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Although a substantial number of hormones and drugs increase cellular cAMP levels, the global impact of cAMP and its major effector mechanism, protein kinase A (PKA), on gene expression is not known. Here we show that treatment of murine wild-type S49 lymphoma cells for 24 h with 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP), a PKA-selective cAMP analog, alters the expression of approximate to 4,500 of approximate to 13,600 unique genes. By contrast, gene expression was unaltered in Kin(-) S49 cells (that lack PKA) incubated with 8-CPT-cAMP. Changes in mRNA and protein expression of several cell-cycle regulators accompanied cAMP-induced G(1)-phase cell-cycle arrest of wild-type S49 cells. Within 2 h, 8-CPT-cAMP altered expression of 152 genes that contain evolutionarily conserved cAMP-response elements within 5 kb of transcriptional start sites, including the circadian clock gene Per1. Thus, cAMP through its activation of PKA produces extensive transcriptional regulation in eukaryotic cells. These transcriptional networks include a primary group of cAMP-response element-containing genes and secondary networks that include the circadian clock.

Context: Infection with the human immunodeficiency virus (HIV) is the only infectious disease for which anonymous testing is publicly funded, an exception that has been controversial.Objective: To assess whether anonymous HIV testing was associated with earlier HIV testing and HIV-related medical care than confidential HIV testing.Design: Retrospective cohort.Setting: Arizona, Colorado, Missouri, New Mexico, North Carolina, Oregon, and Texas.Participants: Probability sample of 835 new acquired immunodeficiency syndrome (AIDS) cases reported to the state health department's HIV/AIDS Reporting System from May 1995 through December 1996. All had responded to the AIDS Patient Survey; 643 had been tested confidentially for HIV, and 192 had been tested anonymously.Main Outcome Measures: First CD4+ cell count; number of days from HIV-positive test result to first HIV-related medical care, from first HIV-related medical care to AIDS, and from first HIV-positive test result to AIDS.Results: Persons tested anonymously sought testing and medical care earlier in the course of HIV disease than did persons tested confidentially. Mean first CD4+ cell count was 0.427x 10(9)/L in persons tested anonymously vs 0.267x 10(9)/L in persons tested confidentially. Persons tested anonymously experienced an average of 918 days in HIV-related medical care before an AIDS diagnosis vs 531 days for persons tested confidentially. The mean time from learning they were HIV positive to the diagnosis of AIDS was 1246 days for persons tested anonymously vs 718 days for persons tested confidentially. After adjustment for the subject's age, sex, race/ethnicity, education, income, insurance status, HIV exposure group, whether the respondent had a regular source of care or symptoms at the time of the HIV test, and state residence, anonymous testing remained significantly associated with earlier entry into medical care (P<.001).Conclusion: Anonymous testing contributes to early HIV testing and medical care. [ABSTRACT FROM AUTHOR]

Objective: To compare specialist and primary care physician participation in California's Medicaid fee-for-service and managed care programs.Design: Cross-sectional survey.Participants: A probability sample stratified by county and by race of 962 specialist physicians and 713 primary care physicians practicing in the 13 largest counties in California in 1998.Measurements and Analysis: We used physician self-report from mailed questionnaires to compare acceptance of new Medicaid and new Medicaid managed care patients by specialists versus primary care physicians and by physician demographics, practice setting, attitudes toward Medicaid patients, and attitudes toward Medicaid managed care. We analyzed results using logistic regression with data weighted to represent the total population of primary care and specialist physicians in the 13 counties.Main Results: Specialists were as likely as primary care physicians to have any Medicaid patients in their practices (56% vs 56%; P=.9). Among physicians accepting any new patients, specialists were more likely than primary care physicians to be taking new Medicaid patients but were significantly more likely to limit their acceptance to only Medicaid fee-for-service patients. Thus, specialists were much less likely than primary care physicians to accept new Medicaid managed care patients. After controlling for physician demographics, practice settings, and attitudes toward Medicaid patients and Medicaid managed care, specialists remained much less likely to accept new Medicaid managed care patients.Conclusions: Expansion of Medicaid managed care may decrease access to specialists as specialists were less likely to accept new Medicaid managed care patients compared to Medicaid fee-for-service patients. Any decrease in access may be mitigated if states are able to contract with group model HMOs and to recruit minority physicians. [ABSTRACT FROM AUTHOR]

Objective: To examine primary care physicians' perceptions of how disease management programs affect their practices, their relationships with their patients, and overall patient care.Design: Cross-sectional mailed survey.Setting: The 13 largest urban counties in California.Participants: General internists, general pediatricians, and family physicians.Measurements and Main Results: Physicians' self-report of the effects of disease management programs on quality of patient care and their own practices. Respondents included 538 (76%) of 708 physicians: 183 (34%) internists, 199 (38%) family practitioners, and 156 (29%) pediatricians. Disease management programs were available 285 to (53%) physicians; 178 had direct experience with the programs. Three quarters of the 178 physicians believed that disease management programs increased the overall quality of patient care and the quality of care for the targeted disease. Eighty-seven percent continued to provide primary care for their patients in these programs, and 70% reported participating in major patient care decisions. Ninety-one percent reported that the programs had no effect on their income, decreased (38%) or had no effect (48%) on their workload, and increased (48%)) their practice satisfaction.Conclusions: Practicing primary care physicians have generally favorable perceptions of the effect of voluntary, primary care-inclusive, disease management programs on their patients and on their own practice satisfaction. [ABSTRACT FROM AUTHOR]

Name-based surveillance of HIV infection is the law in 31 U.S. states but remains controversial. This policy can be advocated solely to support surveillance of the epidemic, but a frequent argument is that it also provides a public health benefit by allowing follow-up of HIV-infected persons. These persons can then receive timely medical care and can be assisted with notifying sex and needle-sharing partners. Few comparative data are available to evaluate the outcomes of these interventions. In five states with name-based surveillance of HIV infection, the Multistate Evaluation of Surveillance for HIV Study Group surveyed a cross-sectional probability sample of persons with AIDS who tested positive for HIV before the date of their AIDS diagnosis. Health department follow-up of a reported HIV infection was not associated with more timely receipt of medical care after a positive HIV test result. Only 8.6% of persons who delayed medical care after their first positive HIV test result gave concern about being reported by name as a reason; no person gave it as the main reason. Persons who were tested anonymously and those who were tested confidentially did not differ in the mean number of sex and needle-sharing partners notified: Those tested anonymously reported personally notifying 3.85 sex and needle-sharing partners, and those tested confidentially reported notifying-personally and through the health department-3.80 partners. Many researchers and policymakers believe that name-based surveillance of HIV infection will have positive or negative effects on partner notification and access to health care. These results suggest that the potential for such effects has been exaggerated. [ABSTRACT FROM AUTHOR]

HIV screening for drug users in treatment began in San Francisco in 1985, and was followed by street screening, community outreach, bleach distribution and other intervention programs. The HIV seroconversion rate fell from 4.5% per year in 1985-86 to 1.7% per year in 1987-88 and has remained stable at about 2% per year since 1988. While this decline cannot be attributed to specific programs, the broad spectrum of interventions in San Francisco appears to be keeping the new infection rate low. Future programs should aim at reducing heterosexual HIV transmission, at intervening with multiply-diagnosed drug users, and at providing service to homeless and other very poor drug-using groups. [ABSTRACT FROM AUTHOR]

The effect on plasma lipoproteins of exchanging fat type within currently recommended reduced-fat diets was studied in a free-living group of 19 men and 20 women who consumed both a polyunsaturated fat-enriched diet and a monounsaturated fat-enriched diet, each for a 12-week period, with saturated fat and cholesterol held constant. Mean plasma concentrations of low-density lipoprotein cholesterol and low-density lipoprotein total mass (analytic ultracentrifuge), and high-density lipoprotein (HDL) cholesterol and HDL total mass, did not change significantly on exchanging fat type. However, HDL2 cholesterol concentration was 50% higher and HDL3 cholesterol concentration was 7% lower for polyunsaturated compared with monounsaturated fat. Mean total mass of HDL2 was also 23.5% higher and concentration of apolipoprotein B was 5.4% lower on transfer to the polyunsaturated fat diet. Contrary to frequent assertions, we find no advantage with respect to plasma HDL concentrations in using predominantly monounsaturated rather than polyunsaturated fats in subjects who consumed reduced-fat, solid-food diets. [ABSTRACT FROM AUTHOR]

Context: Little is known about the problems physicians may be encountering in gaining access to managed care networks and whether the process used by managed care plans to select physicians is discriminatory.Objective: To investigate the incidence and predictors of denials or terminations of physicians' managed care contracts and the impact these denials and terminations had on primary care physicians' involvement with managed care.Design: Cross-sectional mail survey of a probability sample of primary care physicians.Setting: A total of 13 large urban counties in California.Participants: Primary care physicians (family practice, internal medicine, obstetrics and gynecology, or pediatrics) who work in office-based practice.Main Outcome Measures: Denial or termination from a contract with an independent practice association (IPA) or health maintenance organization (HMO) and managed care contracts.Results: Of the 947 respondents (response rate, 71%), 520 were involved in office-based primary care. After adjusting for sampling and response rate, 22% of primary care physicians had been denied or terminated from a contract with an IPA or HMO, but 87% of office-based primary care physicians had at least 1 IPA or direct HMO contract. Solo practice was the strongest predictor of having experienced a denial or termination and of having neither an IPA nor a direct HMO contract. Physician age, sex, and race did not predict the level of involvement with managed care. However, physicians' patient demographics were associated with managed care participation; physicians in managed care had significantly lower percentages of uninsured and nonwhite patients in their practices. Physicians experiencing a denial or termination had fewer capitated patients in their practice.Conclusions: Denials and terminations, although relatively common, do not preclude most primary care physicians from participating in managed care. Managed care selective contracting does not appear to be systematically discriminatory based on physician characteristics, but it may be biased against physicians who provide greater amounts of care to the underserved. [ABSTRACT FROM AUTHOR]

Objective: To examine whether health insurance, a regular place of care, and optimal primary care are independently associated with receiving preventive care services.Design: A cross-sectional telephone survey.Setting: Population based.Participants: Probability sample of 3,846 English-speaking and Spanish-speaking women between the ages of 18 and 64 in urban California.Interventions: Women were asked about their demographic characteristics, financial status, health insurance status, need for ongoing care, regular place of care, and receipt of blood pressure screening, clinical breast examinations, mammograms, and Pap smears. Women who reported a regular place of care were asked about four components of primary care: availability, continuity, comprehensiveness, and communication.Measurements and Main Results: In multivariate analyses that controlled for differences in demographics, financial status, and need for ongoing care, having a regular place of care was the most important factor associated with receiving preventive care services (p < .0001). Having health insurance (p < .001) and receiving optimal primary care from the regular place of care (p < .01) further significantly increased the likelihood of receiving preventive care services.Conclusion: A regular source of care is the single most important factor associated with the receipt of preventive services, but optimal primary care from a regular place increases the likelihood that women will receive preventive care. [ABSTRACT FROM AUTHOR]

Discusses the findings of an HIV testing among populations at risk for HIV infection in the United States from November 1995 to December 1996. Deterrents to testing; How the HIV Testing Survey (HITS) was conducted; Limitations of the findings.

Single-agent intravenous vinblastine, 4 to 8 mg/week, was used to treat 38 patients with Kaposi's sarcoma related to the acquired immunodeficiency syndrome. The dose was titrated in relation to the total leukocyte count. Ten patients had an objective response, and 19 had stable disease during therapy. Apart from expected modest neutropenia, toxicity was minimal. A lower response rate was seen in patients with anemia, an elevated erythrocyte sedimentation rate, or any lymphoma-like B symptom. Opportunistic infections were common regardless of type of response but were commoner in patients who did not respond. Vinblastine used in low doses weekly is effective in treating Kaposi's sarcoma related to the acquired immunodeficiency syndrome and has minimal associated toxicities. [ABSTRACT FROM AUTHOR]

Unlabelled: We introduce GO-Elite, a flexible and powerful pathway analysis tool for a wide array of species, identifiers (IDs), pathways, ontologies and gene sets. In addition to the Gene Ontology (GO), GO-Elite allows the user to perform over-representation analysis on any structured ontology annotations, pathway database or biological IDs (e.g. gene, protein or metabolite). GO-Elite exploits the structured nature of biological ontologies to report a minimal set of non-overlapping terms. The results can be visualized on WikiPathways or as networks. Built-in support is provided for over 60 species and 50 ID systems, covering gene, disease and phenotype ontologies, multiple pathway databases, biomarkers, and transcription factor and microRNA targets. GO-Elite is available as a web interface, GenMAPP-CS plugin and as a cross-platform application., Availability: http://www.genmapp.org/go&#95;elite

The Murphy Roths Large (MRL) mouse, a strain capable of regenerating right ventricular myocardium, has a high postmyocardial infarction (post-MI) survival rate compared with C57BL/6J (C57) mice. The biological processes responsible for this survival advantage are unknown. To assess the effect of genetic background, the LG/J strain, which harbours 75% of the MRL composite genome, was included in the study. The MRL survival advantage versus C57 mice (92 versus 68%, P < 0.05) occurred primarily in the first 5 days; LG/J survival was intermediate (P = n.s.). Microarray data analysis revealed an attenuation of apoptotic (P < 0.05) and stress response transcripts in MRL hearts compared with C57 hearts post-MI. Supporting the microarray results, there were fewer TUNEL-positive cells 1 day post-MI in MRL infarcts compared with C57 infarcts (P = 0.001) and fewer CD45-positive cells in the MRL infarct border zone 2 days post-MI (P < 0.01); the LG/J results were intermediate (P = n.s.). The MRL hearts had smaller infarct scars and attenuated ventricular dilatation 30 days post-MI compared with C57 hearts (P < 0.05). We conclude that the early post-MI survival advantage of MRL mice over the C57 strain is mediated at least in part by reductions in apoptosis and inflammatory infiltration, and that these reductions may influence chronic remodelling. The intermediate survival, apoptosis and inflammation profile of LG/J mice suggests that this high tolerance for MI in the MRL mouse could be derived from its shared genetic background with the LG/J mouse.

The olfactory epithelium is a sensory neuroepithelium that supports adult neurogenesis and tissue regeneration following injury, making it an excellent model for investigating neural stem cell regulation in vivo. Previous studies have identified the horizontal basal cell (HBC) as the neural stem cell of the postnatal olfactory epithelium. However, the molecules and pathways regulating HBC self-renewal and differentiation are unknown. In the present study, we demonstrate that the transcription factor p63, a member of the p53 tumor suppressor gene family known to regulate stem cell dynamics in other epithelia, is highly enriched in HBCs. We show that p63 is required cell autonomously for olfactory stem cell renewal and further demonstrate that p63 functions to repress HBC differentiation. These results provide critical insight into the genetic regulation of the olfactory stem cell in vivo and more generally provide an entrée toward understanding the coordination of stem cell self-renewal and differentiation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The local progenitor population in the olfactory bulb (OB) gives rise to mitral and tufted projection neurons during embryonic development. In contrast, OB interneurons are derived from sources outside the bulb where neurogenesis continues throughout life. While many of the genes involved in OB interneuron development have been characterized, the genetic pathways driving local progenitor cell differentiation in this tissue are largely unknown. To better understand this process, we used transcriptional profiling to monitor gene expression of whole OB at daily intervals from embryonic day 11 through birth, generating a compendium of gene expression encompassing the major developmental events of this tissue. Through hierarchical clustering, bioinformatics analysis, and validation by RNA in situ hybridizations, we identified a large number of transcription factors, DNA binding proteins, and cell cycle-related genes expressed by the local neural progenitor cells (NPCs) of the embryonic OB. Further in silico analysis of transcription factor binding sites identified an enrichment of genes regulated by the E2F-Rb pathway among those expressed in the local NPC population. Together these results provide initial insights into the molecular identity of the OB local NPC population and the transcription factor networks that may regulate their function., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.

Enhanced understanding of differential gene expression and biological pathways associated with distinct phases of intramembranous bone regeneration following femoral marrow ablation surgery will improve future advancements regarding osseointegration of joint replacement implants, biomaterials design, and bone tissue engineering. A rat femoral marrow ablation model was performed and genome-wide microarray data were obtained from samples at 1, 3, 5, 7, 10, 14, 28, and 56 days post-ablation, with intact bones serving as controls at Day 0. Bayesian model-based clustering produced eight distinct groups amongst 9,062 significant gene probe sets based on similar temporal expression profiles, which were further categorized into three major temporal classes of increased, variable, and decreased expression. Osteoblastic- and osteoclastic-associated genes were found to be significantly expressed within the increased expression groups. Chondrogenesis was not detected histologically. Adipogenic marker genes were found within variable/decreased expression groups, emphasizing that adipogenesis was inhibited during osteogenesis. Differential biological processes and pathways associated with each major temporal group were identified, and significantly expressed genes involved were visually represented by heat maps. It was determined that the increased expression group exclusively contains genes involved in pathways for matrix metalloproteinases (MMPs), Wnt signaling, TGF-β signaling, and inflammatory pathways. Only the variable expression group contains genes associated with glycolysis and gluconeogenesis, the notch signaling pathway, natural killer cell mediated cytotoxicity, and the B cell receptor signaling pathway. The decreased group exclusively consists of genes involved in heme biosynthesis, the p53 signaling pathway, and the hematopoietic cell lineage. Significant biological pathways and transcription factors expressed at each time point post-ablation were also identified. These data present the first temporal gene expression profiling analysis of the rat genome during intramembranous bone regeneration induced by femoral marrow ablation.