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PubMed2001

Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress.

Erythropoietin (EPO) promotes neuronal survival after hypoxia and other metabolic insults by largely unknown mechanisms. Apoptosis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study evaluates whether antiapoptotic mechanisms can account for the neuroprotective actions of EPO. Systemic administration of EPO (5,000 units/kg of body weight, i.p.) after middle-cerebral artery occlusion in rats dramatically reduces the volume of infarction 24 h later, in concert with an almost complete reduction in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling of neurons within the ischemic penumbra. In both pure and mixed neuronal cultures, EPO (0.1--10 units/ml) also inhibits apoptosis induced by serum deprivation or kainic acid exposure. Protection requires pretreatment, consistent with the induction of a gene expression program, and is sustained for 3 days without the continued presence of EPO. EPO (0.3 units/ml) also protects hippocampal neurons against hypoxia-induced neuronal death through activation of extracellular signal-regulated kinases and protein kinase Akt-1/protein kinase B. The action of EPO is not limited to directly promoting cell survival, as EPO is trophic but not mitogenic in cultured neuronal cells. These data suggest that inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The neurotrophic actions suggest there may be longer-latency effects as well. Evaluation of EPO, a compound established as clinically safe, as neuroprotective therapy in acute brain injury is further supported.

Animals↗
PubMed2024

Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression.

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.

Decorin↗
PubMed2002

Coaching commitment and turnover: a comparison of current and former coaches.

Although coaching continuity is thought to be important in developing and sustaining quality sport programs, coach turnover is not well understood. Consequently, we used a commitment model to address why some coaches maintain their involvement while others discontinue coaching. For this study, 469 USA Swimming age-group coaches completed a mail survey designed to assess commitment model constructs, including coaching satisfaction, benefits, costs, investments, alternative options, social constraints, and commitment. To test the commitment model, we first used structural equation modeling to assess whether the model provided an adequate fit to the data for current and former coaches. Overall, satisfaction and investments were significantly related to commitment. Moreover, the standardized path coefficients between benefits and costs and satisfaction were also significant. Multivariate analysis of variance andfollow-up analyses revealed that current coaches reported higher commitment as well as less attractive alternative options, higher investments, and higher social constraints compared to former coaches. In replication of past research, we compared current andformer coaches on the benefits and costs associated with coaching.

Adolescent↗
PubMed1998

Evaluating change in medical school curricula: how did we know where we were going?

This chapter compares and contrasts the primary outcomes and methods used to evaluate the curricular changes at the eight schools participating in The Robert Wood Johnson Foundation "Preparing Physicians for the Future: Program in Medical Education." Each school evaluated its own program. The eight evaluators formed an ad hoc group to share information, but the schools did not use a common evaluation system. Although the evaluations were done without common standards, many of the measures were similar. The schools used such quantitative methods as measuring students' performances and their choices of specialties, as well as such qualitative methods as asking students to evaluate their courses and to participate in focus groups. The authors describe the ways in which evaluative data were collected and how evaluation drove curricular change. The authors conclude that program evaluation can sustain schools through the turbulence of curricular change, and that qualitative data and communicating the results of evaluations with faculty and students are essential to successful reform.

Curriculum↗
PubMedDate not supplied

Racial disparities in sense of community and health status: implications in community-based participatory interventions targeting chronic disease in African Americans.

This study examined the relation between sense of community (SOC), sociodemographic characteristics, and health status to inform community-based interventions designed to prevent and reduce chronic disease in African Americans. A telephone survey was conducted with 1463 randomly selected residents in Nashville, Tenn. Respondents were majority female (69%), African American (59%), and single (59%), with a mean age of 55 (+/-17.61 years). African Americans have lower overall SOC scores, or lower scores on the domains related to perceived influence over community and sharing of common community values compared to Whites. High rates of chronic disease and low SES, combined with a low SOC, can hinder efforts to reduce and eliminate disparities. The goal of community-based participatory initiatives is to create programs that are sustainable by the target community after the funding is gone. Thus, to maximize the success, uptake, and sustainability of disease-specific interventions, it is imperative to incorporate assessment of SOC, identify factors that depress SOC, and engage in community collaboration to develop a plan to improve SOC.

Adult↗
PubMed2025

Dual EZH1/2 inhibition enhances DNMT inhibitor efficacy in colon cancer through targeting H3K27me1.

Our recent work showed that low-dose DNMT inhibitor (DNMTi) treatment sensitizes colon cancer cells to EZH2 inhibitors (EZH2i), synergistically upregulating tumor suppressor genes (TSGs) and transposable elements through activation of the calcium-calcineurin-NFAT signaling pathway. A key observation was that EZH2i displayed variable sensitivities in combination therapy, which could not be explained solely by loss of lysine 27 trimethylation on histone H3 (H3K27me3), the most commonly studied EZH2 product. This led us to perform a comprehensive pharmacologic screen of Polycomb Repressive Complex 2 (PRC2) antagonists. Here, we show that compounds targeting both EZH2 and its interchangeable catalytic subunit, EZH1, achieved superior TSG re-expression when combined with DNMTi. Integrative proteomic and epigenomic analyses revealed that EZH1/2 inhibitors reduce all three H3K27 methylation states, whereas EZH2-selective inhibitors preserve EZH1-dependent H3K27me1 at deeply Polycomb-repressed genomic regions. Notably, H3K27me1 loss coincided with deposition of p300/CBP-dependent lysine 27 acetylation on histone H3 (H3K27ac), which proved essential for TSG re-expression. Paradoxically, blocking p300/CBP activity further enhanced the growth-inhibitory effects of combined DNMT and EZH1/2 inhibition. Mechanistically, we show that EZH1/2 inhibition redistributes p300/CBP activity, reducing H3K27ac from oncogenic loci and redirecting it to bivalent regions that enable TSG re-expression. Collectively, these findings reveal a coordinated role for EZH1-dependent H3K27me1 and DNA methylation in sustaining oncogenic transcriptional programs and provide strong rationale for advancing dual EZH1/2 inhibitors for combination epigenetic cancer therapy.

DNA methylation↗
PubMed2005

GERMINATE. a generic database for integrating genotypic and phenotypic information for plant genetic resource collections.

The extensive germplasm resource collections that are now available for major crop plants and their wild relatives will increasingly provide valuable biological and bioinformatics resources for plant physiologists and geneticists to dissect the molecular basis of key traits and to develop highly adapted plant material to sustain future breeding programs. A key to the efficient deployment of these resources is the development of information systems that will enable the collection and storage of biological information for these plant lines to be integrated with the molecular information that is now becoming available through the use of high-throughput genomics and post-genomics technologies. The GERMINATE database has been designed to hold a diverse variety of data types, ranging from molecular to phenotypic, and to allow querying between such data for any plant species. Data are stored in GERMINATE in a technology-independent manner, such that new technologies can be accommodated in the database as they emerge, without modification of the underlying schema. Users can access data in GERMINATE databases either via a lightweight Perl-CGI Web interface or by the more complex Genomic Diversity and Phenotype Connection software. GERMINATE is released under the GNU General Public License and is available at http://germinate.scri.sari.ac.uk/germinate/.

Computational Biology↗
PubMed2005

The beneficial effects of group-based exercises on fall risk profile and physical activity persist 1 year postintervention in older women with low bone mass: follow-up after withdrawal of exercise.

OBJECTIVES: To determine whether exercise-induced reductions in fall risk are maintained in older women 1 year after the cessation of three types of interventions--resistance training, agility training, and general stretching. DESIGN: One-year observational study. SETTING: Community. PARTICIPANTS: Ninety-eight women aged 75 to 85 with low bone mass. MEASUREMENTS: Primary outcome measure was fall risk, measured using the Physiological Profile Assessment tool. Secondary outcome measures were current physical activity level, assessed using the Physical Activity Scale for the Elderly, and formal exercise participation, assessed using an interview. RESULTS: At the end of the follow-up, the fall risk of former participants of all three exercise programs was maintained (i.e., still reduced) from trial completion. Mean fall risk value at the end of follow-up was 43.3% lower than mean baseline value in former participants of the resistance-training group, 40.1% lower in the agility-training group, and 37.4% lower in the general stretching group. Physical activity levels were also maintained from trial completion. Specifically, there was a 3.8% increase in physical activity from baseline for the resistance-training group, a 29.2% increase for the agility-training group, and a 37.7% increase for the general stretching group. CONCLUSION: After three types of group-based exercise programs, benefits are sustained for at least 12 months without further formal exercise intervention. Thus, these 6-month exercise interventions appeared to act as a catalyst for increasing physical activity with resultant reductions in fall risk profile that were maintained for at least 18 months in older women with low bone mass.

Accidental Falls↗
PubMed1984

Serial electrophysiologic testing with a permanent pacemaker after acute myocardial infarction.

Electrophysiologic testing in patients after acute myocardial infarction may predict subsequent sudden death. We used a permanent pacemaker for repetitive electrophysiologic testing in a patient after acute infarction. Programmed, twice-threshold ventricular extrastimulation at two weeks after anteroseptal infarction failed to induce ventricular tachycardia. Subsequent programmed extrastimulation induced sustained ventricular tachycardia on four occasions (6, 16, 29 and 65 weeks) after infarction. As yet (20 months), spontaneous ventricular tachycardia has not occurred. Firm conclusions cannot be drawn from a single case. However, our patient developed a stable ventricular tachycardia circuit which was not apparent at two weeks. Thus, a single electrophysiologic study performed acutely after infarction may not accurately describe the potential for ventricular tachycardia or fibrillation. Serial electrophysiologic testing with an implantable externally triggered pacemaker may more accurately describe the potential for sudden death post-infarction in a few high-risk patients. This report shows that induction of ventricular tachycardia after acute infarction may not predict outcome.

Adult↗
PubMed1997

Reproduction of the owl monkey (Aotus spp.) in captivity.

The reproduction performance of captive owl monkeys, a breed used extensively in biomedical research, was observed at the Battelle Primate Facility (BPF). The colony grew through captive breeding, imports from the Peruvian Primatological Project, and others to a peak size of 730. It included seven karyotypes of Aotus sp. Results showed that owl monkeys can breed successfully in a laboratory in numbers sufficient to sustain modest research programs. Reproductive success increases when pairs are compatible, of the same karyotype, and stabilized; however, mated pairs of different karyotype are also productive. Under conditions of controlled lighting and heating, owl monkeys at BPF showed no birth peak nor birth season.

Animal Welfare↗
PubMed2000

A model for mapping linkages between health and education agencies to improve school health.

Efforts to develop effective and sustainable school health programs evolved in sophistication the past 20 years through research and practical experience. This paper reviews these developments, arguing they were significantly driven by public health priorities, and have not adequately accounted for educational perspectives and priorities. To better understand the differences in perspective, a model is presented which illustrates linkages between different school-based inputs and strategies, and long-term health and educational outcomes. The model describes similarities and differences between the two perspectives. A significant coincidence exists in factors that determine educational attainment and improved health outcomes for students. A more holistic and integrated approach to school health is emerging, and at these interfaces our implementation and research efforts for the 21st century should be concentrated.

Education↗
PubMed1989

Electrophysiological study of young patients with exercise related paroxysms of palpitation: role of atropine and isoprenaline for initiation of supraventricular tachycardia.

Electrophysiological studies were performed in eight patients (four men and four women, mean (SD) age 24 (5) years with paroxysmal attacks of palpitation during or immediately after exercise. Five patients were competitive athletes at college. In two patients spontaneous supraventricular tachycardia during exercise was recorded by ambulatory electrocardiographic monitoring and in another it was induced by treadmill exercise testing. Two had dual atrioventricular nodal pathways, three had manifest atrioventricular accessory pathways, and three had concealed atrioventricular pathways. Programmed stimulation induced sustained supraventricular tachycardia in six patients--in two after intravenous injection of atropine sulphate (1 mg) and in four during infusion of isoprenaline (0.01 microgram/kg/min). In one patient, non-sustained atrioventricular nodal reentrant tachycardia was induced during isoprenaline infusion. In the remaining patient, who had dual atrioventricular nodal pathways, tachycardia was not inducible. AH block prevented maintenance of reentry in five patients. In five patients shortening of the effective refractory period of the atrioventricular node with atropine (one patient) and isoprenaline (four patients) caused sustained supraventricular tachycardia. The present study indicates that treatment with atropine and isoprenaline may be an important factor in the initiation of supraventricular tachycardia in patients with exercise related paroxysms of palpitation.

Adult↗
PubMed1996

Cellular and ionic basis of arrhythmias in postinfarction remodeled ventricular myocardium.

After myocardial infarction (MI), the noninfarcted myocardium undergoes significant hypertrophy as part of the post-MI structural remodeling. Electrophysiological changes associated with the hypertrophied remodeled myocardium may play a key role in arrhythmia generation in the post-MI heart. We investigated the cellular and ionic basis of arrhythmias in remodeled left ventricular (LV) myocardium 3 to 4 weeks after MI in the rat. We analyzed (1) the incidence of induced ventricular tachyarrhythmias (VTs) in the in vivo heart, (2) action potential characteristics and arrhythmia mechanisms in multicellular preparations and isolated remodeled LV myocytes, and (3) the density and kinetics of the L-type Ca2+ current (ICa-L) and the fast and slow components of transient outward K+ currents (Ito-f and Ito-s, respectively). The results were compared with those from sham-operated rats. In vivo, programmed stimulation induced sustained VT in 80% of post-MI rats but not in sham-operated rats. The capacitance of post-MI hypertrophied myocytes was significantly increased compared with myocytes from sham-operated rats. Post-MI myocytes had prolonged action potential duration (APD) with marked heterogeneity of the time course of repolarization. The prolongation of APD could be explained by the significant decrease of the density of both Ito-f and Ito-s. There was no change in the kinetics of both currents compared with control. Both the density and kinetics of ICa-L were not significantly different in post-MI remodeled myocytes compared with control. The cellular studies showed that reentrant excitation secondary to dispersion of repolarization and triggered activity from both early and delayed afterdepolarizations are potential mechanisms for VT in the post-MI remodeled heart.

Animals↗
PubMed1975

The training and role of nurse-therapists in a general hospital's psychiatric unit.

The author's discuss their experience using nurses as therapists on a small unit at St. Joseph's Hospital, a general hospital in Hamilton, Ontario. They describe the training of the first nurse-therapists and the three-level training system established to make the program self-sustaining. The nurse-therapist system is now used on several psychiatric units in the hospital. Problems in role relationships and schedules occurred, but the authors, noting the patient-care, economic, and staff benefits, believe that the system would be especially useful in small inpatient units.

Ambulatory Care↗
PubMedDate not supplied

Diabetes education infrastructure and capacity in hospitals and home health agencies in Maryland and Pennsylvania.

In this study, questionnaire data were described regarding diabetes education program capacity in Maryland and Pennsylvania hospitals, health maintenance organizations (HMOs), and home health agencies (HHAs). Hospitals, HMOs, and HHAs in each state were asked to indicate whether they currently have a diabetes education program and, if not, whether they had such a program anytime within the past 10 years. Home health agencies were less likely to have had programs in the past and more likely to have recently established diabetes education programs. About half of hospitals currently without programs had a program sometime within the past 10 years. Hospitals in Maryland and Pennsylvania responded similarly; Pennsylvania HHAs were more likely to report having diabetes education programs than HHAs in Maryland. On the average, programs showed moderate levels of institutionalization. Respondents to the questionnaire believed that their programs would be sustained; these projections appeared to not be sensitive to availability of reimbursement.

Diabetes Mellitus↗
PubMed2006

Contraceptive use and pregnancy risk among U.S. high school students, 1991-2003.

CONTEXT: Trends in teenagers' contraceptive use have received less attention than trends in adolescent sexual intercourse, despite the importance of contraceptive use to preventing teenage pregnancy. METHODS: Sexually active high school students' use of contraceptives and risk of pregnancy from 1991 to 2003 were examined using data from the national Youth Risk Behavior Survey and published contraceptive failure rates. Changes in pregnancy risk were assessed using weighted least-squares regression. RESULTS: Between 1991 and 2003, contraceptive use improved among sexually active U.S. high school students. Improvements among women included an increase in the proportion reporting condom use at last sex (from 38% to 58%) and declines in the proportions using withdrawal (from 19% to 11%) and no method (18% to 12%). Hormonal method use changed little, as a decline in pill use (from 25% to 20%) was offset by use of injectables (5% in 2003). Similar patterns were found among men. Women's risk of pregnancy declined 21% over the 12 years. The largest improvements in contraceptive use and pregnancy risk occurred among ninth graders, and whites and blacks. In 2003, 46% of pregnancy risk resulted from failure to use any method of contraception, and 54% resulted from contraceptive failure. CONCLUSIONS: Improvement in the use of contraceptives by sexually active high school students during the 1990s is encouraging. To sustain this trend, programs need to encourage contraceptive use among teenagers who do not use it and to stress consistent and correct use among those who do.

Adolescent↗
PubMed2005

Rapid tests for detection of viral markers in blood transfusion.

Since the early 1990s, rapid tests have been available for detection of HIV infection. They were intended for field diagnosis, emergency and home testing. In addition, rapid tests for anti-HIV, hepatitis B surface antigen and antihepatitis C virus have been used for blood screening in many resource-poor areas to save resources and overcome lack of funding, equipment and electrical supply. The performance of rapid tests varies widely but some have sensitivity and specificity levels that meet standards established by enzyme immunoassays for anti-HIV. Compared with genomic detection of hepatitis B virus, hepatitis B surface antigen rapid tests and enzyme immunoassays have insufficient sensitivity. The clinical consequences of this performance deficit remain to be clarified. Anti-hepatitis C virus rapid tests detect chronically infected individuals who are viremic, however, further studies are required to fully assess their performance. In settings where few blood donations are collected and equipment is unavailable, rapid tests provide a flexible, technically undemanding and relatively inexpensive approach to ensuring a safer blood supply. When utilized for predonation screening in areas of high endemicity of viral markers, rapid tests provide the means to limit blood bag wasting, store only clinically usable blood and inform and counsel deferred donors. As with any laboratory assay, adequate training and sustained quality assurance programs are critical to maintain a safe supply of blood. As a means of achieving a safe blood supply, rapid tests for viral markers and nucleic acid testing have a place next to classic enzyme immunoassays in the definition of strategies that are adapted to a setting's epidemiology, the size and type of donor base, equipment, staff training and resources.

Blood↗
PubMed2006

Infestation by Triatoma pallidipennis (Hemiptera: Reduviidae: Triatominae) is associated with housing characteristics in rural Mexico.

Long-term control of Chagas disease requires not only interruption of the human transmission cycle of Trypanosoma cruzi Schyzotrypanum, Chagas, 1909 by controlling its domestic triatomine vectors but also surveillance to prevent reinfestation of residences from sylvatic or persistent peridomestic populations. Although a number of potential risk factors for infestation have been implicated in previous studies, the explanatory power of resulting models has been low. Two years after cessation of triatomine vector control efforts in the town of Chalcatzingo, Morelos, 78 environmental, socioecological, and spatial variables were analyzed for association with infestation by Triatoma pallidipennis Stal 1872 (Hemiptera: Reduviidae: Triatominae), the principal vector of T. cruzi. We studied 712 residences in this rural community to identify specific intradomestic and peridomestic risk factors that predicted infestation with T. pallidipennis. From numerous characteristics that were identified as correlated with infestation, we derived multivariate logistic regression models to predict residences that were more or less likely to be infested with T. pallidipennis. The most important risk factors for infestation included measurements of house age, upkeep, and spatial location in the town. The effects of certain risk factors on infestation were found to be modified by spatial characteristics of residences. The results of this study provide new information regarding risk factors for infestation by T. pallidipennis that may aid in designing sustainable disease control programs in rural Mexico.

Animals↗