RESUMEN
OBJECTIVES: To evaluate a preventative behavioral intervention for managing early childhood caries (ECC) in a cohort of high-risk children. METHODS: This pragmatic trial of the MySmileBuddy Program (MSB) evaluated preventive behavioral outcomes in a 1-y community health worker-delivered intervention to prevent ECC progression. Pre-/postintervention surveys assessed parent-reported child engagement in therapeutic toothbrushing (i.e., adult-assisted brushing with fluoridated toothpaste twice daily) and caries-related dietary behaviors and barriers. Generalized linear model with identity link for continuous variables and logit link for dichotomous outcomes evaluated pre-/postintervention comparisons and generalized estimating equations accounted for within-participant correlation (α = 0.05). RESULTS: Among 1,130 children with postintervention data, the average age was 3.97 y, 99% were Medicaid insured, and 88% were Hispanic. Most parents (95%) were mothers/grandmothers, married or in a committed partnership (75%), unemployed (62%), and with modest education (80% high school degree or less). The odds of reported therapeutic brushing nearly doubled (n = 864; odds ratio [OR] = 1.79, 95% confidence interval [CI] = 1.46, 2.20, P < 0.001); day and night bottle/sippy cup frequencies dropped 0.29 units (n = 871; 95% CI = -0.37, -0.33, P < 0.001) and 0.22 units (n = 1,130; 95% CI = -0.30, -0.15, P < 0.001); nighttime breastfeeding reduced 0.15 units (n = 870; 95% CI = -0.21, -0.10, P < 0.001); sharing utensils reduced 0.30 units (n = 572; 95% CI = -0.39, -0.21, P < 0.001); not using sugary foods to calm child improved 0.37 units (n = 664; 95% CI = 0.31, 0.44, P < 0.001); odds of eating meals and snacks at a table increased (n = 572; OR = 1.57, 95% CI = 1.28, 1.93, P < 0.001; n = 572; OR = 1.80, 95% CI = 1.50, 2.15, P < 0.001) respectively; and reducing barriers to behaviors improved 0.38 units for toothbrushing (n = 666; 95% CI = 0.31, 0.44, P < 0.001) and 0.33 units for diet (n = 668; 95% CI = 0.29, 0.38, P < 0.001). CONCLUSION: Despite limitations inherent to pragmatic trials, significant behavioral changes suggest that MSB yielded an important salutary impact. Forthcoming mediation analyses will explore causal pathways. Findings support integration of MSB's behavior change program in caries management initiatives. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by clinicians, public health leaders, and researchers to inform the development and implementation of community-based, preventative behaviorally focused early childhood caries prevention programs. Study findings may enhance the understanding of the impact of behavioral interventions that engage parents of young children and could lead to more effective prevention for populations at high-risk of caries.
Asunto(s)
Susceptibilidad a Caries Dentarias , Caries Dental , Niño , Femenino , Adulto , Humanos , Preescolar , Caries Dental/prevención & control , Cepillado Dental , Higiene Bucal/educación , BocadillosRESUMEN
Tenofovir diphosphate (TVF-DP) can be quantified in red blood cells (RBCs) and dried blood spots (DBS) and can objectively measure ART adherence and predict viral suppression. Data on the association of TFV-DP with viral load are very limited in adolescents and young adults (AYA) living with perinatally-acquired HIV (PHIV), as are data comparing TFV-DP to other measures of ART adherence, such as self-report and unannounced telephone pill count. Viral load and ART adherence (self-report, TFV-DP and unannounced telephone pill count) were assessed and compared among 61 AYAPHIV recruited from an ongoing longitudinal study (CASAH) in New York City.
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Fármacos Anti-VIH , Infecciones por VIH , Adolescente , Humanos , Adulto Joven , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Autoinforme , Estudios Longitudinales , Cumplimiento de la Medicación , TeléfonoRESUMEN
There are an estimated 2.1 million youth less than 15 years of age living with HIV globally (the majority perinatally HIV-infected [PHIV]) and millions more perinatally HIV-exposed uninfected (PHEU) youth who are expected to survive through adolescence and into adulthood. Transitioning from adolescence to young adulthood requires adaptation to more demanding social interactions, academic pressures, and individual responsibilities which place distinct demands on neurocognitive functions. This study examined longitudinal trajectories of neurocognitive test performance in the domains of processing speed (PS), working memory (WM), and executive functioning (EF) among PHIV and demographically similar PHEU from adolescence through young adulthood. Data for this paper come from four time points, spanning approximately 10 years, within the Child and Adolescent Self-Awareness and Health Study (CASAH). Youth age ranged from 15 to 29 years. Longitudinal linear mixed effect models were computed for each test. Few differences in performance were found on tests of EF and WM between PHIV and PHEU youth as they aged, though PHEU youth showed significantly better PS as they aged than PHIV youth. Future research is needed to understand these vulnerable youth's neurocognitive trajectories as a function of HIV infection and -exposure, biological functions and psychosocial stressors.
Asunto(s)
Infecciones por VIH/psicología , Pruebas de Estado Mental y Demencia , Adolescente , Adulto , Recolección de Datos , Función Ejecutiva , Femenino , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Relaciones Interpersonales , Modelos Lineales , Masculino , Embarazo , Adulto JovenRESUMEN
We examined young gay, bisexual, and other men who have sex with men's (YGBMSM) usage patterns of a pre-coital, applicator-administered rectal placebo gel. An ethnically diverse sample of 94 YGBMSM (aged 18-30 years) were asked to insert hydroxyethylcellulose placebo gel rectally before receptive anal intercourse (RAI) and report their gel use through an interactive voice response system (IVRS) across 12 weeks. We used trajectory analyses to characterize participants' use of the rectal gel over the 12 weeks, and examine whether these trajectories varied based on participants' sociodemographic characteristics, sexual behaviors, application and insertion behaviors, and experiences using the placebo gel. A cubic model was the best fit for these longitudinal data, with two distinct trajectories of gel use observed. The first trajectory ('High with Varying Gel Use per Week') represented YGBMSM (N = 38; 40.3%) who reported using the rectal gel on several occasions per week. The second trajectory ('Low and Consistent Gel Use per Week') represented participants (N = 56; 59.7%) who reported a consistent average use of one gel per week. Participants in the High with Varying Gel Use Trajectory reported trying out a greater number of positions when inserting the gel across the 12-weeks than peers in the Low and Consistent Gel Use Trajectory. YGBMSM reporting more RAI occasions during the trial were more likely be present in the High with Varying Gel Use Trajectory than peers in the Low and Consistent Gel Use Trajectory. Future research examining how to facilitate gel application and adherence among YGBMSM is merited.
Asunto(s)
Antiinfecciosos/administración & dosificación , Bisexualidad , Geles/administración & dosificación , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Aceptación de la Atención de Salud , Satisfacción Personal , Conducta Sexual , Administración Rectal , Adolescente , Adulto , Ensayos Clínicos Fase I como Asunto , Coito , Etnicidad/psicología , Etnicidad/estadística & datos numéricos , Humanos , Masculino , Adulto JovenRESUMEN
Integration of sexual and reproductive health within HIV care services is a promising strategy for increasing access to family planning and STI services and reducing unwanted pregnancies, perinatal HIV transmission and maternal and infant mortality among people living with HIV and their partners. We conducted a Phase II randomized futility trial of a multi-level intervention to increase adherence to safer sex guidelines among those wishing to avoid pregnancy and adherence to safer conception guidelines among those seeking conception in newly-diagnosed HIV-positive persons in four public-sector HIV clinics in Cape Town. Clinics were pair-matched and the two clinics within each pair were randomized to either a three-session provider-delivered enhanced intervention (EI) (onsite contraceptive services and brief milieu intervention for staff) or standard-of-care (SOC) provider-delivered intervention. The futility analysis showed that we cannot rule out the possibility that the EI intervention has a 10 % point or greater success rate in improving adherence to safer sex/safer conception guidelines than does SOC (p = 0.573), indicating that the intervention holds merit, and a larger-scale confirmatory study showing whether the EI is superior to SOC has merit.
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Infecciones por VIH/terapia , Política de Salud , Salud Reproductiva , Conducta Sexual , Salud Sexual , Servicios de Planificación Familiar , Femenino , Infecciones por VIH/transmisión , Humanos , Masculino , Embarazo , Sector Público , Sexo Seguro , Parejas Sexuales , Sudáfrica/epidemiologíaRESUMEN
The paper utilizes data collected at three time points in a longitudinal study of perinatally HIV-infected (PHIV+) and a comparison group of perinatally exposed but HIV-uninfected (PHEU) youths in the United States (N = 325). Using growth curve modeling, the paper examines changes in substance use symptoms among PHIV+ and PHEU youths as they transition through adolescence, and assesses the individual and contextual factors associated with the rate of change in substance use symptoms. Findings indicate that substance use symptoms increased over time among PHIV+ youths, but not among PHEU youths. The rate of change in these symptoms was positively associated with an increasing number of negative life events. Study findings underscore the need for early, targeted interventions for PHIV+ youths, and interventions to reduce adversities and their deleterious effects in vulnerable populations.
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Infecciones por VIH/epidemiología , Transmisión Vertical de Enfermedad Infecciosa , Uso de la Marihuana/epidemiología , Trastornos Relacionados con Sustancias/epidemiología , Consumo de Alcohol en Menores/estadística & datos numéricos , Adolescente , Niño , Femenino , Infecciones por VIH/transmisión , Humanos , Estudios Longitudinales , Masculino , Estados Unidos/epidemiologíaRESUMEN
We examined how experiences with a rectal placebo gel and applicator used with receptive anal intercourse (RAI) related to young men who have sex with men's (YMSM) likelihood of using a rectal microbicide gel and applicator in the future. An ethnically diverse sample of 95 YMSM (aged 18 to 30 years) were asked to insert hydroxyethylcellulose (HEC) placebo gel rectally before RAI during 12 weeks and report the product's acceptability (i.e., satisfaction with applicator and gel, respectively; perceived gel side effects; and sexual satisfaction when gel was used) and likelihood of future microbicide use. Main and interaction effects predicting future use intentions were tested using linear regression. We found a positive association between future use intentions and applicator satisfaction (b = .33, p < .001). In a subsequent interaction effects model, we found that greater gel satisfaction was associated with increased future use intentions; however, the strength of this relationship was magnified when YMSM reported greatest satisfaction with the rectal applicator. Applicator satisfaction may be a salient factor in YMSM's decision-making to use a rectal microbicide in the future. Although the importance of developing a satisfactory rectal microbicide gel for YMSM is undeniable for its future use, our results also emphasize the importance of developing strategies that increase YMSM's comfort and skill when using a rectal applicator. Future research examining how to optimize the design, properties, and characteristics of a rectal applicator as a strategy to promote greater satisfaction and use among YMSM is merited.
Asunto(s)
Antiinfecciosos/administración & dosificación , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Aceptación de la Atención de Salud/estadística & datos numéricos , Administración Rectal , Sistemas de Liberación de Medicamentos , Etnicidad , Geles/administración & dosificación , Humanos , Masculino , Aceptación de la Atención de Salud/psicología , Cooperación del Paciente , Satisfacción Personal , Investigación Cualitativa , Conducta Sexual , Adulto JovenRESUMEN
OBJECTIVE: The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1 gene, encoding the glucose transporter type 1 (GLUT1), for mutations in a group of 95 European patients with familial IGE. METHODS: The affected individuals were examined clinically by EEG and brain imaging. The coding regions of SLC2A1 were sequenced in the index cases of all families. Wild-type and mutant transporters were expressed and functionally characterized in Xenopus laevis oocytes. RESULTS: We detected a novel nonsynonymous SLC2A1 mutation (c.694C>T, p.R232C) in one IGE family. Nine family members were affected mainly by absence epilepsies with a variable age at onset, from early childhood to adulthood. Childhood absence epilepsy in one individual evolved into juvenile myoclonic epilepsy. Eight affected and 4 unaffected individuals carried the mutation, revealing a reduced penetrance of 67%. The detected mutation was not found in 846 normal control subjects. Functional analysis revealed a reduced maximum uptake velocity for glucose, whereas the affinity to glucose and the protein expression were not different in wild-type and mutant transporters. CONCLUSION: Our study shows that GLUT1 defects are a rare cause of classic IGE. SLC2A1 screening should be considered in IGE featuring absence epilepsies with onset from early childhood to adult life, because this diagnosis may have important implications for treatment and genetic counseling.
Asunto(s)
Epilepsia Generalizada/genética , Transportador de Glucosa de Tipo 1/genética , Mutación , Alelos , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , Neuroimagen , Linaje , Fenotipo , Adulto JovenRESUMEN
Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.
Asunto(s)
Epilepsia Refleja/genética , Ligamiento Genético/genética , Genoma Humano/genética , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 8/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , MasculinoRESUMEN
The aim of this study was to assess the frequency of potential drug-drug interactions (pDDIs) and adverse drug events (ADEs) associated with antimycotics in hospitalized patients with hematopoietic SCT (HSCT). Of the 120 HSCT recipients evaluated, 36 received antimycotics. A total of 124 ADEs were recorded in 32 of the 36 patients treated, with 54 ADEs being possibly and 9 probably related to antimycotics. Of the treatments with amphotericin B, 93% were associated with one or more possible and 36% with probable ADEs. The corresponding figures for lipid-based amphotericin B were 100% and 7%, for voriconazole 68% and 11% and for caspofungin 70% and 0%. A total of 57 potentially severe DDIs associated with antimycotics were detected in 31 of the 36 patients. Of these, 14 DDIs were a possible cause of an ADE and 5 (4 times a combination of voriconazole with CYA and once a combination of CYA with conventional amphotericin B) were probably related. Although the prevalence of pDDIs and ADEs is high in HSCT patients, ADEs related with a high probability to treatment with antimycotics are rare. Regarding the high prevalence of pDDIs, our findings underscore the importance of close monitoring of laboratory and clinical parameters, as well as dose adjustment for critical drugs, in patients with HSCT.
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Antifúngicos/efectos adversos , Aspergilosis/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inducido químicamente , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Anfotericina B/efectos adversos , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Caspofungina , Interacciones Farmacológicas , Equinocandinas/efectos adversos , Equinocandinas/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lipopéptidos , Prevalencia , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Estudios Retrospectivos , Triazoles/efectos adversos , Triazoles/uso terapéutico , VoriconazolRESUMEN
We explored the impact of substance dependence on the efficacy of an HIV sexual risk reduction intervention previously shown to be effective among men with severe mental illness by comparing rates of high-risk sexual behaviors among men with (n = 26) and without (n = 31) a lifetime history of substance dependence. We sub-divided subjects by alcohol and drug dependence status, comparing each intervention sub-group to the corresponding control sub-group. At each follow-up interval (six, 12 and 18 months), the intervention group as a whole and the non-substance dependent participants showed a significant reduction in risk; the substance-dependent men showed no difference from controls. These data suggest that among men with severe mental illness, substance dependence may be a further impediment to HIV risk reduction.
Asunto(s)
Infecciones por VIH/prevención & control , Trastornos Mentales/psicología , Trastornos Relacionados con Sustancias/psicología , Sexo Inseguro/prevención & control , Adulto , Estudios de Seguimiento , Infecciones por VIH/psicología , Humanos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Conducta de Reducción del Riesgo , Asunción de RiesgosRESUMEN
At the time of this writing, no randomized controlled trial (RCT) of an intervention to reduce unsafe sex among Latino gay and bisexual men (LGBM) had been published. We report the results of an RCT conducted in New York City in which 180 LGBM were assigned either to an intervention developed specifically for this population or to a wait-list control group. The intervention was based on empowerment theory and used factors identified in prior research as determinants of unsafe sex. By eligibility criteria, all men had engaged in unprotected anal intercourse (UAI) within two months of the baseline assessment. At first (two months) and second (six months later) follow-up assessments, approximately half of the men in the experimental group reported no UAI. Yet, a similar proportion of the control group also reported no UAI. Baseline data indicate that although the men had been the subject of social oppression and sexual prejudice (homophobia), they did not feel disempowered, externally controlled or fatalistic, and they reported self-efficacy and intentionality to enact safer sex. Lessons learned are discussed, as well as notes of caution for future research employing a similar conceptual framework.
Asunto(s)
Bisexualidad/psicología , Infecciones por VIH/prevención & control , Hispánicos o Latinos/psicología , Homosexualidad Masculina/psicología , Sexo Inseguro/prevención & control , Adolescente , Adulto , Anciano , Bisexualidad/etnología , Femenino , Infecciones por VIH/etnología , Homosexualidad Masculina/etnología , Humanos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/etnología , Poder Psicológico , Sexo Inseguro/etnología , Sexo Inseguro/psicología , Salud UrbanaRESUMEN
Androgens play important endocrine roles in development and physiology. Here, we characterize activities of two "Andro" prohormones, androstenedione (A-dione) and 4-androsten-3beta,17beta-diol (A-diol) in MDA-MB-453 (MDA) and LNCaP cells. A-dione and A-diol, like cyproterone acetate, were partial agonists of transfected mouse mammary tumor virus (MMTV) and endogenous prostate-specific antigen (PSA) promoters. Different from bicalutamide but similar to CPA, both are inducers of LNCaP cell proliferation with only mild suppression of 5alpha-dihydrotestosterone (DHT)-enhanced cell growth. Like bicalutamide and cyproterone acetate, A-dione and A-diol significantly antagonized DHT/R1881-induced PSA expression by up to 30% in LNCaP cells. Meanwhile, in MDA cells, EC(50)s for the MMTV promoter were between 10 and 100nM. Co-factor studies showed GRIP1 as most active for endogenous androgen receptor (AR), increasing MMTV transcription by up to five-fold, without substantially altering EC(50)s of DHT, A-dione or A-diol. Consistent with their transcriptional activities, A-dione and A-diol bound full-length endogenous AR from MDA or LNCaP cells with affinities of 30-70nM, although binding to expressed ligand-binding domain (LBD) was >20-fold weaker. In contrast, DHT, R1881, and bicalutamide bound similarly to LBD or aporeceptor. Together, these data suggest that A-dione and A-diol are ligands for AR with partial agonist/antagonist activities in cell-based transcription assays. Binding affinities for both are most accurately assessed by AR aporeceptor complex. In addition to being testosterone precursors in vivo, either may impart its own transcriptional regulation of AR.
Asunto(s)
Androstenodiol/farmacología , Androstenodiona/farmacología , Neoplasias de la Mama/patología , Regiones Promotoras Genéticas/genética , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/patología , Proteínas Adaptadoras Transductoras de Señales , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Andrógenos/farmacología , Anilidas/farmacología , Animales , Neoplasias de la Mama/genética , Células COS , Proteínas Portadoras/metabolismo , División Celular/efectos de los fármacos , Chlorocebus aethiops , Acetato de Ciproterona/farmacología , Dihidrotestosterona/farmacología , Humanos , Ligandos , Macaca mulatta/genética , Masculino , Virus del Tumor Mamario del Ratón/genética , Ratones , Proteínas del Tejido Nervioso/metabolismo , Nitrilos , Neoplasias de la Próstata/genética , Receptores AMPA/metabolismo , Receptores Androgénicos/genética , Compuestos de Tosilo , Transcripción Genética , Células Tumorales CultivadasRESUMEN
This study assessed the short- and long-term effect of a gender-specific group intervention for women on unsafe sexual encounters and strategies for protection against HIV/STD infection. Family planning clients (N = 360) from a high HIV seroprevalence area in New York City were randomized to an eight-session, a four-session or a control condition and followed at one, six and 12 months post-intervention. Using an intention-to-treat analysis, women who were assigned to the eight-session group had about twice the odds of reporting decreased or no unprotected vaginal and anal intercourse compared to controls at one month (OR = 1.93, 95% confidence interval [CI] = 1.07, 3.48, p = 0.03) and at 12-month follow-up (OR = 1.65, 95% CI = 0.94, 2.90, p = 0.08). Relative to controls, women assigned to the eight-session condition reported during the previous month approximately three-and-a-half (p = 0.09) and five (p < 0.01) fewer unprotected sex occasions at one- and 12-month follow-up, respectively. Women in the eight-session group also reduced the number of sex occasions at both follow-ups, and had a greater odds of first time use of an alternative protective strategy (refusal, outercourse, mutual testing) at one-month follow-up. Results for the four-session group were in the expected direction but overall were inconclusive. Thus, gender-specific interventions of sufficient intensity can promote short- and long-term sexual risk reduction among women in a family planning setting.
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Infecciones por VIH/prevención & control , Educación en Salud/métodos , Sexo Seguro , Salud de la Mujer , Adolescente , Adulto , Condones/estadística & datos numéricos , Servicios de Planificación Familiar , Femenino , Estudios de Seguimiento , Identidad de Género , Infecciones por VIH/psicología , Humanos , Ciudad de Nueva York , Asunción de Riesgos , Tamaño de la Muestra , Educación Sexual/métodosRESUMEN
Prostaglandin (PG) E(2) is a potent inducer of cortical and trabecular bone formation in humans and animals. Although the bone anabolic action of PGE(2) is well documented, the cellular and molecular mechanisms that mediate this effect remain unclear. This study was undertaken to examine the effect of pharmacological inactivation of the prostanoid receptor EP(4), one of the PGE(2) receptors, on PGE(2)-induced bone formation in vivo. We first determined the ability of EP(4)A, an EP(4)-selective ligand, to act as an antagonist. PGE(2) increases intracellular cAMP and suppresses apoptosis in the RP-1 periosteal cell line. Both effects were reversed by EP(4)A, suggesting that EP(4)A acts as an EP(4) antagonist in the cells at concentrations consistent with its in vitro binding to EP(4). We then examined the effect of EP(4) on bone formation induced by PGE(2) in young rats. Five- to 6-week-old rats were treated with PGE(2) (6 mg/kg/day) in the presence or absence of EP(4)A (10 mg/kg/day) for 12 days. We found that treatment with EP(4)A suppresses the increase in trabecular bone volume induced by PGE(2). This effect is accompanied by a suppression of bone formation indices: serum osteocalcin, extent of labeled surface, and extent of trabecular number, suggesting that the reduction in bone volume is due most likely to decreased bone formation. The pharmacological evidence presented here provides strong support for the hypothesis that the bone anabolic effect of PGE(2) in rats is mediated by the EP(4) receptor.
Asunto(s)
Huesos/metabolismo , Dinoprostona/metabolismo , Receptores de Prostaglandina E/metabolismo , Animales , Huesos/efectos de los fármacos , Células Cultivadas , Humanos , Masculino , Periostio/citología , Ratas , Ratas Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP4 de Receptores de Prostaglandina E , Compuestos de Sulfhidrilo/farmacología , Tiofenos/farmacologíaRESUMEN
Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.
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Naftiridinas/síntesis química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Propionatos/síntesis química , Sulfonamidas/síntesis química , Animales , Resorción Ósea/patología , Línea Celular , Técnicas de Cultivo , Humanos , Ligandos , Naftiridinas/química , Naftiridinas/farmacología , Agregación Plaquetaria/efectos de los fármacos , Propionatos/química , Propionatos/farmacología , Ratas , Ratas Sprague-Dawley , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: Many reports on Iraq suggest that a rise in rates of death and disease have occurred since the Gulf War of January/February 1991 and the economic sanctions that followed it. METHODS: Four preliminary models, based on unadjusted projections, were developed. A logistic regression model was then developed on the basis of six social variables in Iraq and comparable information from countries in the State of the World's Children report. Missing data were estimated for this model by a multiple imputation procedure. The final model depends on three socio-medical indicators: adult literacy, nutritional stunting of children under 5 years, and access to piped water. RESULTS: The model successfully predicted both the mortality rate in 1990, under stable conditions, and in 1991, following the Gulf War. For 1996, after 5 years of sanctions and prior to receipt of humanitarian food via the oil for food programme, this model shows mortality among children under 5 to have reached an estimated 87 per 1000, a rate last experienced more than 30 years ago. CONCLUSIONS: Accurate and timely estimates of mortality levels in developing countries are costly and require considerable methodological expertise. A rapid estimation technique like the one developed here may be a useful tool for quick and efficient estimation of mortality rates among under 5 year olds in countries where good mortality data are not routinely available. This is especially true for countries with complex humanitarian emergencies where information on mortality changes can guide interventions and the social stability to use standard demographic methods does not exist.
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Protección a la Infancia , Mortalidad/tendencias , Preescolar , Demografía , Planificación en Desastres , Femenino , Humanos , Lactante , Recién Nacido , Irak/epidemiología , Masculino , Análisis Multivariante , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , GuerraRESUMEN
Overexpression of epidermal growth factor receptor (EGFR) and establishment of transforming growth factor alpha (TGF alpha)/EGF autocrine system are frequently detected in tumor cells. In addition to mitogenic ability, we demonstrate in this report that EGF protects a human esophageal carcinoma (CE) cell line, CE81T/VGH, from staurosporine-induced apoptosis. The anti-apoptotic signal of EGF is alleviated by a MEK inhibitor PD98059 or an ERK2 dominant negative mutant but not by a phosphatidylinositol-3'-kinase (PI-3K) inhibitor wortmannin. Furthermore, v-raf blocks apoptosis induced by staurosporine. This evidence implies that the survival signal of EGF is mediated via the Raf-MEK-ERK pathway but not the PI3-K pathway. The survival effect of EGF is coincident with the induction of mcl-1, an antiapoptotic gene in the bcl-2 family. PD98059 also suppresses the induction of Mcl-1 by EGF, implying that EGF may up-regulate Mcl-1 via the MAP kinase pathway. Overexpression of mcl-1 is sufficient to protect against apoptosis, while transfection of a mcl-1 antisense plasmid causes cell death. The expression of mcl-1 antisense plasmid also suppresses the anti-apoptotic effect of EGF. Taken together, these results indicate that EGF may up-regulate Mcl-1 through the MAP kinase pathway to suppress apoptosis.
Asunto(s)
Apoptosis/efectos de los fármacos , Cisteína Endopeptidasas/fisiología , Inhibidores de Cisteína Proteinasa/farmacología , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/fisiología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Quinasa 1 de Quinasa de Quinasa MAP , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/fisiología , Proteínas Proto-Oncogénicas c-bcl-2 , Estaurosporina/antagonistas & inhibidores , Androstadienos/farmacología , Apoptosis/genética , Carcinoma/genética , Carcinoma/patología , ADN sin Sentido/genética , Receptores ErbB/efectos de los fármacos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Flavonoides/farmacología , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/fisiología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas de Neoplasias/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas c-raf/fisiología , Proteínas Recombinantes de Fusión/fisiología , Transfección , Células Tumorales Cultivadas/efectos de los fármacos , WortmaninaRESUMEN
The interaction of tumor necrosis factor-alpha with its receptor CD120a (p55) initiates downstream signaling cascades that include the activation of the mitogen-activated protein kinase (MAPK), p42(mapk/erk2). The membrane proximal region of CD120a (p55) is Ser-, Thr-, and Pro-rich and contains four mitogen-activated protein kinase consensus phosphorylation sites. In recent work, we showed that CD120a (p55) itself is a target of phosphorylation by p42(mapk/erk2), and after phosphorylation, the receptor is redistributed from the cell surface and Golgi complex to intracellular tubular structures associated with elements of the endoplasmic reticulum. The goal of this study was to define the specific amino acid residues that are phosphorylated. Deletional mutagenesis of the cytoplasmic domain of CD120a (p55) indicated that two sites located between residues 207-254 and 250-300 were phosphorylated predominantly on Thr and Ser residues, respectively. Site-directed mutagenesis of Ser and Thr residues contained within the extracellular signal-regulated kinase (ERK) consensus sequences indicated that the preferred residues were Thr-236 and Ser-270. Primary phosphorylation at these sites appeared to enable subsequent phosphorylation at Ser-240 and Ser-244, although the level of phosphorylation of these latter two sites was less than the preferred sites. Through the use of specific ligation of CD120a (p55) alone and mice deficient in CD120a (p55), CD120b (p75), or both receptors, CD120a (p55) was shown to be necessary and sufficient for the induction of kinase activity. These findings thus suggest that the phosphorylation of Thr-236 and Ser-270 within the membrane proximal region of CD120a (p55) are the preferred sites of phosphorylation by p42(mapk/erk2) and may set in motion phosphorylation at other sites.