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Showing papers by "University College London published in 2003"


Journal ArticleDOI
TL;DR: Information is provided about CRP as a protein and an acute-phase reactant, and a knowledge-based framework for interpretation and analysis of clinical observations of CRP in relation to cardiovascular and other diseases, that identifies it as a possible therapeutic target.
Abstract: In the mid 1990s, immunoassays for C-reactive protein (CRP), with greater sensitivity than those previously in routine use, revealed that increased CRP values, even within the range previously considered normal, strongly predict future coronary events. These findings triggered widespread interest, especially, remarkably, in the US, where the clinical use of CRP measurement had been largely ignored for about 30 years. CRP production is part of the nonspecific acute-phase response to most forms of inflammation, infection, and tissue damage and was therefore considered not to provide clinically useful information. Indeed, CRP values can never be diagnostic on their own and can only be interpreted at the bedside, in full knowledge of all other clinical and pathological results. However, they can then contribute powerfully to management, just as universal recording of the patient’s temperature, an equally nonspecific parameter, is of great clinical utility. The present torrent of studies of CRP in cardiovascular disease and associated conditions is facilitated by the ready commercial availability of automated CRP assays and of CRP itself as a research reagent. However, unlike the earlier rejection in the US of CRP as an empirical test because of its perceived lack of specificity, the current enthusiasm over CRP in cardiovascular disease is widely characterized by failure to recognize appropriately the nonspecific nature of the acute-phase response, and by lack of critical biological judgment. Quality control of the source, purity, and structural and functional integrity of the CRP, and the relevance of experimental design before ascribing pathophysiological functions, are also often ignored. This article provides information about CRP as a protein and an acute-phase reactant, and a knowledge-based framework for interpretation and analysis of clinical observations of CRP in relation to cardiovascular and other diseases. We also review the properties of CRP, its possible role in pathogenesis of disease, and our own observations that identify it as a possible therapeutic target.

3,814 citations


Journal ArticleDOI
TL;DR: It is shown here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts.
Abstract: Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.

2,737 citations


Journal ArticleDOI
TL;DR: The results provide the first quantitative demonstration of reliable inference of anatomical connectivity between human gray matter structures using diffusion data and the first connectivity-based segmentation of gray matter.
Abstract: Evidence concerning anatomical connectivities in the human brain is sparse and based largely on limited post-mortem observations. Diffusion tensor imaging has previously been used to define large white-matter tracts in the living human brain, but this technique has had limited success in tracing pathways into gray matter. Here we identified specific connections between human thalamus and cortex using a novel probabilistic tractography algorithm with diffusion imaging data. Classification of thalamic gray matter based on cortical connectivity patterns revealed distinct subregions whose locations correspond to nuclei described previously in histological studies. The connections that we found between thalamus and cortex were similar to those reported for non-human primates and were reproducible between individuals. Our results provide the first quantitative demonstration of reliable inference of anatomical connectivity between human gray matter structures using diffusion data and the first connectivity-based segmentation of gray matter.

2,296 citations


Journal ArticleDOI
TL;DR: The mentalizing (theory of mind) system of the brain is probably in operation from 18 months of age, allowing implicit attribution of intentions and other mental states, and from this age children are able to explain the misleading reasons that have given rise to a false belief.
Abstract: The mentalizing (theory of mind) system of the brain is probably in operation from ca. 18 months of age, allowing implicit attribution of intentions and other mental states. Between the ages of 4 and 6 years explicit mentalizing becomes possible, and from this age children are able to explain the misleading reasons that have given rise to a false belief. Neuroimaging studies of mentalizing have so far only been carried out in adults. They reveal a system with three components consistently activated during both implicit and explicit mentalizing tasks: medial prefrontal cortex (MPFC), temporal poles and posterior superior temporal sulcus (STS). The functions of these components can be elucidated, to some extent, from their role in other tasks used in neuroimaging studies. Thus, the MPFC region is probably the basis of the decoupling mechanism that distinguishes mental state representations from physical state representations; the STS region is probably the basis of the detection of agency, and the temporal poles might be involved in access to social knowledge in the form of scripts. The activation of these components in concert appears to be critical to mentalizing.

2,110 citations


Journal ArticleDOI
TL;DR: Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states.
Abstract: ROCKs, or Rho kinases, are serine/threonine kinases that are involved in many aspects of cell motility, from smooth-muscle contraction to cell migration and neurite outgrowth. Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states.

1,878 citations


Posted ContentDOI
TL;DR: This paper showed the importance of cognitive and non-cognitive skills that are formed early in the life cycle in accounting for racial, ethnic and family background gaps in schooling and other dimensions of socioeconomic success.
Abstract: This paper considers alternative policies for promoting skill formation that are targeted to different stages of the life cycle. We demonstrate the importance of both cognitive and noncognitive skills that are formed early in the life cycle in accounting for racial, ethnic and family background gaps in schooling and other dimensions of socioeconomic success. Most of the gaps in college attendance and delay are determined by early family factors. Children from better families and with high ability earn higher returns to schooling. We find only a limited role for tuition policy or family income supplements in eliminating schooling and college attendance gaps. At most 8% of American youth are credit constrained in the traditional usage of that term. The evidence points to a high return to early interventions and a low return to remedial or compensatory interventions later in the life cycle. Skill and ability beget future skill and ability. At current levels of funding, traditional policies like tuition subsidies, improvements in school quality, job training and tax rebates are unlikely to be effective in closing gaps.

1,656 citations


Journal ArticleDOI
TL;DR: This work proposes here that time, space and quantity are part of a generalized magnitude system and outlines A Theory Of Magnitude (ATOM) as a conceptually new framework within which to re-interpret the cortical processing of these elements of the environment.

1,651 citations


Journal ArticleDOI
TL;DR: The aim of this glossary is to encourage a dialogue that will advance the life course perspective.
Abstract: The aim of this glossary is to encourage a dialogue that will advance the life course perspective.

1,648 citations


Journal ArticleDOI
01 Dec 2003-Leukemia
TL;DR: The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels and is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.
Abstract: Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytc leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35-45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n = 278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.

1,450 citations


Journal ArticleDOI
24 Apr 2003-Neuron
TL;DR: Regression analyses revealed that responses in ventral striatum and orbitofrontal cortex were significantly correlated with this prediction error signal, suggesting that, during appetitive conditioning, computations described by temporal difference learning are expressed in the human brain.

1,433 citations


Journal ArticleDOI
TL;DR: In this paper, a detailed understanding of the sweep flocculation mechanism is provided, especially with regard to the role of charge neutralization and hydroxide precipitation. But the results can be reasonably well explained in terms of established ideas, and there are also some uncertainties regarding the action of pre-hydrolysed coagulants.

Journal ArticleDOI
01 Apr 2003-Brain
TL;DR: The present data support the phonological theory of dyslexia, while acknowledging the presence of additional sensory and motor disorders in certain individuals.
Abstract: A multiple case study was conducted in order to assess three leading theories of developmental dyslexia: (i) the phonological theory, (ii) the magnocellular (auditory and visual) theory and (iii) the cerebellar theory. Sixteen dyslexic and 16 control university students were administered a full battery of psychometric, phonological, auditory, visual and cerebellar tests. Individual data reveal that all 16 dyslexics suffer from a phonological deficit, 10 from an auditory deficit, four from a motor deficit and two from a visual magnocellular deficit. Results suggest that a phonological deficit can appear in the absence of any other sensory or motor disorder, and is sufficient to cause a literacy impairment, as demonstrated by five of the dyslexics. Auditory disorders, when present, aggravate the phonological deficit, hence the literacy impairment. However, auditory deficits cannot be characterized simply as rapid auditory processing problems, as would be predicted by the magnocellular theory. Nor are they restricted to speech. Contrary to the cerebellar theory, we find little support for the notion that motor impairments, when found, have a cerebellar origin or reflect an automaticity deficit. Overall, the present data support the phonological theory of dyslexia, while acknowledging the presence of additional sensory and motor disorders in certain individuals.

Journal ArticleDOI
TL;DR: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
Abstract: Background In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein α4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an α4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. Methods In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing–remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinica...

Journal ArticleDOI
TL;DR: It is suggested that the most important factors underlying inability to replicate these associations are publication bias, failure to attribute results to chance, and inadequate sample sizes, problems that are all rectifiable.

Journal ArticleDOI
07 Feb 2003-Science
TL;DR: The mitochondrial biogenesis induced by exposure to cold was markedly reduced in brown adipose tissue of endothelial nitric oxide synthase null-mutant (eNOS–/–) mice, which had a reduced metabolic rate and accelerated weight gain as compared to wild-type mice.
Abstract: Nitric oxide was found to trigger mitochondrial biogenesis in cells as diverse as brown adipocytes and 3T3-L1, U937, and HeLa cells. This effect of nitric oxide was dependent on guanosine 3',5'-monophosphate (cGMP) and was mediated by the induction of peroxisome proliferator-activated receptor gamma coactivator 1alpha, a master regulator of mitochondrial biogenesis. Moreover, the mitochondrial biogenesis induced by exposure to cold was markedly reduced in brown adipose tissue of endothelial nitric oxide synthase null-mutant (eNOS-/-) mice, which had a reduced metabolic rate and accelerated weight gain as compared to wild-type mice. Thus, a nitric oxide-cGMP-dependent pathway controls mitochondrial biogenesis and body energy balance.

Journal ArticleDOI
TL;DR: The GSMA produced significant genomewide evidence for linkage on chromosome 2q and suggests that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
Abstract: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Journal ArticleDOI
01 Oct 2003-Brain
TL;DR: Converging neuroimaging and clinical findings suggest that ACC function mediates context-driven modulation of bodily arousal states during effortful cognitive and motor behaviour.
Abstract: Human anterior cingulate function has been explained primarily within a cognitive framework. We used functional MRI experiments with simultaneous electrocardiography to examine regional brain activity associated with autonomic cardiovascular control during performance of cognitive and motor tasks. Using indices of heart rate variability, and high- and low-frequency power in the cardiac rhythm, we observed activity in the dorsal anterior cingulate cortex (ACC) related to sympathetic modulation of heart rate that was dissociable from cognitive and motor-related activity. The findings predict that during effortful cognitive and motor behaviour the dorsal ACC supports the generation of associated autonomic states of cardiovascular arousal. We subsequently tested this prediction by studying three patients with focal damage involving the ACC while they performed effortful cognitive and motor tests. Each showed abnormalities in autonomic cardiovascular responses with blunted autonomic arousal to mental stress when compared with 147 normal subjects tested in identical fashion. Thus, converging neuroimaging and clinical findings suggest that ACC function mediates context-driven modulation of bodily arousal states.

Journal ArticleDOI
TL;DR: An activation of pulvinar and superior colliculus by fearful expressions occurred specifically with low-frequency faces, suggesting that these subcortical pathways may provide coarse fear-related inputs to the amygdala.
Abstract: High and low spatial frequency information in visual images is processed by distinct neural channels. Using event-related functional magnetic resonance imaging (fMRI) in humans, we show dissociable roles of such visual channels for processing faces and emotional fearful expressions. Neural responses in fusiform cortex, and effects of repeating the same face identity upon fusiform activity, were greater with intact or high-spatial-frequency face stimuli than with low-frequency faces, regardless of emotional expression. In contrast, amygdala responses to fearful expressions were greater for intact or low-frequency faces than for high-frequency faces. An activation of pulvinar and superior colliculus by fearful expressions occurred specifically with low-frequency faces, suggesting that these subcortical pathways may provide coarse fear-related inputs to the amygdala.

Journal ArticleDOI
TL;DR: A comparative analysis and evaluation of three recent theories of posttraumatic stress disorder is provided, including Foa and Rothbaum's emotional processing theory, and Ehlers and Clark's cognitive theory, to identify promising areas for further research.

Journal ArticleDOI
TL;DR: In this paper, the authors presented two experiments concerning trait emotional intelligence (trait EI) and found that high trait EI participants were faster at identifying the expressions than their low EI counterparts.
Abstract: This paper presents two experiments concerning trait emotional intelligence (‘trait EI’). In study 1, ten high and ten low trait EI individuals were selected from a sample of 85 persons to participate in a computerized experiment involving the recognition of morphed emotional expressions. As hypothesized, high trait EI participants were faster at identifying the expressions than their low trait EI counterparts. In study 2, trait EI scores from 102 persons were residualized on the Big Five and subsequently 15 high and 15 low trait EI individuals were selected to participate in a mood induction experiment. As hypothesized, high trait EI participants exhibited greater sensitivity to the mood induction procedure than their low trait EI counterparts. The findings are discussed in terms of the construct validity of trait EI, with particular emphasis on the issue of incremental validity vis-a-vis broad personality traits. Copyright © 2002 John Wiley & Sons, Ltd.

Journal ArticleDOI
01 Aug 2003-Genetics
TL;DR: In this article, a Markov chain Monte Carlo algorithm is implemented to integrate over uncertain gene trees and branch lengths (or coalescence times) at each locus as well as species divergence times.
Abstract: The effective population sizes of ancestral as well as modern species are important parameters in models of population genetics and human evolution. The commonly used method for estimating ancestral population sizes, based on counting mismatches between the species tree and the inferred gene trees, is highly biased as it ignores uncertainties in gene tree reconstruction. In this article, we develop a Bayes method for simultaneous estimation of the species divergence times and current and ancestral population sizes. The method uses DNA sequence data from multiple loci and extracts information about conflicts among gene tree topologies and coalescent times to estimate ancestral population sizes. The topology of the species tree is assumed known. A Markov chain Monte Carlo algorithm is implemented to integrate over uncertain gene trees and branch lengths (or coalescence times) at each locus as well as species divergence times. The method can handle any species tree and allows different numbers of sequences at different loci. We apply the method to published noncoding DNA sequences from the human and the great apes. There are strong correlations between posterior estimates of speciation times and ancestral population sizes. With the use of an informative prior for the human-chimpanzee divergence date, the population size of the common ancestor of the two species is estimated to be ∼20,000, with a 95% credibility interval (8000, 40,000). Our estimates, however, are affected by model assumptions as well as data quality. We suggest that reliable estimates have yet to await more data and more realistic models.

Journal ArticleDOI
TL;DR: Continuous and simultaneous EEG/fMRI is implemented to identify BOLD signal changes related to spontaneous power fluctuations in the alpha rhythm, the dominant EEG pattern during relaxed wakefulness, and a strong negative correlation of parietal and frontal cortical activity with alpha power was found.

Journal ArticleDOI
TL;DR: Advances in functional neuroimaging, neurophysiology, crossed-lesion neuropsychology and computational modelling highlight the importance of understanding how the medial temporal and frontal lobes interact to allow successful remembering, and provide an opportunity to explore these interactions.
Abstract: Cognitive neuroscience has made considerable progress in understanding the involvement of the medial temporal and frontal lobes in long-term memory. Whereas the medial temporal lobe has traditionally been associated with the encoding, storage and retrieval of long-term memories, the prefrontal cortex has been linked with cognitive control processes such as selection, engagement, monitoring and inhibition. However, there has been little attempt to understand how these regions might interact during encoding and retrieval, and little consideration of the anatomical connections between them. Recent advances in functional neuroimaging, neurophysiology, crossed-lesion neuropsychology and computational modelling highlight the importance of understanding how the medial temporal and frontal lobes interact to allow successful remembering, and provide an opportunity to explore these interactions.

Journal ArticleDOI
01 Nov 2003-Brain
TL;DR: The results further the understanding of the recovery process by demonstrating for the first time a clear temporal relationship between recovery and task-related activation of the motor system after stroke.
Abstract: Recovery of motor function after stroke may occur over weeks or months and is often attributed to cerebral reorganization. We have investigated the longitudinal relationship between recovery after stroke and task-related brain activation during a motor task as measured using functional MRI (fMRI). Eight first-ever stroke patients presenting with hemiparesis resulting from cerebral infarction sparing the primary motor cortex, and four control subjects were recruited. Subjects were scanned on a number of occasions whilst performing an isometric dynamic visually paced hand grip task. Recovery in the patient group was assessed using a battery of outcome measures at each time point. Task-related brain activations decreased over sessions as a function of recovery in a number of primary and non-primary motor regions in all patients, but no session effects were seen in the controls. Furthermore, consistent decreases across sessions correlating with recovery were seen across the whole patient group independent of rate of recovery or initial severity, in primary motor cortex, premotor and prefrontal cortex, supplementary motor areas, cingulate sulcus, temporal lobe, striate cortex, cerebellum, thalamus and basal ganglia. Although recovery-related increases were seen in different brain regions in four patients, there were no consistent effects across the group. These results further our understanding of the recovery process by demonstrating for the first time a clear temporal relationship between recovery and task-related activation of the motor system after stroke.

Journal ArticleDOI
13 Feb 2003-Nature
TL;DR: It is shown, through the use of primary rat astrocytes in a cell migration assay, that Par6–PKCζ interacts directly with and regulates glycogen synthase kinase-3 β (GSK-3β) to promote polarization of the centrosome and to control the direction of cell protrusion.
Abstract: Cell polarity is a fundamental property of all cells. In higher eukaryotes, the small GTPase Cdc42, acting through a Par6-atypical protein kinase C (aPKC) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division and directed cell migration. However, little is known about what lies downstream of this complex. Here we show, through the use of primary rat astrocytes in a cell migration assay, that Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome and to control the direction of cell protrusion. Cdc42-dependent phosphorylation of GSK-3beta occurs specifically at the leading edge of migrating cells, and induces the interaction of adenomatous polyposis coli (Apc) protein with the plus ends of microtubules. The association of Apc with microtubules is essential for cell polarization. We conclude that Cdc42 regulates cell polarity through the spatial regulation of GSK-3beta and Apc. This role for Apc may contribute to its tumour-suppressor activity.

Journal ArticleDOI
TL;DR: Results indicate that subjective status is a strong predictor of ill-health, and that education, occupation and income do not explain this relationship fully for all the health measures examined, and provide further support for the multidimensional nature of both social inequality and health.

Journal ArticleDOI
TL;DR: Tight junctions have long been regarded as simple barriers that separate compartments of different compositions, but recent research indicates that different types of signalling proteins and transduction pathways are associated with these junctions.
Abstract: Tight junctions have long been regarded as simple barriers that separate compartments of different compositions, but recent research indicates that different types of signalling proteins and transduction pathways are associated with these junctions. They receive and convert signals from the cell interior to regulate junction assembly and function, and transmit signals to the cell interior to modulate gene expression and cell behaviour.

Journal ArticleDOI
TL;DR: There is geographic variation in the incidence of epileptic syndromes likely to be associated with genetic and environmental factors, although as yet causality has not been fully established.
Abstract: Purpose of reviewEpidemiology is the study of the dynamics of a medical condition in a population. There are many shortcomings in the understanding of the epidemiology of epilepsy mostly caused by methodological problems. These include diagnostic accuracy, case ascertainment, and selection bias. In

Journal ArticleDOI
01 Nov 2003-Cancer
TL;DR: The results of the first efficacy update are reported along with the results of an updated safety analysis, performed 7 months after the first analysis, based on a median follow‐up period of 47 months.
Abstract: BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer. Copyright 2003 American Cancer Society.

Journal ArticleDOI
TL;DR: It is concluded that many of the work related variables associated with high levels of psychological ill health are potentially amenable to change and shown in intervention studies that have successfully improved psychological health and reduced sickness absence.
Abstract: A literature review revealed the following: key work factors associated with psychological ill health and sickness absence in staff were long hours worked, work overload and pressure, and the effects of these on personal lives; lack of control over work; lack of participation in decision making; poor social support; and unclear management and work role. There was some evidence that sickness absence was associated with poor management style. Successful interventions that improved psychological health and levels of sickness absence used training and organisational approaches to increase participation in decision making and problem solving, increase support and feedback, and improve communication. It is concluded that many of the work related variables associated with high levels of psychological ill health are potentially amenable to change. This is shown in intervention studies that have successfully improved psychological health and reduced sickness absence.