Showing papers by "University of Pittsburgh published in 2005"

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

Abstract: Background We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. Methods The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclit...

Simulations of the formation, evolution and clustering of galaxies and quasars

Abstract: The cold dark matter model has become the leading theoretical picture for the formation of structure in the Universe. This model, together with the theory of cosmic inflation, makes a clear prediction for the initial conditions for structure formation and predicts that structures grow hierarchically through gravitational instability. Testing this model requires that the precise measurements delivered by galaxy surveys can be compared to robust and equally precise theoretical calculations. Here we present a simulation of the growth of dark matter structure using 2,1603 particles, following them from redshift z = 127 to the present in a cube-shaped region 2.230 billion lightyears on a side. In postprocessing, we also follow the formation and evolution of the galaxies and quasars. We show that baryon-induced features in the initial conditions of the Universe are reflected in distorted form in the low-redshift galaxy distribution, an effect that can be used to constrain the nature of dark energy with future generations of observational surveys of galaxies.

Detection of the baryon acoustic peak in the large-scale correlation function of SDSS luminous red galaxies

Abstract: We present the large-scale correlation function measured from a spectroscopic sample of 46,748 luminous red galaxies from the Sloan Digital Sky Survey. The survey region covers 0.72h −3 Gpc 3 over 3816 square degrees and 0.16 < z < 0.47, making it the best sample yet for the study of large-scale structure. We find a well-detected peak in the correlation function at 100h −1 Mpc separation that is an excellent match to the predicted shape and location of the imprint of the recombination-epoch acoustic oscillations on the low-redshift clustering of matter. This detection demonstrates the linear growth of structure by gravitational instability between z ≈ 1000 and the present and confirms a firm prediction of the standard cosmological theory. The acoustic peak provides a standard ruler by which we can measure the ratio of the distances to z = 0.35 and z = 1089 to 4% fractional accuracy and the absolute distance to z = 0.35 to 5% accuracy. From the overall shape of the correlation function, we measure the matter density mh 2 to 8% and find agreement with the value from cosmic microwave background (CMB) anisotropies. Independent of the constraints provided by the CMB acoustic scale, we find m = 0.273 ±0.025+0.123(1+ w0)+0.137K. Including the CMB acoustic scale, we find that the spatial curvature is K = −0.010 ± 0.009 if the dark energy is a cosmological constant. More generally, our results provide a measurement of cosmological distance, and hence an argument for dark energy, based on a geometric method with the same simple physics as the microwave background anisotropies. The standard cosmological model convincingly passes these new and robust tests of its fundamental properties. Subject headings: cosmology: observations — large-scale structure of the universe — distance scale — cosmological parameters — cosmic microwave background — galaxies: elliptical and lenticular, cD

Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Acute Renal Failure in Critically Ill Patients: A Multinational, Multicenter Study

Abstract: ContextAlthough acute renal failure (ARF) is believed to be common in the setting of critical illness and is associated with a high risk of death, little is known about its epidemiology and outcome or how these vary in different regions of the world.ObjectivesTo determine the period prevalence of ARF in intensive care unit (ICU) patients in multiple countries; to characterize differences in etiology, illness severity, and clinical practice; and to determine the impact of these differences on patient outcomes.Design, Setting, and PatientsProspective observational study of ICU patients who either were treated with renal replacement therapy (RRT) or fulfilled at least 1 of the predefined criteria for ARF from September 2000 to December 2001 at 54 hospitals in 23 countries.Main Outcome MeasuresOccurrence of ARF, factors contributing to etiology, illness severity, treatment, need for renal support after hospital discharge, and hospital mortality.ResultsOf 29 269 critically ill patients admitted during the study period, 1738 (5.7%; 95% confidence interval [CI], 5.5%-6.0%) had ARF during their ICU stay, including 1260 who were treated with RRT. The most common contributing factor to ARF was septic shock (47.5%; 95% CI, 45.2%-49.5%). Approximately 30% of patients had preadmission renal dysfunction. Overall hospital mortality was 60.3% (95% CI, 58.0%-62.6%). Dialysis dependence at hospital discharge was 13.8% (95% CI, 11.2%-16.3%) for survivors. Independent risk factors for hospital mortality included use of vasopressors (odds ratio [OR], 1.95; 95% CI, 1.50-2.55; P<.001), mechanical ventilation (OR, 2.11; 95% CI, 1.58-2.82; P<.001), septic shock (OR, 1.36; 95% CI, 1.03-1.79; P = .03), cardiogenic shock (OR, 1.41; 95% CI, 1.05-1.90; P = .02), and hepatorenal syndrome (OR, 1.87; 95% CI, 1.07-3.28; P = .03).ConclusionIn this multinational study, the period prevalence of ARF requiring RRT in the ICU was between 5% and 6% and was associated with a high hospital mortality rate.

Recognizing Contextual Polarity in Phrase-Level Sentiment Analysis

Abstract: This paper presents a new approach to phrase-level sentiment analysis that first determines whether an expression is neutral or polar and then disambiguates the polarity of the polar expressions. With this approach, the system is able to automatically identify the contextual polarity for a large subset of sentiment expressions, achieving results that are significantly better than baseline.

Extended-spectrum beta-lactamases: a clinical update.

Abstract: Extended-spectrum β-lactamases (ESBLs) are a rapidly evolving group of β-lactamases which share the ability to hydrolyze third-generation cephalosporins and aztreonam yet are inhibited by clavulanic acid. Typically, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described. The presence of ESBLs carries tremendous clinical significance. The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. There is substantial debate as to the optimal method to prevent this occurrence. It has been proposed that cephalosporin breakpoints for the Enterobacteriaceae should be altered so that the need for ESBL detection would be obviated. At present, however, organizations such as the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) provide guidelines for the detection of ESBLs in klebsiellae and Escherichia coli. In common to all ESBL detection methods is the general principle that the activity of extended-spectrum cephalosporins against ESBL-producing organisms will be enhanced by the presence of clavulanic acid. ESBLs represent an impressive example of the ability of gram-negative bacteria to develop new antibiotic resistance mechanisms in the face of the introduction of new antimicrobial agents.

Twelve-Month Use of Mental Health Services in the United States Results From the National Comorbidity Survey Replication

Abstract: Background Dramatic changes have occurred in mental health treatments during the past decade. Data on recent treatment patterns are needed to estimate the unmet need for services. Objective To provide data on patterns and predictors of 12-month mental health treatment in the United States from the recently completed National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey using a fully structured diagnostic interview, the World Health Organization’s World Mental Health Survey Initiative version of the Composite International Diagnostic Interview, carried out between February 5, 2001, and April 7, 2003. Participants A total of 9282 English-speaking respondents 18 years and older. Main Outcome Measures Proportions of respondents with 12-monthDSM-IVanxiety, mood, impulse control, and substance disorders who received treatment in the 12 months before the interview in any of 4 service sectors (specialty mental health, general medical, human services, and complementary and alternative medicine). Number of visits and proportion of patients who received minimally adequate treatment were also assessed. Results Of 12-month cases, 41.1% received some treatment in the past 12 months, including 12.3% treated by a psychiatrist, 16.0% treated by a nonpsychiatrist mental health specialist, 22.8% treated by a general medical provider, 8.1% treated by a human services provider, and 6.8% treated by a complementary and alternative medical provider (treatment could be received by >1 source). Overall, cases treated in the mental health specialty sector received more visits (median, 7.4) than those treated in the general medical sector (median, 1.7). More patients in specialty than general medical treatment also received treatment that exceeded a minimal threshold of adequacy (48.3% vs 12.7%). Unmet need for treatment is greatest in traditionally underserved groups, including elderly persons, racial-ethnic minorities, those with low incomes, those without insurance, and residents of rural areas. Conclusions Most people with mental disorders in the United States remain either untreated or poorly treated. Interventions are needed to enhance treatment initiation and quality.

High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal.

Abstract: High-mobility group box 1 protein (HMGB1), which previously was thought to function only as a nuclear factor that enhances transcription, was recently discovered to be a crucial cytokine that mediates the response to infection, injury and inflammation. These observations have led to the emergence of a new field in immunology that is focused on understanding the mechanisms of HMGB1 release, its biological activities and its pathological effects in sepsis, arthritis, cancer and other diseases. Here, we discuss these features of HMGB1 and summarize recent advances that have led to the preclinical development of therapeutics that modulate HMGB1 release and activity.

Cortical inhibitory neurons and schizophrenia

Abstract: Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (γ-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.

Low-level environmental lead exposure and children's intellectual function: an international pooled analysis.

Abstract: Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels < 10 µg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels < 10 µg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5‐10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 µg/dL and declined to 9.4 µg/dL by 5‐7 years of age; 244 (18%) children had a maximal blood lead concentration < 10 µg/dL, and 103 (8%) had a maximal blood lead concentration < 7.5 µg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a loglinear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2‐9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 µg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 µg/dL, 10 to 20 µg/dL, and 20 to 30 µg/dL were 3.9 (95% CI, 2.4‐5.3), 1.9 (95% CI, 1.2‐2.6), and 1.1 (95% CI, 0.7‐1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level < 7.5 µg/dL was significantly greater than that observed for those with a maximal blood lead level ≥ 7.5 µg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels < 7.5 µg/dL is asso

5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression

Abstract: Carriers of the short allele of a functional 5¢ promoter polymorphism of the serotonin transporter gene have increased anxietyrelated temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdalacingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression. Depression is among the four leading causes of disability and disease burden throughout the world and is associated with serious medical conditions and mortality across the lifespan 1,2 . The importance of serotonergic neurotransmission for the pathogenesis of depression is suggested clinically by the efficacy of serotonin re-uptake inhibitors (SSRIs), the first-line treatment of depression and most related anxiety disorders 1 and by induction of depression by tryptophan depletion in susceptible individuals 2 . Post-mortem and in vivo studies of the serotonin transporter (5-HTT) and receptors support a role for this neurotransmitter system in depression and anxiety disorders 1 . Further

Annotating Expressions of Opinions and Emotions in Language

Abstract: This paper describes a corpus annotation project to study issues in the manual annotation of opinions, emotions, sentiments, speculations, evaluations and other private states in language. The resulting corpus annotation scheme is described, as well as examples of its use. In addition, the manual annotation process and the results of an inter-annotator agreement study on a 10,000-sentence corpus of articles drawn from the world press are presented.

Prevalence and Treatment of Mental Disorders, 1990 to 2003.

Abstract: Background Although the 1990s saw enormous change in the mental health care system in the United States, little is known about changes in the prevalence or rate of treatment of mental disorders. Methods We examined trends in the prevalence and rate of treatment of mental disorders among people 18 to 54 years of age during roughly the past decade. Data from the National Comorbidity Survey (NCS) were obtained in 5388 face-to-face household interviews conducted between 1990 and 1992, and data from the NCS Replication were obtained in 4319 interviews conducted between 2001 and 2003. Anxiety disorders, mood disorders, and substance-abuse disorders that were present during the 12 months before the interview were diagnosed with the use of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Treatment for emotional disorders was categorized according to the sector of mental health services: psychiatry services, other mental health services, general...

Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis

Abstract: methods We randomly assigned patients with transient ischemic attack or stroke caused by angiographically verified 50 to 99 percent stenosis of a major intracranial artery to receive warfarin (target international normalized ratio, 2.0 to 3.0) or aspirin (1300 mg per day) in a double-blind, multicenter clinical trial. The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke. results After 569 patients had undergone randomization, enrollment was stopped because of concerns about the safety of the patients who had been assigned to receive warfarin. During a mean follow-up period of 1.8 years, adverse events in the two groups included death (4.3 percent in the aspirin group vs. 9.7 percent in the warfarin group; hazard ratio for aspirin relative to warfarin, 0.46; 95 percent confidence interval, 0.23 to 0.90; P=0.02), major hemorrhage (3.2 percent vs. 8.3 percent, respectively; hazard ratio, 0.39; 95 percent confidence interval, 0.18 to 0.84; P=0.01), and myocardial infarction or sudden death (2.9 percent vs. 7.3 percent, respectively; hazard ratio, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.02). The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group (P=0.16); the rate of death from nonvascular causes was 1.1 percent and 3.8 percent, respectively (P=0.05). The primary end point occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent of those in the warfarin group (hazard ratio, 1.04; 95 percent confidence interval, 0.73 to 1.48; P=0.83). conclusions Warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin in this trial. Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.

A new calibration of stellar parameters of Galactic O stars

Abstract: We present new calibrations of stellar parameters of O stars at solar metallicity taking non-LTE, wind, and line-blanketing effects into account. Gravities and absolute visual magnitudes are derived from results of recent spectroscopic analyses. Two types of effective temperature scales are derived: one from a compilation based on recent spectroscopic studies of a sample of massive stars – the “observational scale” – and the other from direct interpolations on a grid of non-LTE spherically extended line-blanketed models computed with the code CMFGEN (Hillier & Miller 1998) – the “theoretical scale”. These T eff scales are then further used together with the grid of models to calibrate other parameters (bolometric correction, luminosity, radius, spectroscopic mass and ionising fluxes) as a function of spectral type and luminosity class. Compared to the earlier calibrations of Vacca et al. (1996) the main results are: [–] The effective temperature scales of dwarfs, giants and supergiants are cooler by 2000 to 8000 K, the theoretical scale being slightly cooler than the observational one. The reduction is the largest for the earliest spectral types and for supergiants. [–] Bolometric corrections as a function of T eff are reduced by 0.1 mag due to line blanketing which redistributes part of the UV flux in the optical range. For a given spectral type the reduction of BC is larger for early types and for supergiants. Typically BCs derived using the theoretical T eff scale are 0.40 to 0.60 mag lower than that of Vacca et al. (1996), whereas the differences using the observational T eff scale are somewhat smaller. [–] Luminosities are reduced by 0.20 to 0.35 dex for dwarfs, by ~0.25 for all giants and by 0.25 to 0.35 dex for supergiants. The reduction is essentially the same for both T eff scales. It is independent of spectral type for giants and supergiants and is slightly larger for late type than for early type dwarfs. [–] Lyman continuum fluxes are reduced. Our theoretical values for the hydrogen ionising photon fluxes for dwarfs are 0.20 to 0.80 dex lower than those of Vacca et al. (1996), the difference being larger at late spectral types. For giants the reduction is of 0.25 to 0.55 dex, while for supergiants it is of 0.30 to 0.55 dex. Using the observational T eff scale leads to smaller reductions at late spectral types. The present results should represent a significant improvement over previous calibrations, given the detailed treatment of non-LTE line-blanketing in the expanding atmospheres of massive stars.

Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice

Abstract: Single-walled carbon nanotubes (SWCNT) are new materials of emerging technological importance. As SWCNT are introduced into the life cycle of commercial products, their effects on human health and ...

Tamoxifen for the Prevention of Breast Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

Abstract: Background: Initial fi ndings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor – positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical signifi cance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial fi ndings. Methods: Women (n = 13 388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confi dence intervals (CIs). Estimates of the net benefi t from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided. Results: After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically signifi cant. The net benefi t achieved with tamoxifen varied according to age, race, and level of breast cancer risk. Conclusions: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all benefi cial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboem bolic events and endometrial cancer. Readily identifi able sub sets of individuals comprising 2.5 million women could derive a net benefi t from the drug. [J Natl Cancer Inst 2005;97:1652 – 62]

Antecedents of knowledge transfer from consultants to clients in enterprise system implementations

Abstract: Enterprise resource planning (ERP) systems and other complex information systems represent critical organizational resources. For such systems, firms typically use consultants to aid in the implementation process. Client firms expect consultants to transfer their implementation knowledge to their employees so that they can contribute to successful implementations and learn to maintain the systems independent of the consultants. This study examines the antecedents of knowledge transfer in the context of such an interfirm complex information systems implementation environment. Drawing from the knowledge transfer, information systems, and communication literatures, an integrated theoretical model is developed that posits that knowledge transfer is influenced by knowledge-related, motivational, and communication-related factors. Data were collected from consultant-and-client matched-pair samples from 96 ERP implementation projects. Unlike most prior studies, a behavioral measure of knowledge transfer that incorporates the application of knowledge was used. The analysis suggests that all three groups of factors influence knowledge transfer, and provides support for 9 of the 13 hypotheses. The analysis also confirms two mediating relationships. These results (1) adapt prior research, primarily done in non-IS contexts, to the ERP implementation context, (2) enhance prior findings by confirming the significance of an antecedent that has previously shown mixed results, and (3) incorporate new IS-related constructs and measures in developing an integrated model that should be broadly applicable to the interfirm IS implementation context and other IS situations. Managerial and research implications are discussed.

Cystatin C and the risk of death and cardiovascular events among elderly persons.

Abstract: Background Cystatin C is a serum measure of renal function that appears to be independent of age, sex, and lean muscle mass. We compared creatinine and cystatin C levels as predictors of mortality from cardiovascular causes and from all causes in the Cardiovascular Health Study, a cohort study of elderly persons living in the community. Methods Creatinine and cystatin C were measured in serum samples collected from 4637 participants at the study visit in 1992 or 1993; follow-up continued until June 30, 2001. For each measure, the study population was divided into quintiles, with the fifth quintile subdivided into thirds (designated 5a, 5b, and 5c). Results Higher cystatin C levels were directly associated, in a dose–response manner, with a higher risk of death from all causes. As compared with the first quintile, the hazard ratios (and 95 percent confidence intervals) for death were as follows: second quintile, 1.08 (0.86 to 1.35); third quintile, 1.23 (1.00 to 1.53); fourth quintile, 1.34 (1.09 to 1.66);...

Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons

Abstract: BACKGROUND: Lower muscle mass has been correlated with poor physical function; however, no studies have examined this relationship prospectively. This study aims to investigate whether low muscle mass, low muscle strength, and greater fat infiltration into the muscle predict incident mobility limitation. METHODS: Our study cohort included 3075 well-functioning black and white men and women aged 70-79 years participating in the Health, Aging, and Body Composition study. Participants were followed for 2.5 years. Muscle cross-sectional area and muscle tissue attenuation (a measure of fat infiltration) were measured by computed tomography at the mid-thigh, and knee extensor strength by using a KinCom dynamometer. Incident mobility limitation was defined as two consecutive self-reports of any difficulty walking one-quarter mile or climbing 10 steps. RESULTS: Mobility limitations were developed by 22.3% of the men and by 31.8% of the women. Cox's proportional hazards models, adjusting for demographic, lifestyle, and health factors, showed a hazard ratio of 1.90 [95% confidence interval (CI), 1.27-2.84] in men and 1.68 (95% CI, 1.23-2.31) in women for the lowest compared to the highest quartile of muscle area (p <.01 for trend). Results for muscle strength were 2.02 (95% CI, 1.39-2.94) and 1.91 (95% CI, 1.41-2.58), p <.001 trend, and for muscle attenuation were 1.91 (95% CI, 1.31-2.83) and 1.68 (95% CI, 1.20-2.35), p <.01 for trend. When included in one model, only muscle attenuation and muscle strength independently predicted mobility limitation (p < .05). Among men and women, associations were similar for blacks and whites. CONCLUSION: Lower muscle mass (smaller cross-sectional thigh muscle area), greater fat infiltration into the muscle, and lower knee extensor muscle strength are associated with increased risk of mobility loss in older men and women. The association between low muscle mass and functional decline seems to be a function of underlying muscle strength.

Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults.

Abstract: Background— Aging results in vascular stiffening and an increase in the velocity of the pressure wave as it travels down the aorta. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. The objective of this investigation was to determine whether aPWV is associated with total and cardiovascular (CV) mortality and CV events in a community-dwelling sample of older adults. Methods and Results— aPWV was measured at baseline in 2488 participants from the Health, Aging and Body Composition (Health ABC) study. Vital status, cause of death and coronary heart disease (CHD), stroke, and congestive heart failure were determined from medical records. Over 4.6 years, 265 deaths occurred, 111 as a result of cardiovascular causes. There were 341 CHD events, 94 stroke events, and 181 cases of congestive heart failure. Results are presented by quartiles because of a threshold effect between the first and second aPWV quartiles. Higher aPWV was associated wit...

Targeting apoptosis pathways in cancer therapy.

Abstract: Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy. These novel agents include those targeting the extrinsic pathway such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1, and those targeting the intrinsic Bcl-2 family pathway such as antisense bcl-2 oligonucleotides. Many pathways and proteins control the apoptosis machinery. Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001. Because these pathways may be preferentially altered in tumor cells, there is potential for a selective effect in tumors sparing normal tissue. This article reviews the current understanding of the apoptotic pathways, including the extrinsic (cytoplasmic) and intrinsic (mitochondrial) pathways, and the agents being developed to target these pathways.

Failure and Delay in Initial Treatment Contact After First Onset of Mental Disorders in the National Comorbidity Survey Replication

Abstract: Context An understudied crucial step in the help-seeking process is making prompt initial contact with a treatment provider after first onset of a mental disorder. Objective To provide data on patterns and predictors of failure and delay in making initial treatment contact after first onset of a mental disorder in the United States from the recently completed National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey carried out between February 2001 and April 2003. Participants A total of 9282 respondents aged 18 years and older. Main Outcome Measures LifetimeDSM-IVdisorders were assessed with the World Mental Health (WMH) Survey Initiative version of the World Health Organization Composite International Diagnostic Interview (WMH-CIDI), a fully structured interview designed to be administered by trained lay interviewers. Information about age of first professional treatment contact for each lifetimeDSM-IV/WMH-CIDI disorder assessed in the survey was collected and compared with age at onset of the disorder to study typical duration of delay. Results Cumulative lifetime probability curves show that the vast majority of people with lifetime disorders eventually make treatment contact, although more so for mood (88.1%-94.2%) disorders than for anxiety (27.3%-95.3%), impulse control (33.9%-51.8%), or substance (52.7%-76.9%) disorders. Delay among those who eventually make treatment contact ranges from 6 to 8 years for mood disorders and 9 to 23 years for anxiety disorders. Failure to make initial treatment contact and delay among those who eventually make treatment contact are both associated with early age of onset, being in an older cohort, and a number of socio-demographic characteristics (male, married, poorly educated, racial/ethnic minority). Conclusions Failure to make prompt initial treatment contact is a pervasive aspect of unmet need for mental health care in the United States. Interventions to speed initial treatment contact are likely to reduce the burdens and hazards of untreated mental disorder.

Unexpected Increased Mortality After Implementation of a Commercially Sold Computerized Physician Order Entry System

Abstract: Objective. In response to the landmark 1999 report by the Institute of Medicine and safety initiatives promoted by the Leapfrog Group, our institution implemented a commercially sold computerized physician order entry (CPOE) system in an effort to reduce medical errors and mortality. We sought to test the hypothesis that CPOE implementation results in reduced mortality among children who are transported for specialized care. Methods. Demographic, clinical, and mortality data were collected of all children who were admitted via interfacility transport to our regional, academic, tertiary-care level children’s hospital during an 18-month period. A commercially sold CPOE program that operated within the framework of a general, medical-surgical clinical application platform was rapidly implemented hospital-wide over 6 days during this period. Retrospective analyses of pre-CPOE and post-CPOE implementation time periods (13 months before and 5 months after CPOE implementation) were subsequently performed. Results. Among 1942 children who were referred and admitted for specialized care during the study period, 75 died, accounting for an overall mortality rate of 3.86%. Univariate analysis revealed that mortality rate significantly increased from 2.80% (39 of 1394) before CPOE implementation to 6.57% (36 of 548) after CPOE implementation. Multivariate analysis revealed that CPOE remained independently associated with increased odds of mortality (odds ratio: 3.28; 95% confidence interval: 1.94–5.55) after adjustment for other mortality covariables. Conclusions. We have observed an unexpected increase in mortality coincident with CPOE implementation. Although CPOE technology holds great promise as a tool to reduce human error during health care delivery, our unanticipated finding suggests that when implementing CPOE systems, institutions should continue to evaluate mortality effects, in addition to medication error rates, for children who are dependent on time-sensitive therapies.

Responsiveness of the Numeric Pain Rating Scale in Patients with Low Back Pain

Abstract: Study design Cohort study of patients with low back pain (LBP) receiving physical therapy. Objective To examine the responsiveness characteristics of the numerical pain rating scale (NPRS) in patients with LBP using a variety of methods. Summary of background data Although several studies have assessed the reliability and validity of the NPRS, few studies have characterized its responsiveness in patients with LBP. Methods Determination of change on the NPRS during 1 and 4 weeks was examined by calculating mean change, standardized effect size, Guyatt Responsiveness Index, area under a receiver operating characteristic curve, minimum clinically important difference, and minimum detectable change. Change in the NPRS from baseline to the 1 and 4-week follow-up was compared to the average of the patient and therapist's perceived improvement using the 15-point Global Rating of Change scale. Results The majority of patients had clinically meaningful improvement after both 1 and 4 weeks of rehabilitation. The standard error of measure was equal to 1.02, corresponding to a minimum detectable change of 2 points. The area under the curve at the 1 and 4-week follow-up was 0.72 (0.62, 0.81) and 0.92 (0.86, 0.97), respectively. The minimum clinically important difference at the 1 and 4-week follow-up corresponded to a change of 2.2 and 1.5 points, respectively. Conclusions Clinicians can be confident that a 2-point change on the NPRS represents clinically meaningful change that exceeds the bounds of measurement error.

Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors

Abstract: Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B-cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidation during apoptosis. The oxidation is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation.