRATEGY: We searched MEDLINE (1966-2006), EMBASE (1980-2006), Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library issue 2, 2006) and CINAHL (1872-2006). Authors of included studies were contacted, reference lists of identified RCTs and relevant narrative reviews were screened. SELECTION CRITERIA: RCTs comparing HF, HDF, AFB and HD for ESKD were included. Trials enrolling any patient undergoing RRT for ESKD were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes or weighted mean difference (MD) for continuous data with 95% confidence intervals (CI). Heterogeneity was measured using the Chi-square (chi(2)) and I(2) statistic. MAIN RESULTS: Twenty studies (657 patients) were included. Seventeen studies compared HF, HDF or AFB with HD, two compared HDF with AFB and one compared HF with HDF. The studies were generally small with suboptimal quality. Convective modalities (HF, HDF, AFB) did not differ significantly from HD for mortality (RR 1.68, 95% CI 0.23 to 12.13; chi(2)= 2.58, P = 0.11, I(2) = 61.2%), number of hospital admissions/year (MD 0.20, 95% CI -0.07 to 0.47) and dialysis adequacy (Kt/V: MD 0.09, 95% CI 0.02 to 0.17; chi(2) = 3.73, P = 0.29, I(2) = 19.6%). No study assessed number of dialysis treatments associated with "any adverse symptoms", sessions that were stopped early, change of dialysis modality or dialysis-related amyloidosis. AUTHORS' CONCLUSIONS: We were unable to demonstrate whether convective modalities (either HF, HDF or AFB) have significant advantages over HD with regard to clinically important outcomes of mortality, dialysis-related hypotension and hospitalisation. More adequately-powered good quality RCTs assessing clinically important outcomes (mortality, hospitalisation, quality of life) are needed.

Cause of Death↗
PubMed2006

Temporally resolved electro-optic effect.

The electro-optic effect between an ultrafast optical probe pulse and an ultrashort terahertz pulse is shown to depend on the time derivatives of the product of the probe and terahertz electric fields. Application of this theory to temporally resolved single-shot terahertz detection techniques, where the electro-optic effect is temporally localized within an optical probe pulse, shows that the description presented here differs fundamentally and verifiably from that commonly used in literature.

Journal Article↗
PubMed2005

An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition.

Alpha5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has inverse agonist efficacy selective for the alpha5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA(A) receptors containing an alpha5 subunit. In a mouse hippocampal slice model, alpha5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that alpha5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, alpha5IA significantly enhanced performance in a rat hippocampal-dependent test of learning and memory, the delayed-matching-to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice alpha5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, alpha5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABA(A) alpha5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.

Animals↗
PubMed2004

Electro-optic technique with improved time resolution for real-time, nondestructive, single-shot measurements of femtosecond electron bunch profiles.

Electro-optic detection of the Coulomb field of a relativistic electron bunch combined with single-shot cross correlation of optical pulses is used to enable single-shot measurements of the shape and length of femtosecond electron bunches. This method overcomes a fundamental time-resolution limit of previous single-shot electro-optic measurements, which arises from the inseparability of time and frequency properties of the probing optical pulse. Using this new technique we have made real-time measurements of a 50 MeV electron bunch, observing the profile of 650 fs FWHM ( approximately 275 fs rms) long bunches.

Journal Article↗
PubMed2003

High-temporal-resolution, single-shot characterization of terahertz pulses.

A technique for noncollinear cross correlation of electro-optic modulated optical pulses is presented for the single-shot characterization of terahertz waveforms and is compared to established electro-optic terahertz characterization methods. This technique is free from the limitations on time resolution and faithful reproduction of previously demonstrated single-shot amplitude modulation spectral encoding.

Journal Article↗
PubMed2003

End-stage renal disease in Indo-Asians in the North-West of England.

BACKGROUND: The incidence of end-stage renal disease (ESRD) in England is increasing. There is a higher incidence of ESRD in British Indo-Asians than in the White population. AIM: To determine to what degree the increasing demand for renal replacement therapy in the UK is due to Indo-Asian patients. To study the presentation to renal services of Indo-Asian patients with ESRD and report any inequalities in initial treatment of Indo-Asian patients with ESRD compared to their White counterparts. DESIGN: Prospective, inception cohort study. METHODS: Consecutive adult patients with ESRD who started renal replacement therapy between 1 April 2000 and 31 December 2001 in all 14 renal units serving an area from North Cheshire to South Cumbria, including Greater Manchester and Lancashire, were recruited and interviewed. RESULTS: Of the 578 patients, 9.5% were Indo-Asian. The annual acceptance rate for renal replacement therapy was 342 per million population in Indo-Asians, compared with 91 per million population in the White population ( p < 0.001). Indo-Asian patients with ESRD were younger (median age 51 years vs. 60 yrs, p = 0.006) and more socially deprived (81% vs. 36.5% in the 5th Carstairs quintile, p < 0.001). A greater proportion of Indo-Asian patients with ESRD presented late to specialist renal services (31% vs. 19%, p = 0.03). Once adjusting for their younger age, atherosclerotic renovascular disease and/or hypertensive nephropathy was more prevalent in Indo-Asian patients (OR 4.9; p = 0.03). There was no difference in the initial mode of maintenance dialysis or the perception of choice the patients felt they had, based on their ethnicity. DISCUSSION: There is a silent epidemic of ESRD in Indo-Asian patients in the North-West, possibly vascular in aetiology, in which specialist intervention is late. This suggests that Indo-Asian patients should be prioritized for early intervention strategies to reduce the burden of ESRD.

Age Distribution↗
PubMed2002

Single-shot electron-beam bunch length measurements.

We report subpicosecond electro-optic measurements of the length of individual relativistic electron bunches. The longitudinal electron-bunch shape is encoded electro-optically on to the spectrum of a chirped laser pulse. The electron-bunch length is determined by analyzing individual laser-pulse spectra obtained with and without the presence of an electron bunch. Since the length of the chirped laser pulse can be easily changed, the electron bunch can be visualized on different time scales. This single-shot imaging technique is a promising method for real-time electron-bunch diagnostics.

Journal Article↗
PubMed2002

Acute renal failure requiring renal replacement therapy: incidence and outcome.

BACKGROUND: Renal replacement therapy (RRT) for acute renal failure (ARF) may be provided in many settings within the hospital. Such patients require a high level of care and often have a poor prognosis. No prospective studies have accurately defined this population, making the prediction of necessary resources and the planning of services difficult. AIM: To ascertain the incidence, causes and outcomes of acute renal failure requiring renal replacement therapy in Scotland. DESIGN: A prospective observational census of all clinical areas providing renal replacement therapy in three Scottish health boards (Grampian, Highland, Tayside). METHODS: Patients were identified by liaison with each unit providing RRT. Factors precipitating renal failure and reasons for RRT were recorded at the time of initiation. Comorbid disease burden was scored using the Charlson index. Patient status at 90 days was assessed from case-notes, contacting general practitioners where necessary. RESULTS: 375 patients per million population per year received RRT; 203 per million per year for either ARF or acute-on-chronic renal failure. 73.5% of patients receiving RRT for ARF died within 90 days, 23.5% became independent of RRT. The median duration of hospital admission was 19 days. DISCUSSION: The annual incidence of ARF requiring RRT is just over 200 per million population, almost twice that of end-stage renal disease requiring RRT. Such treatment places high demands upon health care resources.

Acute Kidney Injury↗
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

A default mode of brain function.

A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.

Adult↗
PubMed2001

Do the Y-set and double-bag systems reduce the incidence of CAPD peritonitis? A systematic review of randomized controlled trials.

BACKGROUND: Peritonitis is the most frequent serious complication of continuous ambulatory peritoneal dialysis (CAPD). It has a major influence on the number of patients switching from CAPD to haemodialysis and has probably restricted the wider acceptance and uptake of CAPD as an alternative mode of dialysis. This systematic review sought to determine if modifications of the transfer set (Y-set or double-bag systems) used in CAPD exchanges are associated with a reduction in peritonitis and an improvement in other relevant outcomes. METHODS: Based on a comprehensive search strategy, we undertook a systematic review of randomized or quasi-randomized controlled trials comparing double-bag and/or Y-set CAPD exchange systems with standard systems, or comparing double-bag with Y-set systems, in patients with end-stage renal disease (ESRD) treated with CAPD. Only published data were used. Data were abstracted by a single investigator onto a standard form and subsequently entered into Review Manager 4.0.4. Its statistical package, Metaview 3.1, calculated an odds ratio (OR) for dichotomous data and a (weighted) mean difference for continuous data with 95% confidence intervals. RESULTS: Twelve eligible trials with a total of 991 randomized patients were identified. In trials comparing either the Y-set or double-bag systems with the standard systems, significantly fewer patients (133/363 vs 158/263; OR 0.33, 95% CI 0.24-0.46) experienced peritonitis and the number of patient-months on CAPD per episode of peritonitis was consistently greater. When the double-bag systems were compared with the Y-set systems significantly fewer patients experienced peritonitis (44/154 vs 66/138; OR 0.44, 95% CI 0.27-0.71) and the number of patient-months on CAPD per episode of peritonitis was also greater. CONCLUSIONS: Double-bag systems should be the preferred exchange systems in CAPD.

Humans↗
PubMed2000

Active-site variants of Streptomyces griseus protease B with peptide-ligation activity.

BACKGROUND: Peptide-ligating technologies facilitate a range of manipulations for the study of protein structure and function that are not possible using conventional genetic or mutagenic methods. To different extents, the currently available enzymatic and nonenzymatic methodologies are synthetically demanding, sequence-dependent and/or sensitive to denaturants. No single coupling method is universally applicable. Accordingly, new strategies for peptide ligation are sought. RESULTS: Site-specific variants (Ser195-->Gly, S195G, and Ser195-->Ala, S195A) of Streptomyces griseus protease B (SGPB) were generated that efficiently catalyze peptide ligation (i.e., aminolysis of ester-, thioester- and para-nitroanilide-activated peptides). The variants also showed reduced hydrolytic activity relative to the wild-type enzyme. The ratio of aminolysis to hydrolysis was greater for the S195A variant, which was also capable of catalyzing ligation in concentrations of urea as high as 2 M. CONCLUSIONS: Mutagenic substitution of the active-site serine residue of SGPB by either glycine or alanine has created a unique class of peptide-ligating catalysts that are useful for coupling relatively stable ester- and para-nitroanilide-activated substrates. Ligation proceeds through an acyl-enzyme intermediate involving His57. Serine to alanine mutations may provide a general strategy for converting proteases with chymotrypsin-like protein folds into peptide-coupling enzymes.

Amino Acid Sequence↗
PubMed2000

Can we improve early mortality in patients receiving renal replacement therapy?

BACKGROUND: Approximately one in eight patients with end-stage renal disease (ESRD) die within the first three months of starting renal replacement therapy (RRT). We investigated which factors might improve this early mortality. METHODS: We performed a prospective nationwide study of all patients commencing RRT for ESRD in Scotland over one year. Patients were classified according to how they presented to start RRT, their burden of comorbid diseases, access prepared for dialysis, and duration of care by a nephrologist prior to commencing RRT. Those factors most strongly associated with death within 90 days of commencing treatment were determined by logistic regression analysis. RESULTS: Patients with an acute unexpected element to their presentation for RRT had early mortality rates between 6.0 and 8.9 times greater than those who commenced RRT electively after a period of care from a nephrologist. Patients in high and medium comorbidity risk groups had early mortality rates of 4.7 and 2.2 times greater than those in the low-risk group. Low serum albumin had a significant association with early death. Patients who progressed steadily to ESRD, who had a planned start to dialysis, and who had mature access were 3.6 times more likely to survive beyond three months than those with no access; they were, however, also younger with less comorbidity. CONCLUSIONS: The factors principally associated with early mortality are nonelective presentation for RRT, comorbid illness, and low serum albumin. Patients cared for by a nephrologist before requiring RRT who have mature access have better short-term survival than those without access. They are also younger with less comorbidity. It may be possible to improve short-term survival in this "unplanned" group if referred early to facilitate reducing cardiovascular risk factors and preparation for RRT.

Adolescent↗
PubMed2000

Evidence-based medicine in nephrology: identifying and critically appraising the literature.

BACKGROUND: Uncertainties about best management of end-stage renal disease (ESRD) are reflected in wide variations in practice. Systematic reviews aim to reduce uncertainty by strengthening the evidence base for clinical practice, allowing estimation of the benefits and risks of particular interventions, whilst minimizing the potential for bias. This paper describes the methods and conduct of six systematic reviews of aspects of the management of ESRD, and the yield in terms of trials found. METHODS: Our methodology was based on that recommended by the Cochrane Collaboration (an international initiative set up to perform and disseminate systematic reviews of health care). It involved a systematic search of electronic databases and bibliographic reference lists, together with handsearching of Kidney International for studies relevant to the management of ESRD, followed by a systematic assessment of study quality. RESULTS: Around 12,000 abstracts were assessed which had been identified from electronic sources. Of these, 2085 (18%) were deemed to be reports of possible randomized or quasi-randomized controlled trials relevant to the management of ESRD. Three hundred and forty were relevant to the six specific reviews, and after assessment of the full manuscripts, 39 studies were finally included in our reviews. Reports of a further nine trials, which were identified from other sources, were also included. The broad search adopted allowed the parallel development of a register of trials of all aspects of the management of ESRD. CONCLUSIONS: This study has demonstrated that the methodology of systematic reviews, as promoted by the Cochrane Renal Group, is feasible but has significant resource implications. The development of a register of randomized controlled trials (RCTs) related to the management of ESRD will facilitate this form of research in the future.

Databases as Topic↗
PubMed2000

Evaluation of clinical guidelines for the management of end-stage renal disease in europe: the EU BIOMED 1 study.

BACKGROUND: There are wide national and international variations in the management of patients with end-stage renal disease (ESRD). The aim of this study was to develop, harmonize, implement, and evaluate consensus-based clinical guidelines for the management of renal anaemia and renal bone disease in patients with ESRD, and for the prevention and management of cytomegalovirus disease in renal transplant recipients across six renal centres in Europe. METHODS: The trial was a prospective, multicentre, randomized balanced incomplete block design. Nephrologists from the six European renal units were randomized to develop and implement guidelines for two out of the three conditions and to act as a control for the third condition. Data were collected pre- (1 year) and post- (9 months) intervention on aspects of patient monitoring, management, and outcome. RESULTS: Eight hundred and twenty-nine dialysis patients from the six European dialysis centres were included in the study. Multivariate analysis (adjusting for case-mix and secular trends) showed a significant increase in the number of monitoring events in the guideline group compared with control group (6%, 95% CI, 1-11%). There was no concomitant increase in either appropriate management or the number of favourable patient outcomes. CONCLUSIONS: In the first European collaboration on renal guidelines, the introduction of the guidelines improved the monitoring of the patients, but did not improve patient management or outcome. This study suggests the potential for creating clinical guidelines with the aim of standardizing treatment protocols across international boundaries, and improving the quality of the medical care provided.

Adolescent↗