Showing papers by "Johns Hopkins University published in 2001"

Frailty in Older Adults Evidence for a Phenotype

Abstract: Background: Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established. Methods: To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality. Results: Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline). Conclusions: This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.

Current concepts in mild cognitive impairment.

Abstract: The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.

Lag length selection and the construction of unit root tests with good size and power

Abstract: It is widely known that when there are errors with a moving-average root close to -1, a high order augmented autoregression is necessary for unit root tests to have good size, but that information criteria such as the AIC and the BIC tend to select a truncation lag (k) that is very small. We consider a class of Modified Information Criteria (MIC) with a penalty factor that is sample dependent. It takes into account the fact that the bias in the sum of the autoregressive coefficients is highly dependent on k and adapts to the type of deterministic components present. We use a local asymptotic framework in which the moving-average root is local to -1 to document how the MIC performs better in selecting appropriate values of k. In Monte-Carlo experiments, the MIC is found to yield huge size improvements to the DF GLS and the feasible point optimal P T test developed in Elliott, Rothenberg, and Stock (1996). We also extend the M tests developed in Perron and Ng (1996) to allow for GLS detrending of the data. The MIC along with GLS detrended data yield a set of tests with desirable size and power properties.

Mechanisms underlying ubiquitination.

Abstract: ▪ Abstract The conjugation of ubiquitin to other cellular proteins regulates a broad range of eukaryotic cell functions. The high efficiency and exquisite selectivity of ubiquitination reactions reflect the properties of enzymes known as ubiquitin-protein ligases or E3s. An E3 recognizes its substrates based on the presence of a specific ubiquitination signal, and catalyzes the formation of an isopeptide bond between a substrate (or ubiquitin) lysine residue and the C terminus of ubiquitin. Although a great deal is known about the molecular basis of E3 specificity, much less is known about molecular mechanisms of catalysis by E3s. Recent findings reveal that all known E3s utilize one of just two catalytic domains—a HECT domain or a RING finger—and crystal structures have provided the first detailed views of an active site of each type. The new findings shed light on many aspects of E3 structure, function, and mechanism, but also emphasize that key features of E3 catalysis remain to be elucidated.

Final Results from the Hubble Space Telescope Key Project to Measure the Hubble Constant

Abstract: We present here the final results of the Hubble Space Telescope (HST) Key Project to measure the Hubble constant. We summarize our method, the results, and the uncertainties, tabulate our revised distances, and give the implications of these results for cosmology. Our results are based on a Cepheid calibration of several secondary distance methods applied over the range of about 60-400 Mpc. The analysis presented here benefits from a number of recent improvements and refinements, including (1) a larger LMC Cepheid sample to define the fiducial period-luminosity (PL) relations, (2) a more recent HST Wide Field and Planetary Camera 2 (WFPC2) photometric calibration, (3) a correction for Cepheid metallicity, and (4) a correction for incompleteness bias in the observed Cepheid PL samples. We adopt a distance modulus to the LMC (relative to which the more distant galaxies are measured) of μ0 = 18.50 ± 0.10 mag, or 50 kpc. New, revised distances are given for the 18 spiral galaxies for which Cepheids have been discovered as part of the Key Project, as well as for 13 additional galaxies with published Cepheid data. The new calibration results in a Cepheid distance to NGC 4258 in better agreement with the maser distance to this galaxy. Based on these revised Cepheid distances, we find values (in km s-1 Mpc-1) of H0 = 71 ± 2 ± 6 (systematic) (Type Ia supernovae), H0 = 71 ± 3 ± 7 (Tully-Fisher relation), H0 = 70 ± 5 ± 6 (surface brightness fluctuations), H0 = 72 ± 9 ± 7 (Type II supernovae), and H0 = 82 ± 6 ± 9 (fundamental plane). We combine these results for the different methods with three different weighting schemes, and find good agreement and consistency with H0 = 72 ± 8 km s-1 Mpc-1. Finally, we compare these results with other, global methods for measuring H0.

A method for making group inferences from functional MRI data using independent component analysis

Abstract: Independent component analysis (ICA) is a promising analysis method that is being increasingly applied to fMRI data. A principal advantage of this approach is its applicability to cognitive paradigms for which detailed models of brain activity are not available. Independent component analysis has been successfully utilized to analyze single-subject fMRI data sets, and an extension of this work would be to provide for group inferences. However, unlike univariate methods (e.g., regression analysis, Kolmogorov-Smirnov statistics), ICA does not naturally generalize to a method suitable for drawing inferences about groups of subjects. We introduce a novel approach for drawing group inferences using ICA of fMRI data, and present its application to a simple visual paradigm that alternately stimulates the left or right visual field. Our group ICA analysis revealed task-related components in left and right visual cortex, a transiently task-related component in bilateral occipital/parietal cortex, and a non-task-related component in bilateral visual association cortex. We address issues involved in the use of ICA as an fMRI analysis method such as: (1) How many components should be calculated? (2) How are these components to be combined across subjects? (3) How should the final results be thresholded and/or presented? We show that the methodology we present provides answers to these questions and lay out a process for making group inferences from fMRI data using independent component analysis.

Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma

Abstract: PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of sa...

The prevalence of psychological distress by cancer site

Abstract: Purpose: The goal of this project was to determine the prevalence of psychological distress among a large sample of cancer patients (n=4496). In addition, variations in distress among 14 cancer diagnoses were examined. Patients and methods: The sample was extracted from a database that consists of 9000 patients who completed the Brief Symptom Inventory as a component of comprehensive cancer care. Relevant data points for each case included age, diagnosis, gender, insurance status, marital status, race and zip code. Simple frequencies, percentages, measures of central tendency and variability were calculated. In addition, a univariate and multiple regression analysis was used to examine the relationships of these relevant variables to psychological distress. Results: The overall prevalence rate of distress for this sample was 35.1%. The rate varied form 43.4% for lung cancer to 29.6% for gynecological cancers. While some rates were significantly different, diagnoses with a poorer prognosis and greater patient burden produced similar rates of distress. Pancreatic cancer patients produced the highest mean scores for symptoms such as anxiety and depression, while Hodgkin's patients exhibited the highest mean scores for hostility Conclusions: These results offer vital support for the need to identify high-risk patients through psychosocial screening in order to provide early intervention. To simply perceive cancer patients as a homogeneous group is an erroneous assumption. Failure to detect and treat elevated levels of distress jeopardizes the outcomes of cancer therapies, decreases patients' quality of life, and increases health care costs. Copyright © 2001 John Wiley & Sons, Ltd.

The 2dF Galaxy Redshift Survey: spectra and redshifts

Abstract: The 2dF Galaxy Redshift Survey (2dFGRS) is designed to measure redshifts for approximately 250 000 galaxies. This paper describes the survey design, the spectroscopic observations, the redshift measurements and the survey data base. The 2dFGRS uses the 2dF multifibre spectrograph on the Anglo-Australian Telescope, which is capable of observing 400 objects simultaneously over a 2° diameter field. The source catalogue for the survey is a revised and extended version of the APM galaxy catalogue, and the targets are galaxies with extinction-corrected magnitudes brighter than b J = 19.45. The main survey regions are two declination strips, one in the southern Galactic hemisphere spanning 80° × 15° around the SGP, and the other in the northern Galactic hemisphere spanning 75° × 10° along the celestial equator; in addition, there are 99 fields spread over the southern Galactic cap. The survey covers 2000 deg 2 and has a median depth of z = 0.11. Adaptive tiling is used to give a highly uniform sampling rate of 93 per cent over the whole survey region. Redshifts are measured from spectra covering 3600-8000 A at a two-pixel resolution of 9.0 A and a median S/N of 13 pixel - 1 . All redshift identifications are visually checked and assigned a quality parameter Q in the range 1-5; Q ≥ 3 redshifts are 98.4 per cent reliable and have an rms uncertainty of 85 km s - 1 . The overall redshift completeness for Q ≥ 3 redshifts is 91.8 per cent, but this varies with magnitude from 99 per cent for the brightest galaxies to 90 per cent for objects at the survey limit. The 2dFGRS data base is available on the World Wide Web at http://www. mso.anu.edu.au/2dFGRS.

Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint Committee on Cancer Melanoma Staging System

Abstract: PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (≤ 1 mm) melanomas; (2) in the N category, the following three independent factors were ide...

A Gene Hypermethylation Profile of Human Cancer

Abstract: We are in an era where the potential exists for deriving comprehensive profiles of DNA alterations characterizing each form of human cancer. Such profiles would provide invaluable insight into mechanisms underlying the evolution of each tumor type and will provide molecular markers, which could radically improve cancer detection. To date, no one type of DNA change has been defined which accomplishes this purpose. Herein, by using a candidate gene approach, we show that one category of DNA alteration, aberrant methylation of gene promoter regions, can enormously contribute to the above goals. We have now analyzed a series of promoter hypermethylation changes in 12 genes (p16(INK4a), p15(INK4b), p14(ARF), p73, APC,(5) BRCA1, hMLH1, GSTP1, MGMT, CDH1, TIMP3, and DAPK), each rigorously characterized for association with abnormal gene silencing in cancer, in DNA from over 600 primary tumor samples representing 15 major tumor types. The genes play known important roles in processes encompassing tumor suppression, cell cycle regulation, apoptosis, DNA repair, and metastastic potential. A unique profile of promoter hypermethylation exists for each human cancer in which some gene changes are shared and others are cancer-type specific. The hypermethylation of the genes occurs independently to the extent that a panel of three to four markers defines an abnormality in 70-90% of each cancer type. Our results provide an unusual view of the pervasiveness of DNA alterations, in this case an epigenetic change, in human cancer and a powerful set of markers to outline the disruption of critical pathways in tumorigenesis and for derivation of sensitive molecular detection strategies for virtually every human tumor type.

Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.

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

Prevalence and Burden of Migraine in the United States: Data From the American Migraine Study II

Abstract: Objective.—To describe the prevalence, sociodemographic profile, and the burden of migraine in the United States in 1999 and to compare results with the original American Migraine Study, a 1989 population-based study employing identical methods. Methods.—A validated, self-administered questionnaire was mailed to a sample of 20 000 households in the United States. Each household member with severe headache was asked to respond to questions about symptoms, frequency, and severity of headaches and about headache-related disability. Diagnostic criteria for migraine were based on those of the International Headache Society. This report is restricted to individuals 12 years and older. Results.—Of the 43 527 age-eligible individuals, 29 727 responded to the questionnaire for a 68.3% response rate. The prevalence of migraine was 18.2% among females and 6.5% among males. Approximately 23% of households contained at least one member suffering from migraine. Migraine prevalence was higher in whites than in blacks and was inversely related to household income. Prevalence increased from aged 12 years to about aged 40 years and declined thereafter in both sexes. Fifty-three percent of respondents reported that their severe headaches caused substantial impairment in activities or required bed rest. Approximately 31% missed at least 1 day of work or school in the previous 3 months because of migraine; 51% reported that work or school productivity was reduced by at least 50%. Conclusions.—Two methodologically identical national surveys in the United States conducted 10 years apart show that the prevalence and distribution of migraine have remained stable over the last decade. Migraine-associated disability remains substantial and pervasive. The number of migraineurs has increased from 23.6 million in 1989 to 27.9 million in 1999 commensurate with the growth of the population. Migraine is an important target for public health interventions because it is highly prevalent and disabling.

Composite Quasar Spectra from the Sloan Digital Sky Survey

Abstract: We have created a variety of composite quasar spectra using a homogeneous data set of over 2200 spectra from the Sloan Digital Sky Survey (SDSS). The quasar sample spans a redshift range of 0.044 ≤ z ≤ 4.789 and an absolute r' magnitude range of -18.0 to -26.5. The input spectra cover an observed wavelength range of 3800–9200 A at a resolution of 1800. The median composite covers a rest-wavelength range from 800 to 8555 A and reaches a peak signal-to-noise ratio of over 300 per 1 A resolution element in the rest frame. We have identified over 80 emission-line features in the spectrum. Emission-line shifts relative to nominal laboratory wavelengths are seen for many of the ionic species. Peak shifts of the broad permitted and semiforbidden lines are strongly correlated with ionization energy, as previously suggested, but we find that the narrow forbidden lines are also shifted by amounts that are strongly correlated with ionization energy. The magnitude of the forbidden line shifts is 100 km s-1, compared with shifts of up to 550 km s-1 for some of the permitted and semiforbidden lines. At wavelengths longer than the Lyα emission, the continuum of the geometric mean composite is well fitted by two power laws, with a break at ≈5000 A. The frequency power-law index, αν, is -0.44 from ≈1300 to 5000 A and -2.45 redward of ≈5000 A. The abrupt change in slope can be accounted for partly by host-galaxy contamination at low redshift. Stellar absorption lines, including higher order Balmer lines, seen in the composites suggest that young or intermediate-age stars make a significant contribution to the light of the host galaxies. Most of the spectrum is populated by blended emission lines, especially in the range 1500–3500 A, which can make the estimation of quasar continua highly uncertain unless large ranges in wavelength are observed. An electronic table of the median quasar template is available.

Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combinations and designation of Ehrlichia equi and 'HGE agent' as subjective synonyms of Ehrlichia phagocytophila.

Abstract: The genera Anaplasma, Ehrlichia, Cowdria, Neorickettsia and Wolbachia encompass a group of obligate intracellular bacteria that reside in vacuoles of eukaryotic cells and were previously placed in taxa based upon morphological, ecological, epidemiological and clinical characteristics. Recent genetic analyses of 16S rRNA genes, groESL and surface protein genes have indicated that the existing taxa designations are flawed. All 16S rRNA gene and groESL sequences deposited in GenBank prior to 2000 and selected sequences deposited thereafter were aligned and phylogenetic trees and bootstrap values were calculated using the neighbour-joining method and compared with trees generated with maximum-probability, maximum-likelihood, majority-rule consensus and parsimony methods. Supported by bootstrap probabilities of at least 54%, 16S rRNA gene comparisons consistently clustered to yield four distinct clades characterized roughly as Anaplasma (including the Ehrlichia phagocytophila group, Ehrlichia platys and Ehrlichia bovis) with a minimum of 96.1% similarity, Ehrlichia (including Cowdria ruminantium) with a minimum of 97.7% similarity, Wolbachia with a minimum of 95.6% similarity and Neorickettsia (including Ehrlichia sennetsu and Ehrlichia risticii) with a minimum of 94.9% similarity. Maximum similarity between clades ranged from 87.1 to 94.9%. Insufficient differences existed among E. phagocytophila, Ehrlichia equi and the human granulocytic ehrlichiosis (HGE) agent to support separate species designations, and this group was at least 98.2% similar to any Anaplasma species. These 16S rRNA gene analyses are strongly supported by similar groESL clades, as well as biological and antigenic characteristics. It is proposed that all members of the tribes Ehrlichieae and Wolbachieae be transferred to the family Anaplasmataceae and that the tribe structure of the family Rickettsiaceae be eliminated. The genus Anaplasma should be emended to include Anaplasma (Ehrlichia) phagocytophila comb. nov. (which also encompasses the former E. equi and the HGE agent), Anaplasma (Ehrlichia) bovis comb. nov. and Anaplasma (Ehrlichia) platys comb. nov., the genus Ehrlichia should be emended to include Ehrlichia (Cowdria) ruminantium comb. nov. and the genus Neorickettsia should be emended to include Neorickettsia (Ehrlichia) risticii comb. nov. and Neorickettsia (Ehrlichia) sennetsu comb. nov.

Unified huntington’s disease rating scale: Reliability and consistency

Abstract: The Unified Huntington's disease Rating Scale (UHDRS) was developed as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity. We assessed the internal consistency and the intercorrelations for the four domains and examined changes in ratings over time. We also performed an interrater reliability study of the motor assessment. We found there was a high degree of internal consistency within each of the domains of the UHDRS and that there were significant intercorrelations between the domains of the UHDRS, with the exception of the total behavioral score. There was an excellent degree of interrater reliability for the motor scores. Our limited longitudinal database indicates that the UHDRS may be useful for tracking changes in the clinical features of HD over time. The UHDRS assesses relevant clinical features of HD and appears to be appropriate for repeated administration during clinical studies.

Botulinum Toxin as a Biological Weapon: Medical and Public Health Management

Abstract: ObjectiveThe Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population.ParticipantsThe working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine.EvidenceThe primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960–March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement.Consensus ProcessThe first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members.ConclusionsAn aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.

Neighborhood of residence and incidence of coronary heart disease.

Abstract: BACKGROUND: Where a person lives is not usually thought of as an independent predictor of his or her health, although physical and social features of places of residence may affect health and health-related behavior. METHODS: Using data from the Atherosclerosis Risk in Communities Study, we examined the relation between characteristics of neighborhoods and the incidence of coronary heart disease. Participants were 45 to 64 years of age at base line and were sampled from four study sites in the United States: Forsyth County, North Carolina; Jackson, Mississippi; the northwestern suburbs of Minneapolis; and Washington County, Maryland. As proxies for neighborhoods, we used block groups containing an average of 1000 people, as defined by the U.S. Census. We constructed a summary score for the socioeconomic environment of each neighborhood that included information about wealth and income, education, and occupation. RESULTS: During a median of 9.1 years of follow-up, 615 coronary events occurred in 13,009 participants. Residents of disadvantaged neighborhoods (those with lower summary scores) had a higher risk of disease than residents of advantaged neighborhoods, even after we controlled for personal income, education, and occupation. Hazard ratios for coronary events in the most disadvantaged group of neighborhoods as compared with the most advantaged group--adjusted for age, study site, and personal socioeconomic indicators--were 1.7 among whites (95 percent confidence interval, 1.3 to 2.3) and 1.4 among blacks (95 percent confidence interval, 0.9 to 2.0). Neighborhood and personal socioeconomic indicators contributed independently to the risk of disease. Hazard ratios for coronary heart disease among low-income persons living in the most disadvantaged neighborhoods, as compared with high-income persons in the most advantaged neighborhoods were 3.1 among whites (95 percent confidence interval, 2.1 to 4.8) and 2.5 among blacks (95 percent confidence interval, 1.4 to 4.5). These associations remained unchanged after adjustment for established risk factors for coronary heart disease. CONCLUSIONS: Even after controlling for personal income, education, and occupation, we found that living in a disadvantaged neighborhood is associated with an increased incidence of coronary heart disease.

Gene-Expression Profiles in Hereditary Breast Cancer

Abstract: Background Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles. Methods RNA from samples of primary tumors from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype. Results Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each othe...

Regulation of myostatin activity and muscle growth

Abstract: Myostatin is a transforming growth factor-β family member that acts as a negative regulator of skeletal muscle mass. To identify possible myostatin inhibitors that may have applications for promoting muscle growth, we investigated the regulation of myostatin signaling. Myostatin protein purified from mammalian cells consisted of a noncovalently held complex of the N-terminal propeptide and a disulfide-linked dimer of C-terminal fragments. The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA. Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. To determine the functional significance of these interactions in vivo, we generated transgenic mice expressing high levels of the propeptide, follistatin, or a dominant-negative form of Act RIIB by using a skeletal muscle-specific promoter. Independent transgenic mouse lines for each construct exhibited dramatic increases in muscle mass comparable to those seen in myostatin knockout mice. Our findings suggest that the propeptide, follistatin, or other molecules that block signaling through this pathway may be useful agents for enhancing muscle growth for both human therapeutic and agricultural applications.

Color Separation of Galaxy Types in the Sloan Digital Sky Survey Imaging Data

Abstract: We study the optical colors of 147,920 galaxies brighter than g* = 21, observed in five bands by the Sloan Digital Sky Survey (SDSS) over ~100 deg2 of high Galactic latitude sky along the celestial equator. The distribution of galaxies in the g*-r* versus u*-g* color-color diagram is strongly bimodal, with an optimal color separator of u*-r* = 2.22. We use visual morphology and spectral classification of subsamples of 287 and 500 galaxies, respectively, to show that the two peaks correspond roughly to early- (E, S0, and Sa) and late-type (Sb, Sc, and Irr) galaxies, as expected from their different stellar populations. We also find that the colors of galaxies are correlated with their radial profiles, as measured by the concentration index and by the likelihoods of exponential and de Vaucouleurs' profile fits. While it is well known that late-type galaxies are bluer than early-type galaxies, this is the first detection of a local minimum in their color distribution. In all SDSS bands, the counts versus apparent magnitude relations for the two color types are significantly different and demonstrate that the fraction of blue galaxies increases toward the faint end.

The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway

Abstract: ▪ Abstract The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation ...

Spontaneous intracerebral hemorrhage.

Abstract: Nontraumatic intracerebral hemorrhage is bleeding into the parenchyma of the brain that may extend into the ventricles and, in rare cases, the subarachnoid space. Each year, approximately 37,000 to 52,400 people in the United States have an intracerebral hemorrhage.1,2 This rate is expected to double during the next 50 years as a result of the increasing age of the population and changes in racial demographics. Intracerebral hemorrhage accounts for 10 to 15 percent of all cases of stroke and is associated with the highest mortality rate, with only 38 percent of affected patients surviving the first year.3 Depending on . . .

Clinical and Pathological Diagnosis of Frontotemporal Dementia: Report of the Work Group on Frontotemporal Dementia and Pick's Disease

Abstract: An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.

FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity

Abstract: Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O(2)-dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1alpha subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1alpha transactivation domains is also O(2) regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1alpha and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1alpha transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1alpha protein stabilization and transcriptional activation in response to changes in cellular O(2) concentration.