RESUMEN

BACKGROUND: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents. METHODS: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0-tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment. FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0-tau was 148·5 (range 37·2-433·1) µg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 µg/mL (range 1·22-6·19) and 1·15 µg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults. INTERPRETATION: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg. FUNDING: The National Institutes of Health and ViiV Healthcare.

Asunto(s)

Fármacos Anti-VIH , Dicetopiperazinas , Infecciones por VIH , Adolescente , Niño , Humanos , Infecciones por VIH/tratamiento farmacológico , Piridonas , Rilpivirina/efectos adversos , Rilpivirina/uso terapéutico

RESUMEN

BACKGROUND: ATLAS (NCT02951052), a phase 3, multicenter, open-label study, demonstrated that switching to injectable cabotegravir (CAB) with rilpivirine (RPV) long-acting dosed every 4 weeks was noninferior at week (W) 48 to continuing three-drug daily oral current antiretroviral therapy (CAR). Results from the W 96 analysis are presented. METHODS AND DESIGN: Participants completing W 52 of ATLAS were given the option to withdraw, transition to ATLAS-2M (NCT03299049), or enter an Extension Phase to continue long-acting therapy (Long-acting arm) or switch from CAR to long-acting therapy (Switch arm). Endpoints assessed at W 96 included proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, incidence of confirmed virologic failure (CVF; two consecutive HIV-1 RNA ≥200 copies/ml), safety and tolerability, pharmacokinetics, and patient-reported outcomes. RESULTS: Most participants completing the Maintenance Phase transitioned to ATLAS-2M (88%, n = 502/572). Overall, 52 participants were included in the W 96 analysis of ATLAS; of these, 100% (n = 23/23) and 97% (n = 28/29) in the Long-acting and Switch arms had plasma HIV-1 RNA less than 50 copies/ml at W 96, respectively. One participant had plasma HIV-1 RNA 50 copies/ml or higher in the Switch arm (173 copies/ml). No participants met the CVF criterion during the Extension Phase. No new safety signals were identified. All Switch arm participants surveyed preferred long-acting therapy to their previous daily oral regimen (100%, n = 27/27). CONCLUSION: In this subgroup of ATLAS, 98% (n = 51/52) of participants at the Extension Phase W 96 analysis maintained virologic suppression with long-acting therapy. Safety, efficacy, and participant preference results support the therapeutic potential of long-acting CAB+RPV treatment for virologically suppressed people living with HIV-1.

Asunto(s)

Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Dicetopiperazinas , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Piridonas/uso terapéutico , Rilpivirina/uso terapéutico , Carga Viral

RESUMEN

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Asunto(s)

Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Rilpivirina/administración & dosificación , Rilpivirina/uso terapéutico , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Preparaciones de Acción Retardada , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rilpivirina/efectos adversos , Adulto Joven

RESUMEN

BACKGROUND: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence. METHODS: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm. RESULTS: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group. CONCLUSIONS: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.).

Asunto(s)

Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Piridonas/administración & dosificación , Rilpivirina/administración & dosificación , Administración Oral , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Antirretrovirales/uso terapéutico , Recuento de Linfocito CD4 , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , VIH-1/genética , Humanos , Inyecciones Intramusculares/efectos adversos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Mutación , Medición de Resultados Informados por el Paciente , Piridonas/efectos adversos , Piridonas/sangre , ARN Viral/sangre , Rilpivirina/efectos adversos , Rilpivirina/sangre , Carga Viral

RESUMEN

INTRODUCTION: Histaminergic H3 receptors may play a role in modulating cholinergic and monoaminergic neurotransmission. This Phase II study evaluated the efficacy and safety of GSK239512, a highly potent, brain penetrant H3 receptor antagonist as monotherapy treatment for subjects with mild-to-moderate probable Alzheimer's disease (AD). METHODS: In this 16-week, double-blind, randomized, parallel group study, 196 currently untreated subjects with mild-tomoderate AD (Mini Mental State Examination [MMSE] 16-24) received GSK239512 (n=97); or placebo (n=99) administered orally each morning. After a two-week placebo run-in period GSK239512 was up-titrated over 4 weeks in a flexible manner (10-20-40-80 microgram [µg]) followed by a 12-week Maintenance Phase. Co-primary efficacy endpoints were change from baseline in Episodic Memory and Executive Function/Working Memory composite scores from the CogState neuropsychological test battery (NTB) at Week 16. RESULTS: Compared to placebo, GSK239512 improved Episodic Memory at Week 16 (Effect Size [ES] =0.35; p=0.0495). No statistically significant differences were observed on other cognitive domains or on clinical measures including the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADASCog). GSK239512 treatment was associated with mild to moderate adverse events with headache, dizziness and events related to sleep disturbances being the most common and more pronounced in the early titration period when subjects were first being exposed to GSK239512 at the lower 10µg and 20µg doses. There were no clinically relevant changes in other safety parameters. CONCLUSION: GSK239512, at doses up to 80µg/day, improved Episodic Memory in patients with mildto- moderate AD. However, no improvements were observed on Executive Function/Working Memory or other domains of cognition. No changes were observed on any of the clinical measures included as secondary endpoints (including ADAS-Cog) indicating that GSK239512 failed to show benefit in this population. GSK239512 had an acceptable safety and tolerability profile. These findings suggest that H3 antagonists may, at most, have modest and selective effects on cognitive function in patients with mild-to-moderate AD.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Benzazepinas/uso terapéutico , Nootrópicos/uso terapéutico , Anciano , Benzazepinas/efectos adversos , Método Doble Ciego , Función Ejecutiva/efectos de los fármacos , Femenino , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Masculino , Cumplimiento de la Medicación , Memoria Episódica , Memoria a Corto Plazo/efectos de los fármacos , Pruebas Neuropsicológicas , Nootrópicos/efectos adversos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento

RESUMEN

We present here the design, synthesis, and analysis of a series of receptors for peptide ligands inspired by the hydrogen-bonding pattern of protein ß-sheets. The receptors themselves can be regarded as strands 1 and 3 of a three-stranded ß-sheet, with cross-linking between the chains through the 4-position of adjacent phenylalanine residues. We also report on the conformational equilibria of these receptors in solution as well as on their tendency to dimerize. ¹H NMR titration experiments are used to quantify the dimerization constants, as well as the association constant values of the 1:1 complexes formed between the receptors and a series of diamides and dipeptides. The receptors show moderate levels of selectivity in the molecular recognition of the hydrogen-bonding pattern present in the diamide series, selecting the alpha-amino acid-related hydrogen-bonding functionality. Only one of the two cyclic receptors shows modest signs of enantioselectivity and moderate diastereoselectivity in the recognition of the enantiomers and diastereoisomers of the Ala-Ala dipeptide (ΔΔG°1 (DD-DL) = -1.08 kcal/mol and ΔΔG°1 (DD-LD) = -0.89 kcal/mol). Surprisingly, the linear synthetic precursors show higher levels of stereoselectivity than their cyclic counterparts.

RESUMEN

In this study approximately 420 of the described species of Eucalyptus were examined for cyanogenesis. Our work has identified an additional 18 cyanogenic species, 12 from living tissues and a further six from herbarium samples. This brings the total of known cyanogenic species to 23, representing approximately 4% of the genus. The taxonomic distribution of the species within the genus is restricted to the subgenus Symphyomyrtus, with only two exceptions. Within Symphyomyrtus, the species are in three closely related sections. The cyanogenic glycoside was found to be predominantly prunasin (1) in the 11 species where this was examined. We conclude that cyanogenesis is plesiomorphic in Symphyomyrtus (i.e. a common basal trait) but has probably arisen independently in the other two subgenera, consistent with recent phylogenetic treatments of the genus. The results of this study have important implications for the selection of trees for plantations to support wildlife, and to preserve genetic diversity.

Asunto(s)

Eucalyptus/metabolismo , Glicósidos/metabolismo , Eucalyptus/química , Eucalyptus/clasificación , Eucalyptus/genética , Glicósidos/química , Glicósidos/clasificación , Estructura Molecular , Polimorfismo Genético/genética

RESUMEN

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Asunto(s)

Codón sin Sentido/genética , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Enfermedades Genéticas Congénitas/genética , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Biosíntesis de Proteínas/efectos de los fármacos , Alelos , Animales , Disponibilidad Biológica , Distrofina/biosíntesis , Distrofina/genética , Enfermedades Genéticas Congénitas/sangre , Humanos , Ratones , Ratones Endogámicos mdx , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacocinética , Fenotipo , Biosíntesis de Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especificidad por Sustrato

Asunto(s)

Sistemas de Liberación de Medicamentos , Industria Farmacéutica/organización & administración , Predisposición Genética a la Enfermedad/prevención & control , Comercialización de los Servicios de Salud/organización & administración , Grupos Raciales/genética , Sistemas de Liberación de Medicamentos/métodos , Predisposición Genética a la Enfermedad/etnología , Necesidades y Demandas de Servicios de Salud , Proyecto Genoma Humano , Humanos , Prevención Primaria , Grupos Raciales/etnología , Investigación , Problemas Sociales , Estados Unidos/epidemiología

RESUMEN

The plasma membrane urokinase plasminogen activator receptor (uPAR) localizes and enhances activation of pro-uPA. Active uPA, in turn, promotes increased degradation of the extracellular matrix (ECM) by activation of plasminogen. uPAR binds to ECM molecules and integrins, which can affect cellular adhesion, signal transduction, and gene regulation. The current study examines the expression and function of uPAR in developing rat ventral prostates (VPs). We report that newborn VPs express uPAR mRNA and protein. In addition, the function of uPAR-bound uPA during in vitro prostatic development was studied by adding recombinant peptide competitive inhibitors of uPA-uPAR binding. Newborn VP explants were cultured in serum-free media for one week with 10(-8) M testosterone plus chimeric peptides containing a human immunoglobulin G Fc domain and either human uPA amino acids 1-138 (hu-uPA 1-138) as a control or mouse uPA amino acids 1-138 (mo-uPA 1-138) or 1-48 (mo-uPA 1-48). Hu-uPA 1-138-treated VPs underwent normal ductal branching morphogenesis and tissue differentiation. In contrast, VPs treated with mo-uPA 1-138 or mo-uPA 1-48 displayed a dose-dependent perturbation of ductal branching. Differentiation of both epithelial and mesenchymal tissues was also impaired. Mo-uPA 1-48-treated VPs contained significantly more apoptotic cells. These observations suggest that disruption of uPA binding to uPAR results in a retardation of the development of newborn VPs.

Asunto(s)

Próstata/crecimiento & desarrollo , Receptores de Superficie Celular/fisiología , Activador de Plasminógeno de Tipo Uroquinasa/fisiología , Animales , Animales Recién Nacidos , Apoptosis/fisiología , Regulación hacia Abajo , Humanos , Masculino , Ratones , Especificidad de Órganos , Péptidos/metabolismo , Próstata/ultraestructura , Estructura Terciaria de Proteína/fisiología , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas F344 , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa

RESUMEN

Liver transplantation has been performed in individuals with a pretransplant clinical diagnosis of cirrhosis but with nodular regenerative hyperplasia histologically. The purpose of this report is to investigate the results of liver transplantation in patients proven to have nodular regenerative hyperplasia post-transplant. A retrospective review was undertaken of four patients who underwent liver transplantation with a histologic diagnosis of nodular regenerative hyperplasia. All were felt to be cirrhotic on clinical grounds. Final histology of the explanted liver was confirmed by a single pathologist. Their ages ranged from 39 to 54 years, and three of the four were male. Three had pretransplant needle liver biopsies, two percutaneous and one transjugular. All revealed nonspecific reactive changes. Ultrasound and MRI were interpreted as consistent with cirrhosis in four of four and three of four cases, respectively. Portal vein flow was hepatopedal in three and absent in one. Pretransplant clinical characteristics and frequency were as follows: bleeding varices two, clinical ascites three, encephalopathy three, and impaired hepatic synthetic function two. All four patients underwent successful liver transplantation. There were no episodes of acute rejection. All are alive and well with normal graft function 2 to 4 years post-transplant. We conclude the following. 1) Patients with clinical end-stage liver disease due to underlying nodular regenerative hyperplasia can successfully undergo transplantation. 2) Nodular regenerative hyperplasia can present with signs and symptoms of liver failure, is difficult to diagnose by needle biopsy, and can be difficult to discriminate clinically from cirrhosis. 3) Although each case must be individually evaluated transplantation may be the optimal therapy in patients presenting with complications of liver failure.

Asunto(s)

Hiperplasia Nodular Focal/cirugía , Trasplante de Hígado , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos

RESUMEN

BACKGROUND: A growing body of empirical evidence suggests that organisational factors are more important than classroom specific issues in determining teacher morale. Accordingly, it is necessary to have available measures that accurately assess morale, as well as the organisational factors that are likely to underpin the experience of morale. AIM: Three studies were conducted with the aim of developing a psychometrically sound questionnaire that could be used to assess teacher morale and various dimensions of school organisational climate. SAMPLE: A total of 1,520 teachers from 18 primary and 26 secondary schools in the Australian state of Victoria agreed to participate in three separate studies (N = 615, 342 and 563 in Studies 1, 2 and 3, respectively) that were used to develop the questionnaire. The demographic profile of the teachers was similar to that found in the Department as a whole. METHOD: All teaching staff in the participating schools were asked to complete a self-report questionnaire as part of the evaluation of an organisational development programme. RESULTS: A series of exploratory and confirmatory factor analyses were used to establish the questionnaire's factor structure, and correlation analyses were used to examine the questionnaire's convergent and discriminant validity. CONCLUSIONS: The three studies resulted in the 54-item School Organisational Health Questionnaire that measures teacher morale and 11 separate dimensions of school organisational climate: appraisal and recognition, curriculum coordination, effective discipline policy, excessive work demands, goal congruence, participative decision-making, professional growth, professional interaction, role clarity, student orientation, and supportive leadership.

Asunto(s)

Moral , Cultura Organizacional , Instituciones Académicas/organización & administración , Encuestas y Cuestionarios , Enseñanza , Adolescente , Adulto , Agotamiento Profesional/diagnóstico , Agotamiento Profesional/psicología , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Victoria

Asunto(s)

Malformaciones Arteriovenosas/diagnóstico , Gastroscopía , Úlcera Péptica Hemorrágica/diagnóstico , Estómago/irrigación sanguínea , Malformaciones Arteriovenosas/cirugía , Electrocoagulación , Hemostasis Quirúrgica , Humanos , Masculino , Persona de Mediana Edad , Úlcera Péptica Hemorrágica/cirugía

RESUMEN

BACKGROUND: Hepatitis B vaccination is recommended for health care workers but has a nonresponse rate of 5% to 32% and an unknown duration of immunity. There is no standardized postvaccination protocol to confirm, monitor, and maintain immunity. OBJECTIVE: To assess the hepatitis B serologic immune status in health care workers who were previously vaccinated. METHODS: A convenience survey and an objective laboratory study, which included testing for hepatitis B surface antigen, core antibody, and qualitative and quantitative surface antibody (anti-HBs), were performed. The data collected included vaccination date, number of doses of vaccine, whether and when titers had previously been checked, titer results, sex of patient, job description, and age at the time of our study and at vaccination. RESULTS: Group A (n = 109, 71%) had detectable anti-HBs titers, and group B (n = 45, 29%) had no detectable anti-HBs titers. Group A was vaccinated 4.80 +/- 0.30 (mean +/- SEM) years prior to our testing, received 2.91 +/- 0.04 (mean +/- SEM) vaccinations, and had a mean +/- SEM titer of 112.91 +/- 5.18 mIU/mL. There was no statistical significance in time since vaccination, number of doses of vaccine, sex, job description, age at the time of our serologic testing, or age at the time of vaccination between groups A and B. Six of 6 subjects given booster doses of vaccine in group B developed anti-HBs. Only 62 subjects (40%) in the entire study population had anti-HBs status previously determined, with 48 (77%) reporting immunity to hepatitis B virus. CONCLUSIONS: Twenty-nine percent of the health care workers who were vaccinated against hepatitis B showed no serologic evidence of hepatitis B immunity. It is unclear whether these subjects are nonresponders, lost immunity, or retained anamnestic potential. Booster vaccination response in 6 of 6 subjects suggests immunity. We recommend (1) postvaccination testing within 1 to 2 months to document immunity, (2) periodic anti-HBs monitoring, and (3) booster vaccination to maintain protective titer levels.

Asunto(s)

Vacunas contra Hepatitis B/administración & dosificación , Hepatitis B/inmunología , Hepatitis B/prevención & control , Personal de Hospital/estadística & datos numéricos , Adulto , Femenino , Hospitales Urbanos , Humanos , Masculino , Persona de Mediana Edad , Philadelphia , Factores de Tiempo

Asunto(s)

Colangiopancreatografia Retrógrada Endoscópica/normas , Imagen por Resonancia Magnética/normas , Adulto , Conductos Biliares/patología , Niño , Colangiopancreatografia Retrógrada Endoscópica/economía , Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Colangiopancreatografia Retrógrada Endoscópica/métodos , Seguridad de Equipos , Estudios de Evaluación como Asunto , Humanos , Lactante , Imagen por Resonancia Magnética/economía , Imagen por Resonancia Magnética/instrumentación , Imagen por Resonancia Magnética/métodos , Sensibilidad y Especificidad , Estados Unidos

Asunto(s)

Endoscopía Gastrointestinal/efectos adversos , Control de Infecciones/métodos , Infecciones/transmisión , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Equipos de Seguridad/normas , Costos y Análisis de Costo , Endoscopía Gastrointestinal/métodos , Seguridad de Equipos , Estudios de Evaluación como Asunto , Guías como Asunto , Humanos , Control de Infecciones/economía , Infecciones/etiología , Equipos de Seguridad/economía , Sensibilidad y Especificidad , Sociedades Médicas , Estados Unidos

RESUMEN

Binding of the serine protease urokinase (u-PA) to its receptor on tumor cell surfaces facilitates proteolysis and tumor invasion. We undertook this study to determine whether the role of u-PA in prostate cancer induced angiogenesis and secondary tumor growth by developing a homologous, immunocompetent in vivo model in which the tumors cells secrete an inhibitor of the murine u-PA receptor. A mutant recombinant murine u-PA that retains receptor binding but not proteolytic activity was made by PCR mutagenesis. Mutant u-PA and a reporter gene pRK luciferase were transfected and stably expressed in the highly metastatic rat Dunning MAT-LyLu prostate cancer cell line. Several clones expressing mutant u-PA and luciferase were identified by Western blotting, plasminogen zymography, and reverse transcription-PCR. One of these clones, 5C4, was injected s.c. into Copenhagen rats. Compared to animals injected with clones expressing pRK luciferase alone, tumors in animals injected with 5C4 cells were significantly smaller. Moreover, there were fewer lung micrometastases in the 5C4 animals. Primary tumor angiogenesis was measured by microvessel quantification of tissue stained with antibodies against von Willebrand factor. Mean microvessel density in 5C4 tumors was 4.3-fold lower than that in animals with tumors derived from the control tumor cell line (P < 0.0001). Significant inhibition of tumor growth was also observed for two additional MAT-LyLu cell lines expressing mutant u-PA. These findings suggest that cell surface u-PA contributes to prostate cancer growth by enhancing angiogenesis.

Asunto(s)

Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/prevención & control , Neoplasias de la Próstata/prevención & control , Receptores de Superficie Celular/antagonistas & inhibidores , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Genes Reporteros , Luciferasas/genética , Luciferasas/metabolismo , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Masculino , Proteínas de Neoplasias/genética , Neovascularización Patológica/genética , Neoplasias de la Próstata/genética , Ratas , Receptores de Superficie Celular/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Transfección , Activador de Plasminógeno de Tipo Uroquinasa/genética

RESUMEN

Will an effective discipline policy improve student misbehaviour and result in a reduction of teacher stress? It is commonly believed that student misbehaviour is a major cause of teacher stress, and that the degree of student misbehaviour is reflected in student suspension rates. Moreover, it is believed that student misbehaviour can be reduced by improving a school's discipline policy through the collaborative efforts of whole school communities. As a result of growing concern about student misbehaviour and teacher stress, a Whole School Approach to Discipline and Student Welfare programme was implemented throughout the Australian state of Victoria. This paper reports on the evaluation studies that were conducted to assess the effectiveness of the programme and examine the assumptions which underpinned its implementation. Data were obtained from 4,072 primary and secondary school teachers. Although longitudinal analyses suggested that the programme was effective in reducing teacher stress, there was no mean change in student misbehaviour. Structural equation analyses showed that there was little relationship between a school's discipline policy and the perceived level of student misbehaviour. It was also found that student suspension rates were not related to student misbehaviour, but could be predicted on the basis of a school's discipline policy and the self-esteem of teachers. Two and three wave causal analyses also demonstrated the problems associated with using cross-sectional research to support major policy decisions. Overall, these studies showed that there is little point in trying to reduce teacher stress by reducing student misbehaviour. Rather, it is more appropriate to develop a supportive organisational climate that enables teachers to cope with the student misbehaviour that confronts them.

Asunto(s)

Agotamiento Profesional/psicología , Trastornos de la Conducta Infantil/prevención & control , Controles Informales de la Sociedad , Enseñanza , Adolescente , Adulto , Anciano , Agotamiento Profesional/prevención & control , Niño , Trastornos de la Conducta Infantil/psicología , Femenino , Humanos , Control Interno-Externo , Satisfacción en el Trabajo , Masculino , Persona de Mediana Edad , Política Pública , Medio Social , Victoria

RESUMEN

Four water-soluble adenine receptors were synthesized to study the influence of hydrophobic interactions and hydrogen bonding on molecular recognition in aqueous solution. Association constants were measured in aqueous solution at five temperatures from 3-27 degrees C (pH 6, 51 mM ionic strength). For the mono(imide) receptors, delta H was -5.8 kcal/mol (carbazole) and -9.2 kcal/mol (naphthalene). The entropy of association for these was -13 cal.mol-1.K-1 (carbazole) and -26 cal.mol-1.K-1 (naphthalene). The carbazole bis(imide) receptor showed a binding enthalpy of -7.4 kcal/mol and entropy of -18 cal.mol-1.K-1. From this the free energy at 298 K of a single hydrogen bond is estimated to be only 0.2 kcal/mol. The enthalpy of a single hydrogen bond in this solvent-exposed system is estimated to be, at most, 0.8 kcal/mol, indicating that enthalpy just compensates for the unfavorable entropy in this system. These values reflect stronger hydrophobic interactions with the more polarizable naphthalene, as well as enthalpy-entropy compensation effects.

Asunto(s)

Adenina/metabolismo , Receptores Purinérgicos/química , Agua/química , Adenina/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Receptores Purinérgicos/metabolismo , Termodinámica