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Showing papers by "Newcastle University published in 2001"


Journal ArticleDOI
TL;DR: CYP3A5 was more frequently expressed in livers of African Americans than in those of Caucasians, and may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.
Abstract: Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.

2,046 citations


Journal ArticleDOI
TL;DR: Table of contents Preamble Scope of the document: Classification, epidemiology and prognosis and diagnosis strategy of evaluation, method, and findings.
Abstract: Table of contents Preamble Scope of the document 1256 Method 1257 Part 1. Classification, epidemiology and prognosis Definition 1258 Brief overview of pathophysiology of syncope 1258 Classification 1259 Epidemiological considerations 1259 Prognostic stratification: identification of factors predictive of adverse outcome 1260 Part 2. Diagnosis Strategy of evaluation (flow chart) 1262 Initial evaluation (history, physical examination, baseline electrocardiogram) 1264 Echocardiogram 1266 Carotid sinus massage 1266 Tilt testing 1268 Electrocardiographic monitoring (non-invasive and invasive) 1271 Electrophysiological testing 1273 ATP test 1277 Ventricular signal-averaged electrocardiogram 1278 Exercise testing 1278 Cardiac catheterization and angiography 1279 Neurological and psychiatric evaluation 1279 Diagnostic yield and prevalence of causes of syncope 1282

1,046 citations


Journal ArticleDOI
TL;DR: The adherent gastrointestinal mucus gel in vivo is continuous and can be divided into two layers: a loosely adherent layer removable by suction and a layer firmly attached to the mucosa.
Abstract: Divergent results from in vitro studies on the thickness and appearance of the gastrointestinal mucus layer have previously been reported. With an in vivo model, we studied mucus gel thickness over time from stomach to colon. The gastrointestinal tissues of Inactin-anesthetized rats were mounted luminal side up for intravital microscopy. Mucus thickness was measured with a micropipette before and after mucus removal by suction. The mucus layer was translucent and continuous; it was thickest in the colon (∼830 μm) and thinnest in the jejunum (∼123 μm). On mucus removal, a continuous, firmly adherent mucus layer remained attached to the epithelial surface in the corpus (∼80 μm), antrum (∼154 μm), and colon (∼116 μm). In the small intestine, this layer was very thin (∼20 μm) or absent. After mucus removal, there was a continuous increase in mucus thickness with the highest rate in the colon and the lowest rate in the stomach. In conclusion, the adherent gastrointestinal mucus gel in vivo is continuous and can be divided into two layers: a loosely adherent layer removable by suction and a layer firmly attached to the mucosa.

950 citations


Journal ArticleDOI
TL;DR: Cannabinoids derived from herbal cannabis interact with endogenous cannabinoid systems in the body and cause dose-related impairments of psychomotor performance with implications for car and train driving, aeroplane piloting and academic performance.
Abstract: Increasing prevalence of recreational cannabis use among the young population has stimulated debate on the possible effects of acute and long-term use. This paper aims to highlight recent knowledge of mechanisms of action, effects on psychomotor and cognitive performance, and health risks associated with cannabis consumption. The paper reviews recent literature on the prevalence of cannabis use, the potency of modern cannabis preparations and the pharmacological actions of cannabis. The paper outlines that cannabinoids derived form herbal cannabis interact with endogenous cannabinoid systems in the body. Actions on specific brain receptors cause dose-related impairments of psychomotor performance with implications for car and train driving, aeroplane piloting and academic performance. Other constituents of cannabis smoke carry respiratory and cardiovascular health risks similar to those of tobacco smoke. The paper concludes that cannabis is not, as widely perceived, a harmless drug but poses risks to the individual and to society.

773 citations


Journal ArticleDOI
TL;DR: A thorough understanding of the organismal responses occurring during bleaching will help explain changes in coral populations and in the coral reef community, and perhaps assist in predicting the future of reef corals and coral reefs during the next century of global climate change.
Abstract: 'It should be clear that the upper temperature limit for life cannot be accurately defined' (Schmidt-Nielsen 1996). The thermal physiology of zooxanthellate reef corals is reviewed in this paper in the context of organismal and biochemical responses occurring during coral bleaching, with emphasis on methods of detection and interpretation of animal and algal symbiont stress. Coral bleaching, as presently defined in the literature, is a highly subjective term used to describe a variety of conditions pertaining to low symbiont densities in the coral–algal complex, including response to thermal stress. Three general types of high-temperature bleaching are defined: physiological bleaching, which may or may not include higher-than-normal temperature responses; algal-stress bleaching, involving dysfunction of symbiotic algae at high light and/or high temperatures; and animal-stress bleaching, where coral cells containing symbiotic algae are shed from the gastrodermal layer of cells. Since none of these methods of bleaching is mutually exclusive, a combination of intrusive and non-intrusive techniques is necessary to determine which mechanisms of symbiont loss are occurring. While quantification of symbiont densities, algal pigments, and coral tissue biomass provide unambiguous evidence of bleaching severity, measurements of physiological and biochemical degradation offer additional correlative evidence of temperature stress. Pulse-amplitude-modulated (PAM) fluorometry has emerged as an easy and relatively inexpensive non-invasive technique for monitoring symbiotic algal function both in situ and in the laboratory, when proper assumptions and interpretations are made. The roles of global warming, water quality, acclimation/adaptation processes, and relation to coral disease and reef heterogeneity are also discussed. A thorough understanding of the organismal responses occurring during bleaching will help explain changes in coral populations and in the coral reef community, and perhaps assist in predicting the future of reef corals and coral reefs during the next century of global climate change.

736 citations


Journal ArticleDOI
TL;DR: Quiescent stellate cells presumably contribute to the control of blood flow through the sinusoidal capillaries and are important sources of paracrine, autocrine, juxtACrine, and chemoattractant factors that maintain homeostasis in the microenvironment of the hepatic sinusoid.
Abstract: In 1876, von Kupffer described liver Sternzellen (star-shaped cells). The functions of these cells remained enigmatic for 75 years until Ito observed lipid-containing perisinusoidal cells in human liver. In 1971, Wake demonstrated that the Sternzellen of von Kupffer and the fat-storing cells described by Ito were identical. Wake also established that these cells were important sites of vitamin A storage. Soon thereafter, Kent and Popper demonstrated that the stellate cells were intimately linked to the pathogenesis of hepatic fibrosis. Since then, these cells have been studied in detail. Quiescent stellate cells represent 5-8% of the total number of liver cells. They play a cardinal role in storage and controlled release of retinoids. They control extracellular matrix (ECM) turnover in the space of Disse by secreting the correct amounts of a limited number of ECM molecules, and by releasing matrix metalloproteinases and their inhibitors. By virtue of their long cytoplasmic processes, quiescent stellate cells presumably contribute to the control of blood flow through the sinusoidal capillaries. They are important sources of paracrine, autocrine, juxtacrine, and chemoattractant factors that maintain homeostasis in the microenvironment of the hepatic sinusoid.

701 citations


Journal ArticleDOI
Andy Baker1
TL;DR: It is suggested that fluorescence EEM spectrophotometry can provide a useful tool for the analysis of grab samples taken for both routine and investigative monitoring and has the potential for on-line monitoring of STW impacts on river systems.
Abstract: Fluorescence excitation-emission matrix (EEM) spectrophotometry was applied to 10 sample sites in six rivers in northeastern England, some of which were adversely impacted by sewage treatment works (STW) discharges, with the aim to investigate whether STW discharge has a significantly distinct fluorescence signature. Upstream, downstream, and STW discharge samples for two STWs demonstrated that treated sewage has a distinct fluorescence EEM, with high tryptophan and fulvic-like fluorescence intensities that are of approximately equal ratio. This signature could be seen in downstream samples. When all 10 sample locations were compared, two trend lines were apparent where STW impacted rivers plotted separately from the other sample locations. Fluorescence EEM signatures were compared to absorption at 254 nm and demonstrated to provide a better fingerprint of sewage-impacted water. It is suggested that fluorescence EEM spectrophotometry can provide a useful tool for the analysis of grab samples taken for both routine and investigative monitoring and has the potential for on-line monitoring of STW impacts on river systems.

688 citations


Journal ArticleDOI
TL;DR: It is shown that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry, which is associated with male-to-female sex reversal in humans.
Abstract: Mutations in SOX9 are associated with male-to-female sex reversal in humans. To analyze Sox9 function during sex determination, we ectopically expressed this gene in XX gonads. Here, we show that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry.

652 citations


Journal ArticleDOI
26 Sep 2001-JAMA
TL;DR: To assess the current validity of 17 clinical practice guidelines published by the US Agency for Healthcare Research and Quality (AHRQ) that are still in circulation, and to estimate how quickly guidelines become obsolete, criteria for defining when a guideline needs updating are developed.
Abstract: ContextPractice guidelines need to be up-to-date to be useful to clinicians. No published methods are available for assessing whether existing practice guidelines are still valid, nor does any empirical information exist regarding how often such assessments need to be made.ObjectivesTo assess the current validity of 17 clinical practice guidelines published by the US Agency for Healthcare Research and Quality (AHRQ) that are still in circulation, and to use this information to estimate how quickly guidelines become obsolete.Design, Setting, and ParticipantsWe developed criteria for defining when a guideline needs updating, mailed surveys to members of the original AHRQ guideline panels (n = 170; response rate, 71%), and searched the literature for evidence through March 2000 (n = 6994 titles yielding 173 articles plus 159 new guidelines on the same topics).Main Outcome MeasuresIdentification of new evidence calling for a major, minor, or no update of the 17 guidelines; survival analysis of the rate at which guidelines became outdated.ResultsFor 7 guidelines, new evidence and expert judgment indicated that a major update is required; 6 were found to be in need of a minor update; 3 were judged as still valid; and for 1 guideline, we could reach no conclusion. Survival analysis indicated that about half the guidelines were outdated in 5.8 years (95% confidence interval [CI], 5.0-6.6 years). The point at which no more than 90% of the guidelines were still valid was 3.6 years (95% CI, 2.6-4.6 years).ConclusionsMore than three quarters of the AHRQ guidelines need updating. As a general rule, guidelines should be reassessed for validity every 3 years.

520 citations


Journal ArticleDOI
TL;DR: A previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism, was described in this paper.
Abstract: We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460–461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere1. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases2 in which it correlates with visible pathology3, possibly by its involvement in toxic free-radical reactions4. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.

512 citations


Journal ArticleDOI
TL;DR: In conclusion, experiments to genetically engineer expression of fish antifreeze proteins have not improved freezing tolerance of sensitive species, and a better strategy may be to confer tolerance of cellular dehydration.

Journal ArticleDOI
01 Mar 2001-Neuron
TL;DR: It is demonstrated that, in the whisker representation of rat cortex, precise spike timing of single neurons increases the information transmitted about stimulus location by 44%, compared to that transmitted only by the total number of spikes.

Journal ArticleDOI
TL;DR: Both acquired autoimmune and inherited congenital diseases of the neuromuscular junction (NMJ) can significantly reduce, or even transiently increase, safety factor.

Journal ArticleDOI
TL;DR: It is concluded that Indian castes are most likely to be of proto-Asian origin with West Eurasian admixture resulting in rank-related and sex-specific differences in the genetic affinities of castes to Asians and Europeans.
Abstract: The origins and affinities of the ∼1 billion people living on the subcontinent of India have long been contested. This is owing, in part, to the many different waves of immigrants that have influenced the genetic structure of India. In the most recent of these waves, Indo-European-speaking people from West Eurasia entered India from the Northwest and diffused throughout the subcontinent. They purportedly admixed with or displaced indigenous Dravidic-speaking populations. Subsequently they may have established the Hindu caste system and placed themselves primarily in castes of higher rank. To explore the impact of West Eurasians on contemporary Indian caste populations, we compared mtDNA (400 bp of hypervariable region 1 and 14 restriction site polymorphisms) and Y-chromosome (20 biallelic polymorphisms and 5 short tandem repeats) variation in ∼265 males from eight castes of different rank to ∼750 Africans, Asians, Europeans, and other Indians. For maternally inherited mtDNA, each caste is most similar to Asians. However, 20%–30% of Indian mtDNA haplotypes belong to West Eurasian haplogroups, and the frequency of these haplotypes is proportional to caste rank, the highest frequency of West Eurasian haplotypes being found in the upper castes. In contrast, for paternally inherited Y-chromosome variation each caste is more similar to Europeans than to Asians. Moreover, the affinity to Europeans is proportionate to caste rank, the upper castes being most similar to Europeans, particularly East Europeans. These findings are consistent with greater West Eurasian male admixture with castes of higher rank. Nevertheless, the mitochondrial genome and the Y chromosome each represents only a single haploid locus and is more susceptible to large stochastic variation, bottlenecks, and selective sweeps. Thus, to increase the power of our analysis, we assayed 40 independent, biparentally inherited autosomal loci (1 LINE-1 and 39 Alu elements) in all of the caste and continental populations (∼600 individuals). Analysis of these data demonstrated that the upper castes have a higher affinity to Europeans than to Asians, and the upper castes are significantly more similar to Europeans than are the lower castes. Collectively, all five datasets show a trend toward upper castes being more similar to Europeans, whereas lower castes are more similar to Asians. We conclude that Indian castes are most likely to be of proto-Asian origin with West Eurasian admixture resulting in rank-related and sex-specific differences in the genetic affinities of castes to Asians and Europeans.

Journal ArticleDOI
TL;DR: Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as targeted therapy that offers new hope for expanded treatment options for patients with CML.
Abstract: The treatment options for chronic myelogenous leukemia (CML) continue to evolve rapidly. Imatinib mesylate (Gleevec, Glivec, formerly STI571) has continued to show remarkable clinical benefits and the updated results with this agent are reviewed. As relapses using single agent imatinib have occurred, particularly in advanced phase patients, the issue of whether combinations of other antileukemic agents with imatinib may yield improved results is addressed. In addition, data on new agents that have potential in the treatment of CML are reviewed. These agents are presented in the context of their molecular mechanism of action. The most recent data for stem cell transplantation, along with advances in nonmyeloablative transplants, are also reviewed. In Section I, Drs. Stephen O'Brien and Brian Druker update the current status of clinical trials with imatinib and review ongoing investigations into mechanisms of resistance and combinations of imatinib with other agents. They also present their views on integration of imatinib with other therapies. In Section II, Dr. Jorge Cortes describes the most recent data on novel therapies for CML, including farnesyl transferase inhibitors, arsenic trioxide, decitabine, and troxatyl, among others. These agents are discussed in the context of their molecular mechanism of action and rationale for use. In Section III, Dr. Jerald Radich updates the results of stem cell transplants for CML, including emerging data on nonmyeloablative transplants. He also presents data on using microarrays to stratify patients into molecularly defined risk groups.

Journal ArticleDOI
01 Dec 2001-BMJ
TL;DR: Little tracking from childhood overweight to adulthood obesity was found when using a measure of fatness that was independent of build, and the thinnest children tended to have the highest adult risk at every level of adult obesity.
Abstract: Objective: To determine whether being overweight in childhood increases adult obesity and risk of disease. Design: Prospective cohort study. Setting: City of Newcastle upon Tyne. Participants: 932 members of thousand families 1947 birth cohort, of whom 412 attended for clinical examination age 50. Main outcome measures: Blood pressure; carotid artery intima-media thickness; fibrinogen concentration; total, low density lipoprotein, and high density lipoprotein cholesterol concentrations; triglyceride concentration; fasting insulin and 2 hour glucose concentrations; body mass index; and percentage body fat. Results: Body mass index at age 9 years was significantly correlated with body mass index age 50 (r=0.24, P Conclusions: Little tracking from childhood overweight to adulthood obesity was found when using a measure of fatness that was independent of build. Only children who were obese at 13 showed an increased risk of obesity as adults. No excess adult health risk from childhood or teenage overweight was found. Being thin in childhood offered no protection against adult fatness, and the thinnest children tended to have the highest adult risk at every level of adult obesity. What is already known on this topic Many studies have found that body mass index in childhood is significantly correlated with body mass index in adulthood Obese children have been found to have higher all cause mortality as adults What this study adds No excess health risk from childhood overweight was found Childhood body mass index was linked to adulthood body mass index but not percentage body fat Only children who were obese at 13 showed a significant increased risk of obesity as adults People who were thinnest as children and fattest as adults tended to have the highest adult risk

Journal ArticleDOI
TL;DR: This article explains step-by-step the conceptual rationale and methodology of CoCoMac and demonstrates its practical use by an analysis of connectivity in the prefrontal cortex.
Abstract: The need to integrate massively increasing amounts of data on the mammalian brain has driven several ambitious neuroscientific database projects that were started during the last decade. Databasing the brain's anatomical connectivity as delivered by tracing studies is of particular importance as these data characterize fundamental structural constraints of the complex and poorly understood functional interactions between the components of real neural systems. Previous connectivity databases have been crucial for analysing anatomical brain circuitry in various species and have opened exciting new ways to interpret functional data, both from electrophysiological and from functional imaging studies. The eventual impact and success of connectivity databases, however, will require the resolution of several methodological problems that currently limit their use. These problems comprise four main points: (i) objective representation of coordinate-free, parcellation-based data, (ii) assessment of the reliability and precision of individual data, especially in the presence of contradictory reports, (iii) data mining and integration of large sets of partially redundant and contradictory data, and (iv) automatic and reproducible transformation of data between incongruent brain maps. Here, we present the specific implementation of the 'collation of connectivity data on the macaque brain' (CoCoMac) database (http://www.cocomac.org). The design of this database addresses the methodological challenges listed above, and focuses on experimental and computational neuroscientists' needs to flexibly analyse and process the large amount of published experimental data from tracing studies. In this article, we explain step-by-step the conceptual rationale and methodology of CoCoMac and demonstrate its practical use by an analysis of connectivity in the prefrontal cortex.

Book ChapterDOI
TL;DR: It is concluded that accurate biochemical investigation is required for determining the site and severity of the defect along with an understanding of the control that each individual complex has on overall substrate oxidation.
Abstract: Publisher Summary This chapter investigates mitochondrial respiratory complex activity in mitochondria isolated from human cells and tissues. Mitochondrial cytopathies are a heterogeneous group of multisystem disorders predominantly affecting skeletal and cardiac muscle and the central nervous system, but are associated with a broad spectrum of other clinical phenotypes, including neurodegenerative disease. In many patients, the impairment of mitochondrial respiratory chain function is due to a mutation in mitochondrial DNA (mtDNA), which may take the form of a rearrangement or a point mutation in a tRNA, rRNA, or protein-encoding gene. Despite major advances in the molecular investigation of patients with disease due to respiratory chain abnormalities, there are still many unresolved problems in the biochemical investigation of patients, and there is frequently a lack of correlation between biochemical and molecular genetic abnormalities. This chapter concludes that accurate biochemical investigation is required for determining the site and severity of the defect along with an understanding of the control that each individual complex has on overall substrate oxidation.

Journal ArticleDOI
TL;DR: In this article, the effects of long-wavelength (> 100 km), seasonal variability in continental water storage on vertical crustal motions are assessed, and the modeled vertical displace-ments (ARM) have root-mean-square (RMS) values for 1994-1998 as large as 8 mm, with ranges up to 30 mm, and are predominantly annual in character.
Abstract: The effects of long-wavelength (> 100 km), seasonal variability in continental water storage on vertical crustal motions are assessed. The modeled vertical displace- ments (ARM) have root-mean-square (RMS) values for 1994- 1998 as large as 8 mm, with ranges up to 30 mm, and are predominantly annual in character. Regional strains are on the order of 20 nanostrain for tilt and 5 nanostrain for hori- zontal deformation. We compare ArM with observed Global Positioning System (GPS) heights (Aro) (which include ad- justments to remove estimated effects of atmospheric pres- sure and annual tidal and non-tidal ocean loading) for 147 globally distributed sites. When the Aro time series are ad- justed by ArM, their variances are reduced, on average, by an amount equal to the variance of the ArM. Of the Aro time series exhibiting a strong annual signal, more than half

Journal ArticleDOI
TL;DR: These data, together with previously published anatomic and radiologic studies, are consistent with activity-dependent corticospinal axonal withdrawal during development and maintenance of increased corticomotoneuronal projections from the intact hemisphere after unilateral perinatal lesions.
Abstract: Objective: To characterize the development of ipsilateral corticospinal projections from birth and compare to 1) development of contralateral projections in the same subjects and 2) ipsilateral corticospinal projections in subjects with unilateral lesions of the corticospinal system acquired perinatally or in adulthood. Method: Transcranial magnetic stimulation excited the motor cortex, and responses were recorded bilaterally in pectoralis major, biceps brachii, and the first dorsal interosseus muscles. Subjects studied included 9 neonates recruited at birth, studied longitudinally for 2 years; 85 healthy subjects aged from birth to adulthood; 10 subjects with hemiplegic cerebral palsy; and 8 with hemiplegia after stroke. Results: In neonates, ipsilateral responses had significantly shorter onsets than contralateral responses but similar thresholds and amplitudes. Thresholds within both pathways increased in the first 3 months. Differential development was present from 3 months so that by 18 months ipsilateral responses were significantly smaller and had significantly higher thresholds and longer onset latencies than contralateral responses. A similar pattern of smaller and later ipsilateral responses was observed after transcranial magnetic stimulation of the intact cortex in subjects with stroke. In contrast, subjects with hemiplegic cerebral palsy had ipsilateral responses with onsets, thresholds and amplitudes similar to those of contralateral responses. Significant branching of contralateral corticospinal axons from the intact motor cortex was excluded by cross-correlation analysis. Conclusions: These data, together with previously published anatomic and radiologic studies, are consistent with activity-dependent corticospinal axonal withdrawal during development and maintenance of increased corticomotoneuronal projections from the intact hemisphere after unilateral perinatal lesions.

Journal ArticleDOI
TL;DR: There is a poor correlation among the items of the Knee Society Clinical Rating System, but the rating system has adequate convergent construct validity and is preferable for knee arthroplasty outcome studies.
Abstract: Background: The aim of this study was to validate the Knee Society Clinical Rating System (knee and function scores) and to compare its responsiveness with that of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the Medical Outcomes Study Short Form-36 (SF-36). Methods: Patients were recruited as part of a prospective observational study of the outcomes of primary total knee arthroplasty for the treatment of osteoarthritis in four centers in the United States, six centers in the United Kingdom, and two centers in Australia. Independent research assistants at each site collected the Knee Society clinical data. The WOMAC, SF-36, patient satisfaction, and demographic data were obtained with self-administered questionnaires. Results: A total of 862 eligible patients were recruited, and complete preoperative and twelve-month data were available for 697 (80.9%) of them. The mean age was seventy years (range, thirty-eight to ninety years), and the majority of the patients (58.9%) were women. Low correlations were found among the items of both the knee and the function score at both assessment times. The Knee Society pain and function scores had moderate-to-strong correlations with the corresponding pain and function domains of the WOMAC and SF-36 (r = 0.31 to 0.72). Measurement of the standardized response mean showed the Knee Society knee score to be more responsive (standardized response mean, 2.2) than the WOMAC (standardized response means, 2.0 for pain and 1.4 for function) and the SF-36 (standardized response means, 1.0 for bodily pain and 1.1 for physical functioning). The Knee Society function score was the least responsive measure (standardized response mean, 0.8). Correlation of changes in scores at twelve months with patient reports of satisfaction and improvement in health status showed the WOMAC and SF-36 to be more responsive than the Knee Society scores. Conclusions: There is a poor correlation among the items of the Knee Society Clinical Rating System, but the rating system has adequate convergent construct validity. The WOMAC and SF-36 are more responsive measures of outcome of total knee arthroplasty. As they are less labor-intensive for researchers to use and as use of these instruments removes observer bias from the study design, they are preferable for knee arthroplasty outcome studies.

Journal ArticleDOI
TL;DR: Regression analyses showed that although word length, familiarity, and concreteness make independent contributions to the age of acquisition measure, frequency and imageability are the most important predictors of rated age of Acquisition.
Abstract: Age of acquisition and imageability ratings were collected for 2,645 words, including 892 verbs and 213 function words. Words that were ambiguous as to grammatical category were disambiguated: Verbs were shown in their infinitival form, and nouns (where appropriate) were preceded by the indefinite article (such asto crack anda crack). Subjects were speakers of British English selected from a wide age range, so that differences in the responses across age groups could be compared. Within the subset of early acquired noun/verb homonyms, the verb forms were rated as later acquired than the nouns, and the verb homonyms of high-image ability nouns were rated as significantly less imageable than their noun counterparts. A small number of words received significantly earlier or later age of acquisition ratings when the 20–40 years and 50–80 years age groups were compared. These tend to comprise words that have come to be used more frequently in recent years (either through technological advances or social change), or those that have fallen out of common usage. Regression analyses showed that although word length, familiarity, and concreteness make independent contributions to the age of acquisition measure, frequency and imageability are the most important predictors of rated age of acquisition.

Journal ArticleDOI
TL;DR: These neurochemical abnormalities implicate the cholinergic system in developmental disorders such as autism and suggest the potential for intervention based on cholinerential receptor modulation.
Abstract: OBJECTIVE: Measures of cholinergic transmitter activity were investigated in patients with autism because of reported neuropathological abnormalities in cholinergic nuclei in the basal forebrain. METHOD: Levels of cholinergic enzyme and receptor activity were measured in the frontal and parietal cerebral cortex of deceased autistic adults, similarly aged normal adults without mental retardation, and nonautistic mentally retarded adults. The immunoreactivity levels of brain-derived neurotrophic factor and nerve growth factor were measured in the basal forebrain. RESULTS: There were no differences between the autistic and comparison groups in choline acetyltransferase or acetylcholinesterase activity in the cerebral cortex and basal forebrain or in muscarinic M2 receptor or α-bungarotoxin binding within the cortex. Cortical M1 receptor binding was up to 30% lower than normal in the autistic subjects, and the difference reached significance in the parietal cortex. In both the parietal and frontal cortices, d...

Journal ArticleDOI
TL;DR: Mutation screening of the FH gene in 19 familial and 31 sporadic patients with FH demonstrates that familial HUS is likely to be a heterogeneous condition.
Abstract: Several recent studies have established an association between abnormalities of complement factor H (FH) and the development of hemolytic uremic syndrome (HUS). To identify the relative importance of mutations in FH as a cause of HUS, we have undertaken mutation screening of the FH gene in 19 familial and 31 sporadic patients with FH. Mutations were found in two familial and three sporadic patients, and these clustered in exons 18–20, a domain important for host recognition. Moreover, this study demonstrates that familial HUS is likely to be a heterogeneous condition.

Journal ArticleDOI
TL;DR: Behavioural and psychological symptoms in dementia (BPSD) are a common reason for placement in long term care and are often associated with indiscriminate prescription of psychotropic medication.
Abstract: Background Behavioural and psychological symptoms in dementia (BPSD) are a common reason for placement in long term care and are often associated with indiscriminate prescription of psychotropic medication. Aims To determine the prevalence of BPSD in care environments, their relationship with severity of dementia and the pattern of psychotropic medication. Methods Two hundred and thirty-one elderly residents (39% living in social care facilities and 61% in nursing home care) were assessed using a range of standardised psychiatric schedules. Additional information about the residents and medication was obtained from professional carers. Results Overall 90% of residents had dementia, 79% of whom had clinically significant BPSD with 58% receiving psychotropic medication. There was no difference in the prevalence of BPSD between social and nursing care. Depression was most common in people with mild dementia, whilst delusions arose most frequently in those with moderate dementia and aberrant motor behaviour had a high prevalence in people with severe dementia. Conclusion BPSD are common in elderly people with dementia living in care environments. More rigorous guidelines are needed pertaining to the prescription and monitoring of medication and the need to disseminate skills regarding psychosocial management approaches to care staff. Copyright © 2001 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: It is shown that relaxed replication of mtDNA alone can lead, through random genetic drift, to the clonal expansion of single mutant events during human life.
Abstract: Human tissues acquire somatic mitochondrial DNA (mtDNA) mutations with age. Very high levels of specific mtDNA mutations accumulate within individual cells, causing a defect of mitochondrial oxidative metabolism. This is a fundamental property of nondividing tissues, but it is not known how it comes about. To explore this problem, we developed a model of mtDNA replication within single human cells. Using this model, we show that relaxed replication of mtDNA alone can lead, through random genetic drift, to the clonal expansion of single mutant events during human life. Significant expansions primarily develop from mutations acquired during a critical period in childhood or early adult life.

Journal ArticleDOI
TL;DR: There is a strong association between non-accidental falls and cardioinhibitory CSH and carotid sinus hypersensitivity should be considered in all older adults who have non- Accidental falls.

Journal ArticleDOI
TL;DR: The presence, number and distribution of natural teeth are related to the ability to eat certain foods, affecting nutrient intakes and two biochemical measures of nutritional status.
Abstract: Objectives: To assess how the dental status of older people affected their stated ability to eat common foods, their nutrient intake and some nutrition-related blood analytes.Design: Cross-sectional survey part of nation-wide British National Diet and Nutrition Survey: people aged 65 years and older. Data from a questionnaire were linked to clinical data and data from four-day weighed dietary records. Two separate representative samples: a free-living and an institutional sample. Seven-hundred-and-fifty-three free-living and 196 institution subjects had a dental exam and interview.Results: About one in five dentate (with natural teeth) free-living people had difficulty eating raw carrots, apples, well-done steak or nuts. Foods such as nuts, apples and raw carrots could not be eaten easily by over half edentate (without natural teeth but with dentures) people in institutions. In free-living, intakes of most nutrients and fruit and vegetables were significantly lower in edentate than dentate. Perceived chewing ability increased with increasing number of teeth. Daily intake of non-starch polysaccharides, protein, calcium, non-haem iron, niacin, vitamin C and intrinsic and milk sugars were significantly lower in edentate. Plasma ascorbate and retinol were significantly lower in the edentate than dentate. Plasma ascorbate was significantly related to the number of teeth and posterior contacting pairs of teeth.Conclusions: The presence, number and distribution of natural teeth are related to the ability to eat certain foods, affecting nutrient intakes and two biochemical measures of nutritional status.

Journal ArticleDOI
TL;DR: The new technique of pressure perturbation calorimetry (PPC) has enormous potential here as a means of probing solvation-related volumetric changes in biomolecules at modest pressures, as illustrated with preliminary data for a simple protein-inhibitor complex.

Book ChapterDOI
TL;DR: The report is concerned with planning for the adult victims of the new epidemic and this includes the development of appropriate treatment for chronic diseases such as diabetes, stroke and coronary heart disease.
Abstract: NCDs including diabetes, heart disease and stroke arc global epidemics of the 21 st century The greatest burden on health will be in developing countries and sub-Saharan Africa is an area of major challenge: We are concerned with planning for the adult victims of the new epidemic and this includes the development of appropriate treatment Therapy should be cost effective and evidence on the economics of treating chronic conditions in Africa is urgently required Finally, health promotion, primary prevention and health screening strategies for chronic diseases such as diabetes, stroke and coronary heart disease are required