Showing papers by "University College London published in 2004"
TL;DR: A parsimonious and evidence-based model for considering the diffusion of innovations in health service organizations, clear knowledge gaps where further research should be focused, and a robust and transferable methodology for systematically reviewing health service policy and management are discussed.
Abstract: This article summarizes an extensive literature review addressing the question, How can we spread and sustain innovations in health service delivery and organization? It considers both content (defining and measuring the diffusion of innovation in organizations) and process (reviewing the literature in a systematic and reproducible way). This article discusses (1) a parsimonious and evidence-based model for considering the diffusion of innovations in health service organizations, (2) clear knowledge gaps where further research should be focused, and (3) a robust and transferable methodology for systematically reviewing health service policy and management. Both the model and the method should be tested more widely in a range of contexts.
6,140 citations
Goddard Space Flight Center1, University of Milan2, Brera Astronomical Observatory3, University College London4, Pennsylvania State University5, University of Leicester6, Sonoma State University7, University of California, Berkeley8, Universities Space Research Association9, National Research Council10, University of Southampton11, Los Alamos National Laboratory12, National Radio Astronomy Observatory13, Space Telescope Science Institute14, Max Planck Society15, California Institute of Technology16, University of Texas at Austin17, French Alternative Energies and Atomic Energy Commission18, University of Toronto19, University of Maryland, College Park20, Princeton University21, Lawrence Livermore National Laboratory22, University of Cambridge23, University of California, Santa Barbara24, Rice University25, University of Tokyo26, Saitama University27, University of Florence28
TL;DR: The Swift mission as discussed by the authors is a multi-wavelength observatory for gamma-ray burst (GRB) astronomy, which is a first-of-its-kind autonomous rapid-slewing satellite for transient astronomy and pioneers the way for future rapid-reaction and multiwavelength missions.
Abstract: The Swift mission, scheduled for launch in 2004, is a multiwavelength observatory for gamma-ray burst (GRB) astronomy. It is a first-of-its-kind autonomous rapid-slewing satellite for transient astronomy and pioneers the way for future rapid-reaction and multiwavelength missions. It will be far more powerful than any previous GRB mission, observing more than 100 bursts yr � 1 and performing detailed X-ray and UV/optical afterglow observations spanning timescales from 1 minute to several days after the burst. The objectives are to (1) determine the origin of GRBs, (2) classify GRBs and search for new types, (3) study the interaction of the ultrarelativistic outflows of GRBs with their surrounding medium, and (4) use GRBs to study the early universe out to z >10. The mission is being developed by a NASA-led international collaboration. It will carry three instruments: a newgeneration wide-field gamma-ray (15‐150 keV) detector that will detect bursts, calculate 1 0 ‐4 0 positions, and trigger autonomous spacecraft slews; a narrow-field X-ray telescope that will give 5 00 positions and perform spectroscopy in the 0.2‐10 keV band; and a narrow-field UV/optical telescope that will operate in the 170‐ 600 nm band and provide 0B3 positions and optical finding charts. Redshift determinations will be made for most bursts. In addition to the primary GRB science, the mission will perform a hard X-ray survey to a sensitivity of � 1m crab (� 2;10 � 11 ergs cm � 2 s � 1 in the 15‐150 keV band), more than an order of magnitude better than HEAO 1 A-4. A flexible data and operations system will allow rapid follow-up observations of all types of
3,753 citations
TL;DR: Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol.
3,578 citations
TL;DR: Only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy, suggesting that the neural substrate for empathic experience does not involve the entire "pain matrix".
Abstract: Our ability to have an experience of another's pain is characteristic of empathy. Using functional imaging, we assessed brain activity while volunteers experienced a painful stimulus and compared it to that elicited when they observed a signal indicating that their loved one--present in the same room--was receiving a similar pain stimulus. Bilateral anterior insula (AI), rostral anterior cingulate cortex (ACC), brainstem, and cerebellum were activated when subjects received pain and also by a signal that a loved one experienced pain. AI and ACC activation correlated with individual empathy scores. Activity in the posterior insula/secondary somatosensory cortex, the sensorimotor cortex (SI/MI), and the caudal ACC was specific to receiving pain. Thus, a neural response in AI and rostral ACC, activated in common for "self" and "other" conditions, suggests that the neural substrate for empathic experience does not involve the entire "pain matrix." We conclude that only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy.
3,425 citations
TL;DR: The identification of two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families provide a direct molecular link between mitochondria and the pathogenesis of PD.
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6) Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6 We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress These data provide a direct molecular link between mitochondria and the pathogenesis of PD
3,224 citations
Journal Article•
University of British Columbia1, University of Birmingham2, University of Western Australia3, University of Rochester4, Cincinnati Children's Hospital Medical Center5, Federal University of São Paulo6, Capital Medical University7, University of Buenos Aires8, University of Guadalajara9, University of Paris10, University College London11
TL;DR: The second revision of the ILAR Taskforce on Classification of Childhood Arthritis (ILAR-JIA) was presented at the 2001 ILAR Workshop on Rheumatology as discussed by the authors.
Abstract: The primary aim of the International League of Associations for Rheumatology (ILAR) proposals for classification of juvenile idiopathic arthritis (JIA) is to delineate, for research purposes, relatively homogeneous, mutually exclusive categories of idiopathic childhood arthritis based on predominant clinical and laboratory features. As part of a continuing review process, the ILAR Taskforce on Classification of Childhood Arthritis met in Edmonton in 2001 to discuss modifications to the proposed JIA classification. Since the publication of the first revision of the original classification 1 , a number of descriptive studies using the new classification have been reported 2-11. The aims of this communication are 2-fold: to outline modifications to the revised classification proposed as a result of the Edmonton meeting, and to correct misconceptions highlighted by the published studies concerning the clinical use of the classification. The Edmonton Revision The changes embodied in the second revision of the classification are as follows: 1. Clarification of the definitions of each category. 2. Improvement in the congruity between inclusion and exclusion criteria. 3. Removal of the requirement that a dermatologist make the diagnosis of psoriasis. 4. Removal of the requirement that there be medical confirmation of HLA-B27 associated disease in a relative. 5. Reduction in the age for criterion " 3 " of enthesitis related arthritis, and exclusion " b " from 8 years to 6 years of age. 6. Improvement in the consistency of the structure. The impracticality of the requirement that a diagnosis of psoriasis be made by a dermatologist was recognized, and this requirement was modified so that the diagnosis of psori-asis could be made by a physician (not necessarily a dermatologist). Similarly, it is no longer required that there be medical confirmation of an HLA-B27 associated disease in a relative as contained in exclusion " c. " It is evident that it is very difficult to obtain a reliable history of psoriasis or an HLA-B27 associated disease in a second-degree relative. Therefore, a history of importance to the application of the criteria is restricted to the patient or a first-degree relative (parents or siblings) only. The study of Murray, et al 8 indicated that the HLA-B27 association is important in boys over the age of 6 years at onset of arthritis, and this age was substituted for 8 years in exclusion " b. " Discrepancies between inclusion and exclusion criteria were resolved, and the exclusions were identified by the letters …
3,201 citations
TL;DR: In right anterior insular/opercular cortex, neural activity predicted subjects' accuracy in the heartbeat detection task and local gray matter volume correlated with both interoceptive accuracy and subjective ratings of visceral awareness.
Abstract: Influential theories of human emotion argue that subjective feeling states involve representation of bodily responses elicited by emotional events. Within this framework, individual differences in intensity of emotional experience reflect variation in sensitivity to internal bodily responses. We measured regional brain activity by functional magnetic resonance imaging (fMRI) during an interoceptive task wherein subjects judged the timing of their own heartbeats. We observed enhanced activity in insula, somatomotor and cingulate cortices. In right anterior insular/opercular cortex, neural activity predicted subjects' accuracy in the heartbeat detection task. Furthermore, local gray matter volume in the same region correlated with both interoceptive accuracy and subjective ratings of visceral awareness. Indices of negative emotional experience correlated with interoceptive accuracy across subjects. These findings indicate that right anterior insula supports a representation of visceral responses accessible to awareness, providing a substrate for subjective feeling states.
2,972 citations
TL;DR: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotRexate, provided significant improvement in disease symptoms at both weeks 24 and 48.
Abstract: Background An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. Methods We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (≥10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). Results At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab–methotre...
2,469 citations
TL;DR: This work shows that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains, and provides proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
Abstract: Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
2,335 citations
TL;DR: The current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor‐β (TGF‐β), connective tissue growth factor (CTGF, CCN2), and ED‐A fibronectin (ED‐A FN) and the antifib rotic proteins tumor necrosis factor‐α (TNF‐α) and γ‐interferon (IFN‐γ) is discussed.
Abstract: The cause of fibrotic diseases, pathologies characterized by excessive production, deposition, and contraction of extracellular matrix, is unknown. To understand the molecular basis of fibrotic disease, it is essential to appreciate how matrix deposition is normally controlled and how this process is dysregulated in fibrogenesis. This review discusses the current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF, CCN2), and ED-A fibronectin (ED-A FN) and the antifibrotic proteins tumor necrosis factor-α (TNF-α) and γ-interferon (IFN-γ).—Leask, A., Abraham, D. J. TGF-β signaling and the fibrotic response.
2,147 citations
TL;DR: Two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
Abstract: The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
TL;DR: This work scanned human participants with functional magnetic resonance imaging while they engaged in instrumental conditioning to suggest partly dissociable contributions of the ventral and dorsal striatum to the critic and the actor.
Abstract: Instrumental conditioning studies how animals and humans choose actions appropriate to the affective structure of an environment. According to recent reinforcement learning models, two distinct components are involved: a "critic," which learns to predict future reward, and an "actor," which maintains information about the rewarding outcomes of actions to enable better ones to be chosen more frequently. We scanned human participants with functional magnetic resonance imaging while they engaged in instrumental conditioning. Our results suggest partly dissociable contributions of the ventral and dorsal striatum, with the former corresponding to the critic and the latter corresponding to the actor.
TL;DR: An automatic method for recognizing natively disordered regions from amino acid sequence is described and benchmarked against predictors that were assessed at the latest critical assessment of techniques for protein structure prediction (CASP) experiment and represents a statistically significant improvement on the methods evaluated on the same targets at CASP.
TL;DR: A psychometrically well-justified measure of work-related stress (ERI) grounded in sociological theory is available for comparative socioepidemiologic investigations in advanced societies within and beyond Europe.
TL;DR: Improvements in therapy consist of more effective and better-tolerated drugs to lower intraocular pressure, and more effective surgical procedures to directly treat and protect the retinal ganglion cells that are damaged in glaucoma.
TL;DR: This work shows that subjects internally represent both the statistical distribution of the task and their sensory uncertainty, combining them in a manner consistent with a performance-optimizing bayesian process.
Abstract: When we learn a new motor skill, such as playing an approaching tennis ball, both our sensors and the task possess variability. Our sensors provide imperfect information about the ball's velocity, so we can only estimate it. Combining information from multiple modalities can reduce the error in this estimate. On a longer time scale, not all velocities are a priori equally probable, and over the course of a match there will be a probability distribution of velocities. According to bayesian theory, an optimal estimate results from combining information about the distribution of velocities-the prior-with evidence from sensory feedback. As uncertainty increases, when playing in fog or at dusk, the system should increasingly rely on prior knowledge. To use a bayesian strategy, the brain would need to represent the prior distribution and the level of uncertainty in the sensory feedback. Here we control the statistical variations of a new sensorimotor task and manipulate the uncertainty of the sensory feedback. We show that subjects internally represent both the statistical distribution of the task and their sensory uncertainty, combining them in a manner consistent with a performance-optimizing bayesian process. The central nervous system therefore employs probabilistic models during sensorimotor learning.
Lund University1, University of Colorado Denver2, University of California, San Diego3, University of Grenoble4, Mayo Clinic5, University of Hawaii6, University of Washington7, University of Portland8, University of Melbourne9, University of Medicine and Dentistry of New Jersey10, University of Lyon11, University of Edinburgh12, University College London13, University of Michigan14
TL;DR: The CEAP classification for chronic venous disorders was developed in 1994 by an international ad hoc committee of the American Venous Forum, endorsed by the Society for Vascular Surgery, and incorporated into "Reporting Standards in Venous Disease" in 1995.
22 Aug 2004
TL;DR: An approach to multi--task learning based on the minimization of regularization functionals similar to existing ones, such as the one for Support Vector Machines, that have been successfully used in the past for single-- task learning is presented.
Abstract: Past empirical work has shown that learning multiple related tasks from data simultaneously can be advantageous in terms of predictive performance relative to learning these tasks independently. In this paper we present an approach to multi--task learning based on the minimization of regularization functionals similar to existing ones, such as the one for Support Vector Machines (SVMs), that have been successfully used in the past for single--task learning. Our approach allows to model the relation between tasks in terms of a novel kernel function that uses a task--coupling parameter. We implement an instance of the proposed approach similar to SVMs and test it empirically using simulated as well as real data. The experimental results show that the proposed method performs better than existing multi--task learning methods and largely outperforms single--task learning using SVMs.
TL;DR: Rho GTPases control signal transduction pathways that link cell surface receptors to a variety of intracellular responses, and their role in cell migration is reviewed.
TL;DR: In this article, a load theory of attention in which distractor rejection depends on the level and type of load involved in current processing was tested, and it was shown that whereas high perceptual load reduces distractor interference, working memory load or dual-task coordination load increases distractor interferences.
Abstract: A load theory of attention in which distractor rejection depends on the level and type of load involved in current processing was tested. A series of experiments demonstrates that whereas high perceptual load reduces distractor interference, working memory load or dual-task coordination load increases distractor interference. These findings suggest 2 selective attention mechanisms: a perceptual selection mechanism serving to reduce distractor perception in situations of high perceptual load that exhaust perceptual capacity in processing relevant stimuli and a cognitive control mechanism that reduces interference from perceived distractors as long as cognitive control functions are available to maintain current priorities (low cognitive load). This theory resolves the long-standing early versus late selection debate and clarifies the role of cognitive control in selective attention.
TL;DR: This review outlines recent findings from human neuroimaging concerning the role of a highly interconnected network of brain areas including orbital and medial prefrontal cortex, amygdala, striatum and dopaminergic mid-brain in reward processing.
TL;DR: It is concluded that human attachment employs a push-pull mechanism that overcomes social distance by deactivating networks used for critical social assessment and negative emotions, while it bonds individuals through the involvement of the reward circuitry, explaining the power of love to motivate and exhilarate.
TL;DR: These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of Regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
Abstract: Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
TL;DR: The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website have been developed to store somatic mutation data in a single location and display the data and other information related to human cancer.
Abstract: The discovery of mutations in cancer genes has advanced our understanding of cancer. These results are dispersed across the scientific literature and with the availability of the human genome sequence will continue to accrue. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website have been developed to store somatic mutation data in a single location and display the data and other information related to human cancer. To populate this resource, data has currently been extracted from reports in the scientific literature for somatic mutations in four genes, BRAF, HRAS, KRAS2 and NRAS. At present, the database holds information on 66 634 samples and reports a total of 10 647 mutations. Through the web pages, these data can be queried, displayed as figures or tables and exported in a number of formats. COSMIC is an ongoing project that will continue to curate somatic mutation data and release it through the website.
TL;DR: In this paper, the authors investigated the relationship between product market competition and innovation and found a robust inverted-U relationship between competition and patenting, and developed an endogenousm growth model with step-by-step innovation that can deliver this inverted U pattern.
Abstract: This paper investigates the relationship between product market competition and innovation. It uses the radical policy reforms in the UK as instruments for changes in product market competition, and finds a robust inverted-U relationship between competition and patenting. It then develops an endogenousm growth model with step-by-step innovation that can deliver this inverted-U pattern. In this model, competition has an ambiguous effect on innovation. On the one hand, it discourages laggard firms from innovating, as it reduces their rents from catching up with the leaders in the same industry. On the other hand, it encourages neck-and-neck firms to innovate in order to escape competition with their rival. The inverted-U pattern results from the interplay between these two effects, together with the effect of competition on the equilibrium industry structure. The model generates two additional predictions: on the relationship between competition and the average technological distance between leaders and followers across industries; and on the relationship between the distance of an industry to its technological frontier and the steepness of the inverted-U. Both predictions are supported by the data.
TL;DR: The results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.
Abstract: Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.
TL;DR: Examining 4 food choice behaviors in a large sample of young adults from 23 countries finds that women were more likely than men to report avoiding high-fat foods, eating fruit and fiber, and limiting salt, and together they explained almost 50%.
Abstract: Background: Gender differences in health behaviors have been reported in many studies but causal mechanisms have been neglected.Purpose and Methods: This study examines 4 food choice behaviors in a large sample of young adults from 23 countries and tests 2 possible explanatory mechanisms for the gender differences—women’s greater likelihood of dieting and women’s greater beliefs in the importance of healthy diets.Results: Women were more likely than men to report avoiding high-fat foods, eating fruit and fiber, and limiting salt (to a lesser extent) in almost all of the 23 countries. They were also more likely to be dieting and attached greater importance to healthy eating. Dieting status explained around 22% of the gender difference in fat choices, 23% of fiber choices, and 7% of fruit, but none of the gender difference in salt. Health beliefs explained around 40% of the differences in each of the dietary behaviors and together they explained almost 50%. Gender differences in food choices therefore appear to be partly attributable to women’s greater weight control involvement and partly to their stronger belifs in healthy eating.Conclusions: Further research is needed to understand the additional factors that could promote men’s participation in simple healthy eating practices.
Istanbul University1, University of Bergen2, University of Manchester3, University of Kiel4, Autonomous University of Barcelona5, University of Groningen6, University College London7, Innsbruck Medical University8, Université de Montréal9, University of Lisbon10, VU University Amsterdam11, Novartis12
TL;DR: In this paper, the effects of the dual cholinesterase inhibitor rivastigmine in patients with mild-to-moderate dementia associated with Parkinson's disease were investigated.
Abstract: background Cholinergic deficits are prominent in patients who have dementia associated with Parkinson’s disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. methods Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson’s disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and Alzheimer’s Disease Cooperative Study–Clinician’s Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer’s Disease Cooperative Study–Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini–Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. results A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer’s disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). conclusions In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson’s disease but also with higher rates of nausea, vomiting, and tremor.
TL;DR: A gene map of the xMHC is presented and its content in relation to paralogy, polymorphism, immune function and disease is reviewed.
Abstract: The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.
Saint Louis University1, Amgen2, University of New South Wales3, University of Toronto4, University College London5, Yale University6, Washington University in St. Louis7, University of Pennsylvania8, Katholieke Universiteit Leuven9, Indiana University – Purdue University Indianapolis10, University of Picardie Jules Verne11, University of Paris12, University of California, Los Angeles13
TL;DR: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.
Abstract: BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.