Showing papers by "Johns Hopkins University published in 1999"

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

Abstract: A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.

Why Don't Physicians Follow Clinical Practice Guidelines?: A Framework for Improvement

Abstract: ContextDespite wide promulgation, clinical practice guidelines have had limited effect on changing physician behavior. Little is known about the process and factors involved in changing physician practices in response to guidelines.ObjectiveTo review barriers to physician adherence to clinical practice guidelines.Data SourcesWe searched the MEDLINE, Educational Resources Information Center (ERIC), and HealthSTAR databases (January 1966 to January 1998); bibliographies; textbooks on health behavior or public health; and references supplied by experts to find English-language article titles that describe barriers to guideline adherence.Study SelectionOf 5658 articles initially identified, we selected 76 published studies describing at least 1 barrier to adherence to clinical practice guidelines, practice parameters, clinical policies, or national consensus statements. One investigator screened titles to identify candidate articles, then 2 investigators independently reviewed the texts to exclude articles that did not match the criteria. Differences were resolved by consensus with a third investigator.Data ExtractionTwo investigators organized barriers to adherence into a framework according to their effect on physician knowledge, attitudes, or behavior. This organization was validated by 3 additional investigators.Data SynthesisThe 76 articles included 120 different surveys investigating 293 potential barriers to physician guideline adherence, including awareness (n = 46), familiarity (n = 31), agreement (n = 33), self-efficacy (n = 19), outcome expectancy (n = 8), ability to overcome the inertia of previous practice (n = 14), and absence of external barriers to perform recommendations (n = 34). The majority of surveys (70 [58%] of 120) examined only 1 type of barrier.ConclusionsStudies on improving physician guideline adherence may not be generalizable, since barriers in one setting may not be present in another. Our review offers a differential diagnosis for why physicians do not follow practice guidelines, as well as a rational approach toward improving guideline adherence and a framework for future research.

Starburst99: Synthesis Models for Galaxies with Active Star Formation

Abstract: Starburst99 is a comprehensive set of model predictions for spectrophotometric and related properties of galaxies with active star formation. The models are an improved and extended version of the data set previously published by Leitherer & Heckman. We have upgraded our code by implementing the latest set of stellar evolution models of the Geneva group and the model atmosphere grid compiled by Lejeune et al. Several predictions which were not included in the previous publication are shown here for the first time. The models are presented in a homogeneous way for five metallicities between Z = 0.040 and 0.001 and three choices of the initial mass function. The age coverage is 106—109 yr. We also show the spectral energy distributions which are used to compute colors and other quantities. The full data set is available for retrieval at a Web site, which allows users to run specific models with nonstandard parameters as well. We also make the source code available to the community.

Functional Characterization of the S. cerevisiae Genome by Gene Deletion and Parallel Analysis

Abstract: The functions of many open reading frames (ORFs) identified in genome-sequencing projects are unknown. New, whole-genome approaches are required to systematically determine their function. A total of 6925 Saccharomyces cerevisiae strains were constructed, by a high-throughput strategy, each with a precise deletion of one of 2026 ORFs (more than one-third of the ORFs in the genome). Of the deleted ORFs, 17 percent were essential for viability in rich medium. The phenotypes of more than 500 deletion strains were assayed in parallel. Of the deletion strains, 40 percent showed quantitative growth defects in either rich or minimal medium.

A simplified system for generating recombinant adenoviruses

Abstract: Recombinant adenoviruses provide a versatile system for gene expression studies and therapeutic applications. This invention describes a strategy which simplifies the generation and production of such viruses. A recombinant adenoviral plasmid is generated with a minimum of enzymatic manipulations, employing homologous recombination in bacteria rather than in eucaryotic cells. Following transfections of such plasmids into a mammalian packaging cell line, viral production can be conveniently followed with the aid of green fluorescent protein, encoded by a gene incorporated into the viral backbone. Homogeneous viruses can be obtained from this procedure without plaque purification. This system expedites the process of generating and testing recombinant adenoviruses.

Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging.

Abstract: The relationship between brain structure and complex behavior is governed by large-scale neurocognitive networks. The availability of a noninvasive technique that can visualize the neuronal projections connecting the functional centers should therefore provide new keys to the understanding of brain function. By using high-resolution three-dimensional diffusion magnetic resonance imaging and a newly designed tracking approach, we show that neuronal pathways in the rat brain can be probed in situ. The results are validated through comparison with known anatomical locations of such fibers.

Natural history of progression after PSA elevation following radical prostatectomy.

Abstract: Context In men who develop an elevated serum prostate-specific antigen level (PSA) after having undergone a radical prostatectomy, the natural history of progression to distant metastases and death due to prostate cancer is unknown. Objective To characterize the time course of disease progression in men with biochemical recurrence after radical prostatectomy. Design A retrospective review of a large surgical series with median (SD) follow-up of 5.3 (3.7) years (range, 0.5-15 years) between April 1982 and April 1997. SettingAn urban academic tertiary referral institution.Patients A total of 1997 men undergoing radical prostatectomy, by a single surgeon, for clinically localized prostate cancer. None received neoadjuvant therapy, and none had received adjuvant hormonal therapy prior to documented distant metastases. Main Outcome Measures After surgery, men were followed up with PSA assays and digital rectal examinations every 3 months for the first year, semiannually for the second year, and annually thereafter. A detectable serum PSA level of at least 0.2 ng/mL was evidence of biochemical recurrence. Distant metastases were diagnosed by radionuclide bone scan, chest radiograph, or other body imaging, which was performed at the time of biochemical recurrence and annually thereafter. Results The actuarial metastasis-free survival for all 1997 men was 82% (95% confidence interval, 76%-88%) at 15 years after surgery. Of the 1997 men, 315 (15%) developed biochemical PSA level elevation. Eleven of these underwent early hormone therapy after the recurrence and are not included in the study. Of the remaining 304 men, 103 (34%) developed metastatic disease within the study period. The median actuarial time to metastases was 8 years from the time of PSA level elevation. In survival analysis, time to biochemical progression (P<.001), Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease. An algorithm combining these parameters was constructed to stratify men into risk groups. Once men developed metastatic disease, the median actuarial time to death was 5 years. The time interval from surgery to the appearance of metastatic disease was predictive of time until death (P<.02). Conclusions Several clinical parameters help predict the outcomes of men with PSA elevation after radical prostatectomy. These data may be useful in the design of clinical trials, the identification of men for enrollment into experimental protocols, and counseling men regarding the timing of administration of adjuvant therapies.

CpG island methylator phenotype in colorectal cancer.

Abstract: Aberrant methylation of promoter region CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia. To understand global patterns of CpG island methylation in colorectal cancer, we have used a recently developed technique called methylated CpG island amplification to examine 30 newly cloned differentially methylated DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-dependent manner in normal colon, 7 (23%) were methylated in a cancer-specific manner, and 4 (13%) were methylated only in cell lines. Thus, a majority of CpG islands methylated in colon cancer are also methylated in a subset of normal colonic cells during the process of aging. In contrast, methylation of the cancer-specific clones was found exclusively in a subset of colorectal cancers, which appear to display a CpG island methylator phenotype (CIMP). CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation. We thus define a pathway in colorectal cancer that appears to be responsible for the majority of sporadic tumors with mismatch repair deficiency.

Overexpression of Hypoxia-inducible Factor 1α in Common Human Cancers and Their Metastases

Abstract: Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1α subunit. In this study, HIF-1α expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1α was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1α expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1α, whereas benign tumors in breast and uterus did not. HIF-1α overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1α immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1α may play an important role in human cancer progression.

Race, gender, and partnership in the patient-physician relationship.

Abstract: ContextMany studies have documented race and gender differences in health care received by patients. However, few studies have related differences in the quality of interpersonal care to patient and physician race and gender.ObjectiveTo describe how the race/ethnicity and gender of patients and physicians are associated with physicians' participatory decision-making (PDM) styles.Design, Setting, and ParticipantsTelephone survey conducted between November 1996 and June 1998 of 1816 adults aged 18 to 65 years (mean age, 41 years) who had recently attended 1 of 32 primary care practices associated with a large mixed-model managed care organization in an urban setting. Sixty-six percent of patients surveyed were female, 43% were white, and 45% were African American. The physician sample (n=64) was 63% male, with 56% white, and 25% African American.Main Outcome MeasurePatients' ratings of their physicians' PDM style on a 100-point scale.ResultsAfrican American patients rated their visits as significantly less participatory than whites in models adjusting for patient age, gender, education, marital status, health status, and length of the patient-physician relationship (mean [SE] PDM score, 58.0 [1.2] vs 60.6 [3.3]; P=.03). Ratings of minority and white physicians did not differ with respect to PDM style (adjusted mean [SE] PDM score for African Americans, 59.2 [1.7] vs whites, 61.7 [3.1]; P=.13). Patients in race-concordant relationships with their physicians rated their visits as significantly more participatory than patients in race-discordant relationships (difference [SE], 2.6 [1.1]; P=.02). Patients of female physicians had more participatory visits (adjusted mean [SE] PDM score for female, 62.4 [1.3] vs male, 59.5 [3.1]; P=.03), but gender concordance between physicians and patients was not significantly related to PDM score (unadjusted mean [SE] PDM score, 76.0 [1.0] for concordant vs 74.5 [0.9] for discordant; P=.12). Patient satisfaction was highly associated with PDM score within all race/ethnicity groups.ConclusionsOur data suggest that African American patients rate their visits with physicians as less participatory than whites. However, patients seeing physicians of their own race rate their physicians' decision-making styles as more participatory. Improving cross-cultural communication between primary care physicians and patients and providing patients with access to a diverse group of physicians may lead to more patient involvement in care, higher levels of patient satisfaction, and better health outcomes.

Annual Deaths Attributable to Obesity in the United States

Abstract: ContextObesity is a major health problem in the United States, but the number of obesity-attributable deaths has not been rigorously estimated.ObjectiveTo estimate the number of deaths, annually, attributable to obesity among US adults.DesignData from 5 prospective cohort studies (the Alameda Community Health Study, the Framingham Heart Study, the Tecumseh Community Health Study, the American Cancer Society Cancer Prevention Study I, and the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study) and 1 published study (the Nurses' Health Study) in conjunction with 1991 national statistics on body mass index distributions, population size, and overall deaths.SubjectsAdults, 18 years or older in 1991, classified by body mass index (kg/m2) as overweight (25-30), obese (30-35), and severely obese (>35).Main Outcome MeasureRelative hazard ratio (HR) of death for obese or overweight persons.ResultsThe estimated number of annual deaths attributable to obesity varied with the cohort used to calculate the HRs, but findings were consistent overall. More than 80% of the estimated obesity-attributable deaths occurred among individuals with a body mass index of more than 30 kg/m2. When HRs were estimated for all eligible subjects from all 6 studies, the mean estimate of deaths attributable to obesity in the United States was 280,184 (range, 236,111-341,153). Hazard ratios also were calculated from data for nonsmokers or never-smokers only. When these HRs were applied to the entire population (assuming the HR applied to all individuals), the mean estimate for obesity-attributable death was 324,940 (range, 262,541-383,410).ConclusionsThe estimated number of annual deaths attributable to obesity among US adults is approximately 280,000 based on HRs from all subjects and 325,000 based on HRs from only nonsmokers and never-smokers.

Latent infection of CD4 + T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy

Abstract: Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes

Abstract: OBJECTIVE To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE). METHODS An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests. RESULTS Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed. CONCLUSION The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.

Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase.

Abstract: The copper chaperone for the superoxide dismutase (CCS) gene is necessary for expression of an active, copper-bound form of superoxide dismutase (SOD1) in vivo in spite of the high affinity of SOD1 for copper (dissociation constant = 6 fM) and the high intracellular concentrations of both SOD1 (10 μM in yeast) and copper (70 μM in yeast). In vitro studies demonstrated that purified Cu(I)-yCCS protein is sufficient for direct copper activation of apo-ySOD1 but is necessary only when the concentration of free copper ions ([Cu] free ) is strictly limited. Moreover, the physiological requirement for yCCS in vivo was readily bypassed by elevated copper concentrations and abrogation of intracellular copper-scavenging systems such as the metallothioneins. This metallochaperone protein activates the target enzyme through direct insertion of the copper cofactor and apparently functions to protect the metal ion from binding to intracellular copper scavengers. These results indicate that intracellular [Cu] free is limited to less than one free copper ion per cell and suggest that a pool of free copper ions is not used in physiological activation of metalloenzymes.

Smallpox as a Biological Weapon Medical and Public Health Management

Abstract: Donald A. Henderson, MD, MPHThomas V. Inglesby, MDJohn G. Bartlett, MDMichael S. Ascher, MDEdward Eitzen, MD, MPHPeter B. Jahrling, PhDJerome Hauer, MPHMarcelle Layton, MDJoseph McDade, PhDMichael T. Osterholm, PhD, MPHTara O’Toole, MD, MPHGerald Parker, PhD, DVMTrish Perl, MD, MScPhilip K. Russell, MDKevin Tonat, PhDfor the Working Group onCivilian Biodefense

HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage.

Abstract: A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Dust Absorption and the Ultraviolet Luminosity Density at z ≈ 3 as Calibrated by Local Starburst Galaxies*

Abstract: We refine a technique to measure the absorption-corrected ultraviolet (UV) luminosity of starburst galaxies using rest-frame UV quantities alone and apply it to Lyman-limit U dropouts at z ? 3 found in the Hubble Deep Field (HDF). The method is based on an observed correlation between the ratio of far-infrared (FIR) to UV fluxes with spectral slope ? (a UV color). A simple fit to this relation allows the UV flux absorbed by dust and reprocessed to the FIR to be calculated, and hence the dust-free UV luminosity to be determined. International Ultraviolet Explorer spectra and Infrared Astronomical Satellite fluxes of local starbursts are used to calibrate the FFIR/F1600 versus ? relation in terms of A1600 (the dust absorption at 1600 ?) and the transformation from broadband photometric color to ?. Both calibrations are almost completely independent of theoretical stellar-population models. We show that the recent marginal and nondetections of HDF U dropouts at radio and submillimeter wavelengths are consistent with their assumed starburst nature and our calculated A1600. This is also true of recent observations of the ratio of optical emission-line flux to UV flux density in the brightest U dropouts. This latter ratio turns out not to be a good indicator of dust extinction. In U dropouts, absolute magnitude M1600,0 correlates with ?: brighter galaxies are redder, as is observed to be the case for local starburst galaxies. This suggests that a mass-metallicity relationship is already in place at z ? 3. The absorption-corrected UV luminosity function of U dropouts extends up to M1600,0 ? -24 AB mag, corresponding to a star formation rate ~200 ? yr-1 (H0 = 50 km s-1 Mpc-3 and q0 = 0.5 are assumed throughout). The absorption-corrected UV luminosity density at z ? 3 is ?1600,0 ? 1.4 ? 1027 ergs-1 Hz-1 Mpc-1. It is still a lower limit since completeness corrections have not been done and because only galaxies with A1600 3.6 mag are blue enough in the UV to be selected as U dropouts. The luminosity-weighted mean dust-absorption factor of our sample is 5.4 ? 0.9 at 1600 ?.

Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia

Abstract: The DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the O6 position of guanine. MGMT expression is decreased in some tumor tissues, and lack of activity has been observed in some cell lines. Loss of expression is rarely due to deletion, mutation, or rearrangement of the MGMT gene, but methylation of discrete regions of the CpG island of MGMT has been associated with the silencing of the gene in cell lines. We used methylation-specific PCR to study the promoter methylation of the MGMT gene. All normal tissues and expressing cancer cell lines were unmethylated, whereas nonexpressing cancer cell lines were methylated. Among the more than 500 primary human tumors examined, MGMT hypermethylation was present in a subset of specific types of cancer. In gliomas and colorectal carcinomas, aberrant methylation was detected in 40% of the tumors, whereas in non-small cell lung carcinomas, lymphomas, and head and neck carcinomas, this alteration was found in 25% of the tumors. MGMT methylation was found rarely or not at all in other tumor types. We also analyzed MGMT expression by immunohistochemistry in relation to the methylation status in 31 primary tumors. The presence of aberrant hypermethylation was associated with loss of MGMT protein, in contrast to retention of protein in the majority of tumors without aberrant hypermethylation. Our results suggest that epigenetic inactivation of MGMT plays an important role in primary human neoplasia.

Oral gene delivery with chitosan--DNA nanoparticles generates immunologic protection in a murine model of peanut allergy.

Abstract: Food allergy is a common and often fatal disease with no effective treatment We describe here a new immunoprophylactic strategy using oral allergen-gene immunization to modulate peanut antigen-induced murine anaphylactic responses Oral administration of DNA nanoparticles synthesized by complexing plasmid DNA with chitosan, a natural biocompatible polysaccharide, resulted in transduced gene expression in the intestinal epithelium Mice receiving nanoparticles containing a dominant peanut allergen gene (pCMVArah2) produced secretory IgA and serum IgG2a Compared with non-immunized mice or mice treated with 'naked' DNA, mice immunized with nanoparticles showed a substantial reduction in allergen-induced anaphylaxis associated with reduced levels of IgE, plasma histamine and vascular leakage These results demonstrate that oral allergen-gene immunization with chitosan-DNA nanoparticles is effective in modulating murine anaphylactic responses, and indicate its prophylactic utility in treating food allergy

Dust Absorption And The Ultraviolet Luminosity Density At z \approx 3 As Calibrated By Local Starburst Galaxies

Abstract: We refine a technique to measure the absorption corrected ultraviolet (UV) luminosity of starburst galaxies using rest frame UV quantities alone, and apply it to U-dropouts at z ~ 3 found in the Hubble Deep Field. The method is based on an observed correlation between the ratio of far infrared (FIR) to UV fluxes with spectral slope \beta (a UV color). A simple fit to this relation allows the UV flux absorbed by dust to be calculated, and hence the dust-free UV luminosity to be determined. IUE spectra and IRAS fluxes of local starbursts are used to calibrate the ratio in terms of 1600 Angstrom absorption A_{1600}, and the transformation from broad band color to \beta. We show that the recent marginal and non-detections of HDF U-dropouts in the radio and sub-mm are consistent with our calculated A_{1600}. This is also true of observations of the ratio of optical emission line flux to UV flux density in the brightest U-dropouts. This latter ratio turns out not to be a good indicator of dust extinction. In U-dropouts, absolute magnitude correlates with \beta: brighter galaxies are redder, as is observed in local starburst galaxies. This suggests that a mass-metallicity relationship is in place by z ~ 3. The UV luminosity function of U-dropouts extends up to M_{1600,0} ~ -24 ABmag corresponding to a star formation rate ~ 200 \Msun/yr (H_0 = 50 km/s/Mpc, q_0 = 0.5). The absorption-corrected UV luminosity density at z ~ 3 is \rho_{1600,0} => 1.4x10^{27} erg/s/Hz/Mpc^3; still a lower limit since completeness corrections have not been done and because only galaxies with A_{1600} < ~3.6 mag are blue enough to be selected as U-dropouts. The luminosity weighted mean dust absorption factor of our sample is 5.4 +/- 0.9$ at 1600\AA (abridged).

Adjusting for Nonignorable Drop-Out Using Semiparametric Nonresponse Models

Abstract: Consider a study whose design calls for the study subjects to be followed from enrollment (time t = 0) to time t = T, at which point a primary endpoint of interest Y is to be measured. The design of the study also calls for measurements on a vector V t) of covariates to be made at one or more times t during the interval [0, T). We are interested in making inferences about the marginal mean μ0 of Y when some subjects drop out of the study at random times Q prior to the common fixed end of follow-up time T. The purpose of this article is to show how to make inferences about μ0 when the continuous drop-out time Q is modeled semiparametrically and no restrictions are placed on the joint distribution of the outcome and other measured variables. In particular, we consider two models for the conditional hazard of drop-out given (V(T), Y), where V(t) denotes the history of the process V t) through time t, t ∈ [0, T). In the first model, we assume that λQ(t|V(T), Y) exp(α0 Y), where α0 is a scalar paramet...

Disruption of p53 in human cancer cells alters the responses to therapeutic agents

Abstract: We have examined the effects of commonly used chemotherapeutic agents on human colon cancer cell lines in which the p53 pathway has been specifically disrupted by targeted homologous recombination. We found that p53 had profound effects on drug responses, and these effects varied dramatically depending on the drug. The p53-deficient cells were sensitized to the effects of DNA-damaging agents as a result of the failure to induce expression of the cyclin-dependent kinase inhibitor p21. In contrast, p53 disruption rendered cells strikingly resistant to the effects of the antimetabolite 5-fluorouracil (5-FU), the mainstay of adjuvant therapy for colorectal cancer. The effects on 5-FU sensitivity were observed both in vitro and in vivo, were independent of p21, and appeared to be the result of perturbations in RNA, rather than DNA, metabolism. These results have significant implications for future efforts to maximize therapeutic efficacy in patients with defined genetic alterations.

DD3::A New Prostate-specific Gene, Highly Overexpressed in Prostate Cancer

Abstract: Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. Despite the tremendous efforts that have been made to improve the early detection of this disease and to design new treatment modalities, there is still an urgent need for new markers and therapeutic targets for the management of prostate cancer patients. Using differential display analysis to compare the mRNA expression patterns of normal versus tumor tissue of the human prostate, we identified a cDNA, DD3, which is highly overexpressed in 53 of 56 prostatic tumors in comparison to nonneoplastic prostatic tissue of the same patients. Reverse transcription-PCR analysis using DD3-specific primers indicated that the expression of DD3 is very prostate specific because no product could be amplified in 18 different normal human tissues studied. Also, in a sampling of other tumor types and a large number of cell lines, no expression of DD3 could be detected. Molecular characterization of the DD3 transcription unit revealed that alternative splicing and alternative polyadenylation occur. The fact that no extensive open reading frame could be found suggests that DD3 may function as a noncoding RNA. The DD3 gene was mapped to chromosome 9q21-22, and no homology of DD3 to any gene present in the computer databases was found. Our data indicate that DD3 is one of the most prostate cancer-specific genes yet described, and this makes DD3 a promising marker for the early diagnosis of prostate cancer and provides a powerful tool for the development of new treatment strategies for prostate cancer patients.

Immunologic basis of antigen-induced airway hyperresponsiveness

Abstract: ▪ Abstract The incidence, morbidity, and mortality of asthma has increased worldwide over the last two decades. Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), and airway inflammation. The inflammatory response in the asthmatic lung is characterized by infiltration of the airway wall with mast cells, lymphocytes, and eosinophils. Although asthma is multifactorial in origin, the inflammatory process in the most common form of the disease (extrinsic asthma) is believed to be a result of inappropriate immune responses to common aero-allergens in genetically susceptible individuals. As such, it has been hypothesized that CD4+ T cells that produce a Th2 pattern of cytokines play a pivotal role in the pathogenesis of this disease. Through the release of cytokines such as IL-4, IL-13, and IL-5, these cells orchestrate the recruitment and activation of the primary effector cells of the allergic response, the mast cell and the eo...