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Showing papers by "Johns Hopkins University published in 2003"


Journal ArticleDOI
TL;DR: There is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities, and the exploratory data analyses of the probe level data motivate a new summary measure that is a robust multi-array average (RMA) of background-adjusted, normalized, and log-transformed PM values.
Abstract: SUMMARY In this paper we report exploratory analyses of high-density oligonucleotide array data from the Affymetrix GeneChip R � system with the objective of improving upon currently used measures of gene expression. Our analyses make use of three data sets: a small experimental study consisting of five MGU74A mouse GeneChip R � arrays, part of the data from an extensive spike-in study conducted by Gene Logic and Wyeth’s Genetics Institute involving 95 HG-U95A human GeneChip R � arrays; and part of a dilution study conducted by Gene Logic involving 75 HG-U95A GeneChip R � arrays. We display some familiar features of the perfect match and mismatch probe ( PM and MM )v alues of these data, and examine the variance–mean relationship with probe-level data from probes believed to be defective, and so delivering noise only. We explain why we need to normalize the arrays to one another using probe level intensities. We then examine the behavior of the PM and MM using spike-in data and assess three commonly used summary measures: Affymetrix’s (i) average difference (AvDiff) and (ii) MAS 5.0 signal, and (iii) the Li and Wong multiplicative model-based expression index (MBEI). The exploratory data analyses of the probe level data motivate a new summary measure that is a robust multiarray average (RMA) of background-adjusted, normalized, and log-transformed PM values. We evaluate the four expression summary measures using the dilution study data, assessing their behavior in terms of bias, variance and (for MBEI and RMA) model fit. Finally, we evaluate the algorithms in terms of their ability to detect known levels of differential expression using the spike-in data. We conclude that there is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities. ∗ To whom correspondence should be addressed

10,711 citations


Journal ArticleDOI
TL;DR: Three methods of performing normalization at the probe intensity level are presented: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure and the simplest and quickest complete data method is found to perform favorably.
Abstract: Motivation: When running experiments that involve multiple high density oligonucleotide arrays, it is important to remove sources of variation between arrays of non-biological origin. Normalization is a process for reducing this variation. It is common to see non-linear relations between arrays and the standard normalization provided by Affymetrix does not perform well in these situations. Results: We present three methods of performing normalization at the probe intensity level. These methods are called complete data methods because they make use of data from all arrays in an experiment to form the normalizing relation. These algorithms are compared to two methods that make use of a baseline array: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure. Two publicly available datasets are used to carry out the comparisons. The simplest and quickest complete data method is found to perform favorably. Availabilty: Software implementing all three of the complete data normalization methods is available as part of the R package Affy, which is a part of the Bioconductor project http://www.bioconductor.org. Contact: bolstad@stat.berkeley.edu Supplementary information: Additional figures may be found at http://www.stat.berkeley.edu/∼bolstad/normalize/ index.html

8,324 citations


Journal ArticleDOI
TL;DR: In addition to HPV types 16 and 18, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82Should be considered carcinogenic, or high-risk, types, and types 26, 53, and 66 should be considered probably carcinogenic.
Abstract: Background Infection with human papilloma virus (HPV) is the main cause of cervical cancer, but the risk associated with the various HPV types has not been adequately assessed. Methods We pooled data from 11 case–control studies from nine countries involving 1918 women with histologically confirmed squamous-cell cervical cancer and 1928 control women. A common protocol and questionnaire were used. Information on risk factors was obtained by personal interviews, and cervical cells were collected for detection of HPV DNA and typing in a central laboratory by polymerase-chain-reaction–based assays (with MY09/MY11 and GP5+/6+ primers). Results HPV DNA was detected in 1739 of the 1918 patients with cervical cancer (90.7 percent) and in 259 of the 1928 control women (13.4 percent). With the GP5+/6+ primer, HPV DNA was detected in 96.6 percent of the patients and 15.6 percent of the controls. The most common HPV types in patients, in descending order of frequency, were types 16, 18, 45, 31, 33, 52, 58, and 35. A...

5,979 citations


Journal ArticleDOI
John W. Belmont1, Paul Hardenbol, Thomas D. Willis, Fuli Yu1, Huanming Yang2, Lan Yang Ch'Ang, Wei Huang3, Bin Liu2, Yan Shen3, Paul K.H. Tam4, Lap-Chee Tsui4, Mary M.Y. Waye5, Jeffrey Tze Fei Wong6, Changqing Zeng2, Qingrun Zhang2, Mark S. Chee7, Luana Galver7, Semyon Kruglyak7, Sarah S. Murray7, Arnold Oliphant7, Alexandre Montpetit8, Fanny Chagnon8, Vincent Ferretti8, Martin Leboeuf8, Michael S. Phillips8, Andrei Verner8, Shenghui Duan9, Denise L. Lind10, Raymond D. Miller9, John P. Rice9, Nancy L. Saccone9, Patricia Taillon-Miller9, Ming Xiao10, Akihiro Sekine, Koki Sorimachi, Yoichi Tanaka, Tatsuhiko Tsunoda, Eiji Yoshino, David R. Bentley11, Sarah E. Hunt11, Don Powell11, Houcan Zhang12, Ichiro Matsuda13, Yoshimitsu Fukushima14, Darryl Macer15, Eiko Suda15, Charles N. Rotimi16, Clement Adebamowo17, Toyin Aniagwu17, Patricia A. Marshall18, Olayemi Matthew17, Chibuzor Nkwodimmah17, Charmaine D.M. Royal16, Mark Leppert19, Missy Dixon19, Fiona Cunningham20, Ardavan Kanani20, Gudmundur A. Thorisson20, Peter E. Chen21, David J. Cutler21, Carl S. Kashuk21, Peter Donnelly22, Jonathan Marchini22, Gilean McVean22, Simon Myers22, Lon R. Cardon22, Andrew P. Morris22, Bruce S. Weir23, James C. Mullikin24, Michael Feolo24, Mark J. Daly25, Renzong Qiu26, Alastair Kent, Georgia M. Dunston16, Kazuto Kato27, Norio Niikawa28, Jessica Watkin29, Richard A. Gibbs1, Erica Sodergren1, George M. Weinstock1, Richard K. Wilson9, Lucinda Fulton9, Jane Rogers11, Bruce W. Birren25, Hua Han2, Hongguang Wang, Martin Godbout30, John C. Wallenburg8, Paul L'Archevêque, Guy Bellemare, Kazuo Todani, Takashi Fujita, Satoshi Tanaka, Arthur L. Holden, Francis S. Collins24, Lisa D. Brooks24, Jean E. McEwen24, Mark S. Guyer24, Elke Jordan31, Jane Peterson24, Jack Spiegel24, Lawrence M. Sung32, Lynn F. Zacharia24, Karen Kennedy29, Michael Dunn29, Richard Seabrook29, Mark Shillito, Barbara Skene29, John Stewart29, David Valle21, Ellen Wright Clayton33, Lynn B. Jorde19, Aravinda Chakravarti21, Mildred K. Cho34, Troy Duster35, Troy Duster36, Morris W. Foster37, Maria Jasperse38, Bartha Maria Knoppers39, Pui-Yan Kwok10, Julio Licinio40, Jeffrey C. Long41, Pilar N. Ossorio42, Vivian Ota Wang33, Charles N. Rotimi16, Patricia Spallone29, Patricia Spallone43, Sharon F. Terry44, Eric S. Lander25, Eric H. Lai45, Deborah A. Nickerson46, Gonçalo R. Abecasis41, David Altshuler47, Michael Boehnke41, Panos Deloukas11, Julie A. Douglas41, Stacey Gabriel25, Richard R. Hudson48, Thomas J. Hudson8, Leonid Kruglyak49, Yusuke Nakamura50, Robert L. Nussbaum24, Stephen F. Schaffner25, Stephen T. Sherry24, Lincoln Stein20, Toshihiro Tanaka 
18 Dec 2003-Nature
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

5,926 citations


Journal ArticleDOI
TL;DR: It is found that the performance of the current version of the default expression measure provided by Affymetrix Microarray Suite can be significantly improved by the use of probe level summaries derived from empirically motivated statistical models.
Abstract: High density oligonucleotide array technology is widely used in many areas of biomedical research for quantitative and highly parallel measurements of gene expression. Affymetrix GeneChip arrays are the most popular. In this technology each gene is typically represented by a set of 11–20 pairs of probes. In order to obtain expression measures it is necessary to summarize the probe level data. Using two extensive spike-in studies and a dilution study, we developed a set of tools for assessing the effectiveness of expression measures. We found that the performance of the current version of the default expression measure provided by Affymetrix Microarray Suite can be significantly improved by the use of probe level summaries derived from empirically motivated statistical models. In particular, improvements in the ability to detect differentially expressed genes are demonstrated.

5,119 citations


Journal ArticleDOI
TL;DR: In this paper, the authors examined the properties of the host galaxies of 22 623 narrow-line active galactic nuclei (AGN) with 0.02 < z < 0.3 selected from a complete sample of 122 808 galaxies from the Sloan Digital Sky Survey.
Abstract: We examine the properties of the host galaxies of 22 623 narrow-line active galactic nuclei (AGN) with 0.02 < z < 0.3 selected from a complete sample of 122 808 galaxies from the Sloan Digital Sky Survey. We focus on the luminosity of the [O III] λ5007 emission line as a tracer of the strength of activity in the nucleus. We study how AGN host properties compare with those of normal galaxies and how they depend on L[O III]. We find that AGN of all luminosities reside almost exclusively in massive galaxies and have distributions of sizes, stellar surface mass densities and concentrations that are similar to those of ordinary early-type galaxies in our sample. The host galaxies of low-luminosity AGN have stellar populations similar to normal early types. The hosts of high-luminosity AGN have much younger mean stellar ages. The young stars are not preferentially located near the nucleus of the galaxy, but are spread out over scales of at least several kiloparsecs. A significant fraction of high-luminosity AGN have strong Hδ absorption-line equivalent widths, indicating that they experienced a burst of star formation in the recent past. We have also examined the stellar populations of the host galaxies of a sample of broad-line AGN. We conclude that there is no significant difference in stellar content between type 2 Seyfert hosts and quasars (QSOs) with the same [O III] luminosity and redshift. This establishes that a young stellar population is a general property of AGN with high [O III] luminosities.

3,781 citations


Journal ArticleDOI
TL;DR: The mechanisms of gene silencing in cancer and clinical applications of this phenomenon are reviewed, especially tumor-suppressor genes.
Abstract: This article reviews the mechanisms of gene silencing in cancer and clinical applications of this phenomenon. The silencing of genes, especially tumor-suppressor genes, is a key event in the development of cancer. The silencing can be effected by a disabling mutation or by a shutting down of the promoter region, the site at which transcription of the gene begins.

3,285 citations


Journal ArticleDOI
TL;DR: R/qtl is an extensible, interactive environment for mapping quantitative trait loci (QTLs) in experimental populations derived from inbred lines and includes functions for estimating genetic maps, identifying genotyping errors, and performing single-QTL and two-dimensional, two- QTL genome scans by multiple methods.
Abstract: Summary R/qtl is an extensible, interactive environment for mapping quantitative trait loci (QTLs) in experimental populations derived from inbred lines. It is implemented as an add-on package for the freely-available statistical software, R, and includes functions for estimating genetic maps, identifying genotyping errors, and performing single-QTL and two-dimensional, two-QTL genome scans by multiple methods, with the possible inclusion of covariates. Availability The package is freely available at http://www.biostat.jhsph.edu/~kbroman/qtl.

3,111 citations


Journal ArticleDOI
TL;DR: In patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for larynGEal preservation and locoregional control.
Abstract: Background Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown. Methods We randomly assigned patients with locally advanced cancer of the larynx to one of three treatments: induction cisplatin plus fluorouracil followed by radiotherapy, radiotherapy with concurrent administration of cisplatin, or radiotherapy alone. The primary end point was preservation of the larynx. Results A total of 547 patients were randomly assigned to one of the three study groups. The median follow-up period was 3.8 years. At two years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin (88 percent) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy (75 percent, P=0.005) or radiotherapy alone (70 ...

2,730 citations


Journal ArticleDOI
TL;DR: The importance of undernutrition as an underlying cause of child deaths associated with infectious diseases, the effects of multiple concurrent illnesses, and recognition that pneumonia and diarrhoea remain the diseases that are most often associated with child deaths as mentioned in this paper.

2,680 citations


Journal ArticleDOI
TL;DR: The findings show that the interventions needed to achieve the millennium development goal of reducing child mortality by two-thirds by 2015 are available, but that they are not being delivered to the mothers and children who need them.

Journal ArticleDOI
TL;DR: In this paper, the authors used Monte Carlo realizations of different star formation histories, including starbursts of varying strength and a range of metallicities, to constrain the mean stellar ages of galaxies and the fractional stellar mass formed in bursts over the past few Gyr.
Abstract: We develop a new method to constrain the star formation histories, dust attenuation and stellar masses of galaxies. It is based on two stellar absorption-line indices, the 4000-A break strength and the Balmer absorption-line index Hδ A . Together, these indices allow us to constrain the mean stellar ages of galaxies and the fractional stellar mass formed in bursts over the past few Gyr. A comparison with broad-band photometry then yields estimates of dust attenuation and of stellar mass. We generate a large library of Monte Carlo realizations of different star formation histories, including starbursts of varying strength and a range of metallicities. We use this library to generate median likelihood estimates of burst mass fractions, dust attenuation strengths, stellar masses and stellar mass-to-light ratios for a sample of 122 808 galaxies drawn from the Sloan Digital Sky Survey. The typical 95 per cent confidence range in our estimated stellar masses is ′40 per cent. We study how the stellar mass-to-light ratios of galaxies vary as a function of absolute magnitude, concentration index and photometric passband and how dust attenuation varies as a function of absolute magnitude and 4000-A break strength. We also calculate how the total stellar mass of the present Universe is distributed over galaxies as a function of their mass, size, concentration, colour, burst mass fraction and surface mass density. We find that most of the stellar mass in the local Universe resides in galaxies that have, to within a factor of approximately 2, stellar masses ∼5 x 10 1 0 M O ., half-light radii ∼3 kpc and half-light surface mass densities ∼10 9 M O .kpc - 2 . The distribution of D n (4000) is strongly bimodal, showing a clear division between galaxies dominated by old stellar populations and galaxies with more recent star formation.


Journal ArticleDOI
TL;DR: The use of the pneumococcal conjugate vaccine is preventing disease in young children, for whom the vaccine is indicated, and may be reducing the rate of disease in adults.
Abstract: Background In early 2000, a protein–polysaccharide conjugate vaccine targeting seven pneumococcal serotypes was licensed in the United States for use in young children. Methods We examined population-based data from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention to evaluate changes in the burden of invasive disease, defined by isolation of Streptococcus pneumoniae from a normally sterile site. Serotyping and susceptibility testing of isolates were performed. We assessed trends using data from seven geographic areas with continuous participation from 1998 through 2001 (population, 16 million). Results The rate of invasive disease dropped from an average of 24.3 cases per 100,000 persons in 1998 and 1999 to 17.3 per 100,000 in 2001. The largest decline was in children under two years of age. In this group, the rate of disease was 69 percent lower in 2001 than the base-line rate (59.0 cases per 100,000 vs. 188.0 per 100,000, P<0.001); the rate of disease caused by va...

Journal ArticleDOI
TL;DR: The completion of the genome sequence of Leptospira interrogans serovar lai, and other continuing leptospiral genome sequencing projects, promise to guide future work on the disease.
Abstract: In the past decade, leptospirosis has emerged as a globally important infectious disease. It occurs in urban environments of industrialised and developing countries, as well as in rural regions worldwide. Mortality remains significant, related both to delays in diagnosis due to lack of infrastructure and adequate clinical suspicion, and to other poorly understood reasons that may include inherent pathogenicity of some leptospiral strains or genetically determined host immunopathological responses. Pulmonary haemorrhage is recognised increasingly as a major, often lethal, manifestation of leptospirosis, the pathogenesis of which remains unclear. The completion of the genome sequence of Leptospira interrogans serovar lai, and other continuing leptospiral genome sequencing projects, promise to guide future work on the disease. Mainstays of treatment are still tetracyclines and beta-lactam/cephalosporins. No vaccine is available. Prevention is largely dependent on sanitation measures that may be difficult to implement, especially in developing countries.

Journal ArticleDOI
TL;DR: The NOBLE studies do not support the commonly held notion that women are considerably more likely than men to have urgency-related bladder control problems, and overactive bladder, with and without urge incontinence, has a clinically significant impact on quality-of-life, quality- of-sleep, and mental health, in both men and women.
Abstract: Context: the National Overactive BLadder Evaluation (NOBLE) Program was initiated to better understand the prevalence and burden of overactive bladder in a broad spectrum of the United States population. Objective: to estimate the prevalence of overactive bladder with and without urge incontinence in the US, assess variation in prevalence by sex and other factors, and measure individual burden. Design: US national telephone survey using a clinically validated interview and a follow-up nested study comparing overactive bladder cases to sex- and age-matched controls. Setting: noninstitutionalized US adult population. Participants: a sample of 5,204 adults ≥18 years of age and representative of the US population by sex, age, and geographical region. Main outcome measures: prevalence of overactive bladder with and without urge incontinence and risk factors for overactive bladder in the US. In the nested case-control study, SF-36, CES-D, and MOS sleep scores were used to assess impact. Results: the overall prevalence of overactive bladder was similar between men (16.0%) and women (16.9%), but sex-specific prevalence differed substantially by severity of symptoms. In women, prevalence of urge incontinence increased with age from 2.0% to 19% with a marked increase after 44 years of age, and in men, increased with age from 0.3% to 8.9% with a marked increase after 64 years of age. Across all age groups, overactive bladder without urge incontinence was more common in men than in women. Overactive bladder with and without urge incontinence was associated with clinically and significantly lower SF-36 quality-of-life scores, higher CES-D depression scores, and poorer quality of sleep than matched controls. Conclusions: the NOBLE studies do not support the commonly held notion that women are considerably more likely than men to have urgency-related bladder control problems. The overall prevalence of overactive bladder does not differ by sex; however, the severity and nature of symptom expression does differ. Sex-specific anatomic differences may increase the probability that overactive bladder is expressed as urge incontinence among women compared with men. Nonetheless, overactive bladder, with and without incontinence, has a clinically significant impact on quality-of-life, quality-of-sleep, and mental health, in both men and women.

Journal ArticleDOI
TL;DR: These findings demonstrate a coordination of biochemical and mechanical signals to regulate cell adhesion and mechanics, and they introduce the use of arrays of mechanically isolated sensors to manipulate and measure the mechanical interactions of cells.
Abstract: We describe an approach to manipulate and measure mechanical interactions between cells and their underlying substrates by using microfabricated arrays of elastomeric, microneedle-like posts. By controlling the geometry of the posts, we varied the compliance of the substrate while holding other surface properties constant. Cells attached to, spread across, and deflected multiple posts. The deflections of the posts occurred independently of neighboring posts and, therefore, directly reported the subcellular distribution of traction forces. We report two classes of force-supporting adhesions that exhibit distinct force–size relationships. Force increased with size of adhesions for adhesions larger than 1 m2, whereas no such correlation existed for smaller adhesions. By controlling cell adhesion on these micromechanical sensors, we showed that cell morphology regulates the magnitude of traction force generated by cells. Cells that were prevented from spreading and flattening against the substrate did not contract in response to stimulation by serum or lysophosphatidic acid, whereas spread cells did. Contractility in the unspread cells was rescued by expression of constitutively active RhoA. Together, these findings demonstrate a coordination of biochemical and mechanical signals to regulate cell adhesion and mechanics, and they introduce the use of arrays of mechanically isolated sensors to manipulate and measure the mechanical interactions of cells.

Journal ArticleDOI
TL;DR: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy, although it does yield a survival advantages for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity.
Abstract: Background Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of patients have not been established. Methods A total of 1218 patients with severe emphysema underwent pulmonary rehabilitation and were randomly assigned to undergo lung-volume-reduction surgery or to receive continued medical treatment. Results Overall mortality was 0.11 death per person-year in both treatment groups (risk ratio for death in the surgery group, 1.01; P=0.90). After 24 months, exercise capacity had improved by more than 10 W in 15 percent of the patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P Conclusions Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity. Patients previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain.

Journal ArticleDOI
13 Feb 2003-Nature
TL;DR: Crystal structures of the entire extracellular regions of rat and human HER2 reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding.
Abstract: HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.

Journal ArticleDOI
TL;DR: It is shown that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly that eradication is unlikely.
Abstract: Latent HIV-1 persists in resting memory CD4+ T cells, even in patients receiving highly active antiretroviral therapy (HAART). It has been unclear how stable this latent reservoir is and whether its persistence reflects replenishment by low-level viremia. Here we show that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly (t(1/2) = 44 months) that eradication is unlikely.

Journal ArticleDOI
23 Apr 2003-JAMA
TL;DR: Both behavioral interventions significantly reduced weight, improved fitness, and lowered sodium intake and the established plus DASH intervention also increased fruit, vegetable, and dairy intake.
Abstract: CONTEXT Weight loss, sodium reduction, increased physical activity, and limited alcohol intake are established recommendations that reduce blood pressure (BP). The Dietary Approaches to Stop Hypertension (DASH) diet also lowers BP. To date, no trial has evaluated the effects of simultaneously implementing these lifestyle recommendations. OBJECTIVE To determine the effect on BP of 2 multicomponent, behavioral interventions. DESIGN, SETTING, AND PARTICIPANTS Randomized trial with enrollment at 4 clinical centers (January 2000-June 2001) among 810 adults (mean [SD] age, 50 [8.9] years; 62% women; 34% African American) with above-optimal BP, including stage 1 hypertension (120-159 mm Hg systolic and 80-95 mm Hg diastolic), and who were not taking antihypertensive medications. INTERVENTION Participants were randomized to one of 3 intervention groups: (1) "established," a behavioral intervention that implemented established recommendations (n = 268); (2) "established plus DASH,"which also implemented the DASH diet (n = 269); and (3) an "advice only" comparison group (n = 273). MAIN OUTCOME MEASURES Blood pressure measurement and hypertension status at 6 months. RESULTS Both behavioral interventions significantly reduced weight, improved fitness, and lowered sodium intake. The established plus DASH intervention also increased fruit, vegetable, and dairy intake. Across the groups, gradients in BP and hypertensive status were evident. After subtracting change in advice only, the mean net reduction in systolic BP was 3.7 mm Hg (P<.001) in the established group and 4.3 mm Hg (P<.001) in the established plus DASH group; the systolic BP difference between the established and established plus DASH groups was 0.6 mm Hg (P =.43). Compared with the baseline hypertension prevalence of 38%, the prevalence at 6 months was 26% in the advice only group, 17% in the established group (P =.01 compared with the advice only group), and 12% in the established plus DASH group (P<.001 compared with the advice only group; P =.12 compared with the established group). The prevalence of optimal BP (<120 mm Hg systolic and <80 mm Hg diastolic) was 19% in the advice only group, 30% in the established group (P =.005 compared with the advice only group), and 35% in the established plus DASH group (P<.001 compared with the advice only group; P =.24 compared with the established group). CONCLUSION Individuals with above-optimal BP, including stage 1 hypertension, can make multiple lifestyle changes that lower BP and reduce their cardiovascular disease risk.

Journal ArticleDOI
TL;DR: For a complete sample of 122 808 galaxies drawn from the Sloan Digital Sky Survey (SDSS), this article studied the relationship between stellar mass, star formation history, size and internal structure.
Abstract: We study the relations between stellar mass, star formation history, size and internal structure for a complete sample of 122 808 galaxies drawn from the Sloan Digital Sky Survey We show that low-redshift galaxies divide into two distinct families at a stellar mass of 3 x 10 1 0 M O Lower-mass galaxies have young stellar populations, low surface mass densities and the low concentrations typical of discs Their star formation histories are more strongly correlated with surface mass density than with stellar mass A significant fraction of the lowest-mass galaxies in our sample have experienced recent starbursts At given stellar mass, the sizes of low-mass galaxies are lognormally distributed with dispersion σ(In R 5 0 ) ∼05, in excellent agreement with the idea that they form with little angular momentum loss through cooling and condensation in a gravitationally dominant dark matter halo Their median stellar surface mass density scales with stellar mass as μ * M * 054, suggesting that the stellar mass of a disc galaxy is proportional to the three halves power of its halo mass All of this suggests that the efficiency of the conversion of baryons into stars in low-mass galaxies increases in proportion to halo mass, perhaps as a result of supernova feedback processes At stellar masses above 3 x 10 1 0 M O , there is a rapidly increasing fraction of galaxies with old stellar populations, high surface mass densities and the high concentrations typical of bulges In this regime, the size distribution remains lognormal, but its dispersion decreases rapidly with increasing mass and the median stellar mass surface density is approximately constant This suggests that the star formation efficiency decreases in the highest-mass haloes, and that little star formation occurs in massive galaxies after they have assembled

Journal ArticleDOI
TL;DR: MRI scans of 92 nondemented older adults in the Baltimore Longitudinal Study of Aging provide essential information on the rate and regional pattern of age-associated changes against which pathology can be evaluated and suggest slower rates of brain atrophy in individuals who remain medically and cognitively healthy.
Abstract: Age-related loss of brain tissue has been inferred from cross-sectional neuroimaging studies, but direct measurements of gray and white matter changes from longitudinal studies are lacking. We quantified longitudinal magnetic resonance imaging (MRI) scans of 92 nondemented older adults (age 59-85 years at baseline) in the Baltimore Longitudinal Study of Aging to determine the rates and regional distribution of gray and white matter tissue loss in older adults. Using images from baseline, 2 year, and 4 year follow-up, we found significant age changes in gray (p < 0.001) and white (p < 0.001) volumes even in a subgroup of 24 very healthy elderly. Annual rates of tissue loss were 5.4 +/- 0.3, 2.4 +/- 0.4, and 3.1 +/- 0.4 cm3 per year for total brain, gray, and white volumes, respectively, and ventricles increased by 1.4 +/- 0.1 cm3 per year (3.7, 1.3, 2.4, and 1.2 cm3, respectively, in very healthy). Frontal and parietal, compared with temporal and occipital, lobar regions showed greater decline. Gray matter loss was most pronounced for orbital and inferior frontal, cingulate, insular, inferior parietal, and to a lesser extent mesial temporal regions, whereas white matter changes were widespread. In this first study of gray and white matter volume changes, we demonstrate significant longitudinal tissue loss for both gray and white matter even in very healthy older adults. These data provide essential information on the rate and regional pattern of age-associated changes against which pathology can be evaluated and suggest slower rates of brain atrophy in individuals who remain medically and cognitively healthy.

Journal ArticleDOI
TL;DR: Despite extensive work, the basis for raft formation in cell membranes and the size of rafts and their stability are all uncertain and recent work converges on very small rafts <10 nm in diameter that may enlarge and stabilize when their constituents are cross-linked.
Abstract: ▪ Abstract Lipid raft microdomains were conceived as part of a mechanism for the intracellular trafficking of lipids and lipid-anchored proteins. The raft hypothesis is based on the behavior of defined lipid mixtures in liposomes and other model membranes. Experiments in these well-characterized systems led to operational definitions for lipid rafts in cell membranes. These definitions, detergent solubility to define components of rafts, and sensitivity to cholesterol deprivation to define raft functions implicated sphingolipid- and cholesterol-rich lipid rafts in many cell functions. Despite extensive work, the basis for raft formation in cell membranes and the size of rafts and their stability are all uncertain. Recent work converges on very small rafts <10 nm in diameter that may enlarge and stabilize when their constituents are cross-linked.

Journal ArticleDOI
TL;DR: Aminotransferase elevation was common in the United States, and the majority could not be unexplained by alcohol consumption, viral hepatitis or hemochromatosis, and thus may represent nonalcoholic fatty liver disease.

Journal ArticleDOI
23 Oct 2003-Nature
TL;DR: A wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathways antagonist.
Abstract: Activation of the Hedgehog (Hh) signalling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is associated with tumorigenesis in skin, the cerebellum and skeletal muscle. Here we show that a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumours in vivo. Unlike in Gorlin's syndrome tumours, pathway activity and cell growth in these digestive tract tumours are driven by endogenous expression of Hh ligands, as indicated by the presence of Sonic hedgehog and Indian hedgehog transcripts, by the pathway- and growth-inhibitory activity of a Hh-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added Hh ligand. Our results identify a group of common lethal malignancies in which Hh pathway activity, essential for tumour growth, is activated not by mutation but by ligand expression.

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TL;DR: It is shown that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung, and that perturbation of this function can contribute to the pathogenesis of disease.
Abstract: Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1‐3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome 4 . Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-β attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

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TL;DR: This work reviews recent advances in computational stereo, focusing primarily on three important topics: correspondence methods, methods for occlusion, and real-time implementations.
Abstract: Extraction of three-dimensional structure of a scene from stereo images is a problem that has been studied by the computer vision community for decades. Early work focused on the fundamentals of image correspondence and stereo geometry. Stereo research has matured significantly throughout the years and many advances in computational stereo continue to be made, allowing stereo to be applied to new and more demanding problems. We review recent advances in computational stereo, focusing primarily on three important topics: correspondence methods, methods for occlusion, and real-time implementations. Throughout, we present tables that summarize and draw distinctions among key ideas and approaches. Where available, we provide comparative analyses and we make suggestions for analyses yet to be done.

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TL;DR: There are identifiable risk factors for intimate partner femicides and they include perpetrator's access to a gun and previous threat with a weapon, perpetrator's stepchild in the home, and estrangement, especially from a controlling partner.
Abstract: Objectives. This 11-city study sought to identify risk factors for femicide in abusive relationships. Methods. Proxies of 220 intimate partner femicide victims identified from police or medical examiner records were interviewed, along with 343 abused control women. Results. Preincident risk factors associated in multivariate analyses with increased risk of intimate partner femicide included perpetrator’s access to a gun and previous threat with a weapon, perpetrator’s stepchild in the home, and estrangement, especially from a controlling partner. Never living together and prior domestic violence arrest were associated with lowered risks. Significant incident factors included the victim having left for another partner and the perpetrator’s use of a gun. Other significant bivariate-level risks included stalking, forced sex, and abuse during pregnancy. Conclusions. There are identifiable risk factors for intimate partner femicides.

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TL;DR: HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of The most common HPV type in genital cancers (HPV16) was also the most common in these tumors.
Abstract: = 1.5, 95% CI = 1.1 to 2.1) and the oropharynx (OR = 3.5, 95% CI = 2.1 to 5.9). Antibodies against HPV16 E6 or E7 were also associated with risk for cancers of the oral cavity (OR = 2.9, 95% CI = 1.7 to 4.8) and the oropharynx (OR = 9.2, 95% CI = 4.8 to 17.7). CONCLUSIONS: HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the oral cavity. The most common HPV type in genital cancers (HPV16) was also the most common in these tumors. The mechanism of transmission of HPV to the oral cavity warrants further investigation.