RESUMEN
BACKGROUND: This cluster randomised control trial is designed to evaluate whether the Communities That Care intervention (CTC) is effective in reducing the proportion of secondary school age adolescents who use alcohol before the Australian legal purchasing age of 18 years. Secondary outcomes are other substance use and antisocial behaviours. Long term economic benefits of reduced alcohol use by adolescents for the community will also be assessed. METHODS: Fourteen communities and 14 other non-contiguous communities will be matched on socioeconomic status (SES), location, and size. One of each pair will be randomly allocated to the intervention in three Australian states (Victoria, Queensland and Western Australia). A longitudinal survey will recruit grade 8 and 10 students (M = 15 years old, N = 3500) in 2017 and conduct follow-up surveys in 2019 and 2021 (M = 19 years old). Municipal youth populations will also be monitored for trends in alcohol-harms using hospital and police administrative data. DISCUSSION: Community-led interventions that systematically and strategically implement evidence-based programs have been shown to be effective in producing population-level behaviour change, including reduced alcohol and drug use. We expect that the study will be associated with significant effects on alcohol use amongst adolescents because interventions adopted within communities will be based on evidence-based practices and target specific problems identified from surveys conducted within each community. TRIAL REGISTRATION: The trial was retrospectively registered in September, 2017 ( ACTRN12616001276448 ), as communities were selected prior to trial registration; however, participants were recruited after registration. Findings will be disseminated in peer-review journals and community fora.
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Conducta del Adolescente , Trastornos Relacionados con Alcohol/prevención & control , Consumo de Alcohol en Menores/prevención & control , Adolescente , Trastornos Relacionados con Alcohol/epidemiología , Australia/epidemiología , Femenino , Encuestas Epidemiológicas , Humanos , Estudios Longitudinales , Masculino , Evaluación de Programas y Proyectos de Salud , Proyectos de Investigación , Estudiantes/psicología , Estudiantes/estadística & datos numéricos , Consumo de Alcohol en Menores/estadística & datos numéricos , Adulto JovenRESUMEN
AIMS: To test the relative contribution of two key Social Learning Theory constructs, alcohol expectancies (AEs) and drinking refusal self-efficacy (DRSE), in predicting early adolescent drinking behavior and examine the possible mediational role of DRSE over AE. METHODS: High school students (N = 192, mean age 14) were administered measures assessing AE (Drinking Expectancy Questionnaire--Adolescent version; DEQ-A), DRSE (Drinking Refusal Self-Efficacy Questionnaire--Revised Adolescent version; DRSEQ-RA) and indices of alcohol consumption and problem drinking. Age, gender, peer drinking, tobacco use and positive and negative behavioral characteristics were included in the statistical models as known predictors of alcohol misuse. Subjects were followed up at 12 months, with 88.5% retention. RESULTS: Initial confirmatory factor analyses verified factor structures of the DEQ-A and DRSEQ-RA. Prospective structural models controlling for Time 1 drinking behavior, age, gender, peer alcohol use, tobacco use and behavior problems identified that DRSE but not AE was associated with problem drinking 12-month post-initial assessment. DRSE mediated AE in predicting problem drinking. CONCLUSION: Results suggest that DRSE is a more salient cognitive construct than AE in early adolescence alcohol use. In this age group, prevention and treatment strategies that build refusal self-efficacy may be more effective than strategies that challenge AEs.
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Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/psicología , Autoeficacia , Adolescente , Consumo de Bebidas Alcohólicas/prevención & control , Consumo de Bebidas Alcohólicas/tendencias , Alcoholismo/prevención & control , Femenino , Humanos , Masculino , Modelos Psicológicos , Grupo Paritario , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Estudiantes/psicología , Encuestas y CuestionariosRESUMEN
The effects on thrombosis and hemostasis of thrombin-induced activation of endogenous protein C (PC) were evaluated in baboons. Thrombosis was induced by placing into arteriovenous shunts a segment of Dacron vascular graft, which generated arterial platelet-rich thrombus, followed by an expansion region of low-shear blood flow, which in turn accumulated fibrin-rich venous-type thrombus. Thrombosis was quantified by 111In-platelet imaging and 125I-fibrinogen accumulation. Intravenous infusion of alpha-thrombin, 1-2 U/kg-min for 1 h, increased baseline activated PC levels (approximately 5 ng/ml) to 250-500 ng/ml (P < 0.01). The lower thrombin dose, which did not deplete circulating platelets, fibrinogen, or PC, reduced arterial graft platelet deposition by 48% (P < 0.05), and platelet and fibrin incorporation into venous-type thrombus by > 85% (P < 0.01). Thrombin infusion prolonged the activated partial thromboplastin clotting time, elevated fibrinopeptide A (FPA), thrombin-antithrombin III complex (T:AT III), and fibrin D-dimer plasma levels (P < 0.01), but did not affect bleeding times. Thrombin's antithrombotic effects were blocked by infusing a monoclonal antibody (HPC-4) which prevented PC activation in vivo, caused shunt occlusion, increased the consumption of platelets and fibrinogen, elevated plasma FPA and T:AT III levels, and reduced factor VIII (but not factor V) procoagulant activity (P < 0.05). We conclude that activated PC is a physiologic inhibitor of thrombosis, and that activation of endogenous PC may represent a novel and effective antithrombotic strategy.
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Plaquetas/fisiología , Proteína C/metabolismo , Trombina/farmacología , Trombosis/prevención & control , Animales , Derivación Arteriovenosa Quirúrgica , Plaquetas/efectos de los fármacos , Factor V/metabolismo , Factor VII/metabolismo , Fibrina/metabolismo , Fibrinógeno/metabolismo , Fibrinopéptido A/metabolismo , Masculino , Papio , Tiempo de Tromboplastina Parcial , Tereftalatos Polietilenos , Trombosis/fisiopatologíaRESUMEN
We have investigated the hormonal and hypothalamic neuropeptidergic substrates of dehydration-associated anorexia. In situ hybridization and hormone analyses of anorexic and paired food-restricted rats revealed two distinct profiles. First, both groups had the characteristic gene expression and endocrine signatures usually associated with starvation: increased neuropeptide Y and decreased proopiomelanocortin and neurotensin mRNAs in the arcuate nucleus (ARH); increased circulating glucocorticoid but reduced leptin and insulin. Dehydrated animals are strongly anorexic despite these attributes, showing that the output of leptin- and insulin-sensitive ARH neurons that ordinarily stimulate eating must be inhibited. The second pattern occurred only in anorexic animals and had two components: (1) reduced corticotropin-releasing hormone (CRH) mRNA in the neuroendocrine paraventricular nucleus (PVH) and (2) increased CRH and neurotensin mRNAs in the lateral hypothalamic (LHA) and retrochiasmatic areas. However, neither corticosterone nor suppressed PVH CRH gene expression is required for anorexia after dehydration because PVH CRH mRNA in dehydrated adrenalectomized animals is unchanged from euhydrated adrenalectomized controls. We also showed that LHA CRH mRNA was strongly correlated with the intensity of anorexia, increased LHA CRH gene expression preceded the onset of anorexia, and dehydrated adrenalectomized animals (which also develop anorexia) had elevated LHA CRH gene expression with a distribution pattern similar to intact animals. Finally, we identified specific efferents from the CRH-containing region of the LHA to the PVH, thereby providing a neuroanatomical framework for the integration by the PVH of neuropeptidergic signals from the ARH and the LHA. Together, these observations suggest that CRH and neurotensin neurons in the LHA constitute a novel anatomical substrate for their well known anorexic effects.
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Anorexia/fisiopatología , Núcleo Arqueado del Hipotálamo/metabolismo , Deshidratación/fisiopatología , Regulación de la Expresión Génica/fisiología , Área Hipotalámica Lateral/metabolismo , Neuropéptidos/genética , Adrenalectomía , Hormona Adrenocorticotrópica/sangre , Animales , Anorexia/sangre , Anorexia/etiología , Núcleo Arqueado del Hipotálamo/fisiopatología , Transporte Axonal , Peso Corporal , Corticosterona/sangre , Hormona Liberadora de Corticotropina/genética , Deshidratación/sangre , Deshidratación/complicaciones , Privación de Alimentos , Área Hipotalámica Lateral/fisiopatología , Insulina/sangre , Leptina , Masculino , Neuropéptido Y/genética , Neurotensina/genética , Núcleo Hipotalámico Paraventricular/metabolismo , Fitohemaglutininas , Proopiomelanocortina/genética , Proteínas/metabolismo , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Timo/patología , Factores de Tiempo , Transcripción GenéticaRESUMEN
BACKGROUND: The hypothesis that thrombin mediates the formation of neointimal vascular lesions at sites of mechanical vascular injury has been tested in baboons by measurement of the effects of hirudin delivered by retrovirus-transduced hirudin-secreting vascular endothelial cells (ECs) lining surgically implanted arterial vascular grafts (AVGs). METHODS AND RESULTS: The antithrombotic efficacy of baboon ECs transduced with cDNA encoding hirudin was assessed in vitro and in vivo on thrombogenic segments in chronically exteriorized femoral arteriovenous (AV) shunts. Bilateral brachial AVGs lined with hirudin-transduced versus nonhirudin control ECs at confluent density were surgically implanted, and vascular lesion formations at distal graft-vessel anastomoses were compared after 30 days. Hirudin-transduced ECs secreted 20+/-6 ng x 10(6) cells(-1) x 24 h(-1) (range, 14 to 24 ng x 10(6) cells(-1) x 24 h(-1)) hirudin in supernatants of static cultures. Hirudin-secreting ECs on segments of collagen-coated graft interposed in chronic AV shunts decreased the accumulation of (111)In-labeled platelets to 0.52+/-0.34 x 10(9) platelets, compared with 0.82+/-0.49 x 10(9) platelets in controls (P = 0.03) and reduced platelet deposition in propagated thrombotic tails extending downstream from segments of vascular graft from 1.38+/-0.41 x 10(9) platelets in controls to 0.59+/-0.22 x 10(9) platelets (P = 0.04). ECs recovered from 30-day AVG implants generated 17+/-9 ng x 10(6) cells(-1) x 24 h(-1) (range, 9 to 25 ng x 10(6) cells(-1) x 24 h(-1)) hirudin. Hirudin-secreting ECs reduced neointimal lesion formation at distal graft-vessel anastomoses, ie, 1.02 mm(2) (range, 0.88 to 1.95 mm(2)) versus 1.82 mm(2) (range, 0.88 to 2.56 mm(2)) in contralateral AVGs bearing nonhirudin control ECs (P<0.01). CONCLUSIONS: Viral vector-directed secretion of hirudin from ECs lining implanted AVGs significantly reduces the formation of thrombus and neointimal vascular lesions.
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Antitrombinas/uso terapéutico , Prótesis Vascular , Endotelio Vascular/metabolismo , Terapia con Hirudina , Músculo Liso Vascular/patología , Retroviridae/genética , Trombosis/prevención & control , Animales , Hirudinas/genética , Masculino , Papio , TransfecciónRESUMEN
To determine the importance of angiotensin converting enzyme (ACE) activity in the development of arterial proliferative lesions in a primate model, the response to vascular injury was studied in five baboons treated with oral cilazapril (20 mg/kg/day) and in five untreated control animals. Each animal underwent three procedures: 1) carotid artery endarterectomy, 2) balloon catheter deendothelialization of the superficial femoral artery, and 3) surgical placement of bilateral aorto-iliac expanded polytetrafluoroethylene (Gore-Tex) vascular grafts. Cilazapril therapy was initiated 1 week preoperatively and continued throughout the study interval. At 1 and 3 weeks postoperatively, plasma ACE activity was inhibited by more than 96% versus control values. After animals were killed at 3 months, injured vessel and graft segments were evaluated morphometrically. Although the response between animals was variable, average cross-sectional areas of neointima did not differ between the cilazapril-treated and control groups at sites of carotid endarterectomy (0.26 +/- 0.12 versus 0.34 +/- 0.17 mm2, respectively; p greater than 0.5), femoral artery ballooning (0.15 +/- 0.08 versus 0.11 +/- 0.01 mm2; p greater than 0.5), or at graft anastomoses (1.86 +/- 0.50 versus 1.72 +/- 0.50 mm2; p greater than 0.5). Thus, cilazapril did not reduce intimal thickening over 3 months in these primate arterial injury models. However, a possible beneficial effect of cilazapril, which might be apparent at earlier time points or with larger animal groups, cannot be excluded.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Arterias/patología , Músculo Liso Vascular/patología , Piridazinas/farmacología , Animales , Aorta/trasplante , Arterias/efectos de los fármacos , División Celular/efectos de los fármacos , Cilazapril , Endarterectomía/efectos adversos , Arteria Femoral/efectos de los fármacos , Arteria Femoral/patología , Hiperplasia , Arteria Ilíaca/trasplante , Masculino , Músculo Liso Vascular/efectos de los fármacos , Papio , Especificidad de la EspecieRESUMEN
We have previously shown in dehydrated rats that cellular levels of the mRNAs encoding the precursor peptides for corticotropin-releasing hormone and neurotensin/neuromedin N significantly increase in a restricted region of the lateral hypothalamic area (Watts, 1992, Brain Res. 581:208-216). The experiments reported here address the role that forebrain osmosensitive cells groups or regions associated with autonomic regulation play in developing this mRNA response. The first experiment showed that unilateral knife cuts placed between the rostral forebrain and the lateral hypothalamic area (LHA) will unilaterally attenuate the mRNA response in the LHA to dehydration. In a second experiment, small injections of the retrograde tracer Fluorogold into the region of the LHA containing these mRNAs revealed a direct input from the osmosensitive median preoptic nucleus and subfornical organ and from the fusiform nucleus of the bed nuclei of the stria terminalis, which is part of a complex of cell groups associated with autonomic regulation. We found that at least 30% of the neurons in the median preoptic nucleus and subfornical organ and 14% of the neurons in the fusiform nucleus of the bed nuclei of the stria terminalis that project to the LHA responded to a rapid increase in plasma osmolality with increased c-fos mRNA levels. In the final experiment, injections of Fluorogold into the LHA were made simultaneously with ipsilateral rostral knife cuts. Here the numbers of neurons accumulating Fluorogold in the median preoptic nucleus, subfornical organ, and the fusiform nucleus were all significantly decreased concomitantly with attenuated mRNA responses in the LHA to dehydration. We conclude that the LHA receives direct and functional projections from the median preoptic nucleus, subfornical organ, and the fusiform nucleus. These projections appear capable of mediating a substantial part of the response of peptidergic mRNAs in the LHA to dehydration.
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Deshidratación/metabolismo , Regulación de la Expresión Génica/fisiología , Área Hipotalámica Lateral/metabolismo , Neuropéptidos/genética , Prosencéfalo/fisiología , Vías Aferentes/fisiología , Animales , Sistema Nervioso Autónomo/fisiología , Homeostasis , Masculino , Neuronas/fisiología , Concentración Osmolar , Prosencéfalo/citología , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
Neurons in a restricted part of the lateral hypothalamic area (LHA) show increased expression of corticotropin-releasing hormone (CRH) mRNA as a consequence of cellular dehydration. In the present study, we have investigated the organization of their efferent projections by using anterograde and retrograde tracing techniques. Additionally, we have compared the distribution of CRH mRNA-containing neurons after cellular dehydration and intraventricular (i.c.v.) colchicine injections. Our results show that cellular dehydration activates a more restricted neuronal population than does i.c.v. colchicine. Iontophoretic injections of Phaseolus vulgaris leucoagglutinin (PHAL) were placed in the LHA of animals drinking hypertonic saline and their proximity to activated CRH neurons determined by in situ hybridization for CRH mRNA. Although labelled fibers from these injections were seen throughout the brain, the region of the parabrachial nucleus and nucleus of the solitary tract (NTS) were most conspicuous in also having CRH immunoreactive fibers. Injections of Fluoro-Gold placed in these two structures were used to confirm these findings in dehydrated animals. Significant numbers of neurons containing both Fluoro-Gold and CRH mRNA were seen in the lateral hypothalamus after injections in the lateral and medial parts of the parabrachial nucleus; far fewer were seen after injections in the NTS. These results strongly suggest that the CRH neurons in the LHA activated by cellular dehydration provide an input to the region of the parabrachial nucleus. The altered biochemical composition of this pathway may well be able to modify sensory and motor patterns both during and after dehydration.
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Mapeo Encefálico , Hormona Liberadora de Corticotropina/genética , Área Hipotalámica Lateral/fisiología , Neuronas/metabolismo , Puente/fisiología , Estilbamidinas , Animales , Colchicina , Deshidratación , Colorantes Fluorescentes , Área Hipotalámica Lateral/citología , Masculino , Vías Nerviosas/fisiología , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Núcleo Solitario/efectos de los fármacosRESUMEN
Thrombin mediates acute vascular thrombosis and subsequent vascular lesion formation following mechanical denuding injury or spontaneous atherosclerotic plaque rupture. In the process of generating thrombin Factor VII/VIIa binds avidly with tissue factor (TF) exposed on cellular membranes, and coagulation serine proteases are sequentially cleaved via macromolecular catalytic complexes on phospholipid surfaces. Thrombin activates platelets, blood leukocytes, endothelium and vascular smooth muscle cells (SMCs) by cleaving G protein-coupled thrombin receptors (TRs), leading to SMC intimal proliferation and synthesis of extracellular matrix in the local formation of stenosing neointimal vascular lesions. Therapeutic strategies include inactivation of bound thrombin, inhibition of TR activation by thrombin, and interruption of thrombin generation. In patients having orthopedic surgery, inactivating bound thrombin with direct antithrombins markedly reduces venous thromboembolic events, compared with heparin or its derivatives, without significant impairment of hemostasis. However, acute coronary syndrome patients are not benefitted when given systemic direct antithrombins at safe levels, because interrupting TR-dependent platelet thrombosis demands systemic levels of direct antithrombins that concurrently compromise hemostatic function. Local drug delivery strategies have yet to be explored. In preclinical studies: a) enhancing the formation of endogenous activated Protein C (APC) by Protein C-selective thrombin mutants produces antithrombotic levels of APC; b) inhibiting thrombin activation of TRs abolishes platelet recruitment in arterial thrombogenesis in nonhuman primates, while sparing fibrin formation in hemostatic plugs; and c) preventing thrombin generation by inhibiting precursor serine protease function interrupts the formation of both acute thrombosis and chronic stenotic lesions after denuding vascular damage without significant hemostatic compromise. TF antagonists appear to have a highly favorable efficacy:safety therapeutic relationship for preventing the formation of thrombosis and vascular lesions.
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Fibrinolíticos/uso terapéutico , Receptores de Trombina/antagonistas & inhibidores , Trombina/antagonistas & inhibidores , Trombosis/tratamiento farmacológico , Vasos Sanguíneos/lesiones , Humanos , Hemorragia Posoperatoria/prevención & control , Proteína C/metabolismo , Trombina/biosíntesisRESUMEN
Slow neuron regression develops during the adult phase of life in select brain systems of mammals. We describe a model in adult rats that resolves several phases in a slow atrophic process that differentially influences levels of mRNA and protein for tyrosine hydroxylase (TH). Responses of striatal dopaminergic markers to 6-hydroxydopamine (6-OHDA) lesions in rats indicated that the striatal terminals maintained TH protein, despite greater than 3-fold loss of TH mRNA in the substantia nigra pars compacta (SNC) cell bodies whose axons project to the striatum. The loss of TH mRNA/cell was progressive up to 9 months, whereas SNC cell body shrinkage stabilized by 3 months post-lesioning. Consideration of possible mechanisms in protein turnover motivated a search for PEST motifs in the TH of rats and other vertebrates that could be a point of regulation by altering the rate of TH protein turnover.
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Monoaminas Biogénicas/metabolismo , Cuerpo Estriado/metabolismo , Regulación Enzimológica de la Expresión Génica , Neuronas/fisiología , Oxidopamina/farmacología , ARN Mensajero/metabolismo , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/genética , Ácido 3,4-Dihidroxifenilacético/metabolismo , Envejecimiento , Secuencia de Aminoácidos , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/crecimiento & desarrollo , Dopamina/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Ácido Homovanílico/metabolismo , Humanos , Ácido Hidroxiindolacético/metabolismo , Inmunohistoquímica , Masculino , Datos de Secuencia Molecular , Neuronas/efectos de los fármacos , Neuronas/enzimología , Norepinefrina/metabolismo , Hibridación de Ácido Nucleico , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas , Ratas Endogámicas F344 , Homología de Secuencia de Ácido Nucleico , Serotonina/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/crecimiento & desarrolloRESUMEN
The authors have demonstrated in rats that the ingestion of hypertonic saline for 5 days provides an increasingly complex dehydrating stimulus to the rats. Initially, the stimulus leads to cellular dehydration, but extracellular dehydration develops as ingestion continues beyond 3 days. The initial cellular dehydration provokes modifications to corticotropin-releasing hormone and neurotensin/neuromedin N messenger RNAs (mRNAs) in some neurons of the limbic forebrain, changes that are either maintained or are modified as extracellular dehydration develops. These changes in mRNA content occur in neurosecretory neurons as well as in neurons in hypothalamic and telencephalic regions associated with behavior and autonomic regulation. The authors propose that alterations in peptide mRNAs are allied to altered neuronal signaling processes that direct the different components of the homeostatic response to dehydration.
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Ingestión de Líquidos/fisiología , Sistema Límbico/fisiología , Neurotensina/genética , Fragmentos de Péptidos/genética , Sed/fisiología , Equilibrio Hidroelectrolítico/fisiología , Animales , Peso Corporal/fisiología , Mapeo Encefálico , Espacio Extracelular/fisiología , Expresión Génica/fisiología , Hematócrito , Masculino , Neuronas/fisiología , ARN Mensajero/genética , Ratas , Ratas Sprague-DawleyRESUMEN
We have compared the acute antithrombotic effects of aspirin-treated versus normal endothelial cell (EC) coverage of endarterectomized baboon aortic segments (EAS) incorporated into chronic exteriorized arteriovenous shunts in baboons. Human ECs grown in culture were incubated in control medium or medium containing aspirin (100 mumols/ml) and then attached at saturation density by incubating EC suspensions (6 x 10(5) cells/100 microliters) within EAS for 20 minutes. Nonendarterectomized aortic segments and untreated EAS served as negative and positive controls, respectively. The inhibitory effect of aspirin treatment on EC production of prostacyclin was confirmed by radioimmunoassay of its stable metabolic breakdown product, 6-keto-prostaglandin F1 alpha in supernatant medium. Thrombus formation in vivo was measured as the accumulation of indium 111-labeled platelets on endarterectomy sites in real time by scintillation camera imaging. 111In-labeled platelets were deposited rapidly, reaching a plateau by 60 minutes of 4.40 +/- 0.89 x 10(9) platelets/cm, compared with 111In-labled platelet deposition on nonendarterectomized segments of 0.89 +/- 0.26 x 10(9) platelets/cm (p = 0.008). Coverage of EAS with normal cultured ECs significantly reduced platelet deposition on EAS (1.05 +/- 0.45 x 10(9) platelets/cm; p = 0.009 at 1 hour compared with EAS not incubated with ECs). Aspirin-treated ECs also produced a marked reduction in platelet disposition (0.71 +/- 0.24 x 10 platelets/cm; p = 0.007 compared with EAS without ECs) that was equivalent to the effect of non-aspirin-treated ECs (p greater than 0.5). Scanning and transmission electron microscopy confirmed the antithrombotic effects of attached ECs. We conclude that endarterectomy of normal arteries produces a highly thrombogenic surface and the thrombogenicity is abolished by acutely attaching cultured human ECs.
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Aspirina/farmacología , Endotelio Vascular/fisiología , Trombosis/prevención & control , Animales , Aorta/citología , Aorta/fisiología , Adhesión Celular , Células Cultivadas , Endarterectomía , Endotelio Vascular/citología , Endotelio Vascular/ultraestructura , Masculino , Microscopía Electrónica , Microscopía Electrónica de Rastreo , Recuento de Plaquetas , Valores de ReferenciaRESUMEN
BACKGROUND: Because the adhesive glycoprotein von Willebrand Factor (vWF) mediates initial platelet attachment at sites of vascular injury and may also contribute to shear-dependent platelet thrombus formation, we have determined in vivo the relative antithrombotic efficacy and hemostatic safety of infusing murine monoclonal antibodies against vWF. METHODS: In baboons with chronic arteriovenous shunts, thrombus formation was initiated by interposition of thrombogenic Dacron vascular grafts (VG) and endarterectomized baboon aortic segments (EAS). Thrombus formation on VG and EAS was assessed by use of real-time scintillation camera imaging of indium 111-labeled platelet deposition. In control and treated animals (anti-vWF antibody) platelet hemostatic competence was evaluated by means of serial measurements of platelet count, bleeding time, and ex vivo platelet aggregation in response to adenosine diphosphate and ristocetin. RESULTS: Although bolus antibody infusions did not affect circulating platelet counts, bleeding times were immediately prolonged to 28 +/- 4 minutes (vs 4.7 +/- 0.4 minutes before treatment, p = 0.01). Bleeding times normalized within 24 hours after antibody administration. Platelet aggregation in response to adenosine diphosphate was unchanged by antibody therapy, whereas ristocetin-induced platelet aggregation was abolished acutely and remained impaired for 24 hours. Platelet deposition on VG after 60 minutes of exposure to flowing blood was 2.95 +/- 0.74 x 10(9) platelets/cm in six control animals as compared to 1.86 +/- 0.16 x 10(9) platelets/cm in five treated animals (p = 0.04). Similarly, platelet deposition on EAS averaged 4.40 +/- 0.89 x 10(9) platelets/cm in control studies and was reduced significantly by antibody therapy (1.52 +/- 0.50 x 10(9) platelets/cm, p = 0.02). CONCLUSIONS: Despite profound interruption of platelet hemostatic functions, therapeutic targeting of vWF modestly inhibits platelet-dependent thrombosis.
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Anticuerpos Monoclonales/uso terapéutico , Hemostasis/efectos de los fármacos , Trombosis/prevención & control , Factor de von Willebrand/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Aorta/fisiología , Aorta/cirugía , Derivación Arteriovenosa Quirúrgica , Plaquetas/efectos de los fármacos , Plaquetas/fisiología , Prótesis Vascular , Endarterectomía , Masculino , Papio , Valores de Referencia , Flujo Sanguíneo Regional , Trombosis/etiología , Grado de Desobstrucción Vascular/efectos de los fármacosRESUMEN
AIM: To evaluate the efficacy of a short-term alcohol-focused intervention for maritally distressed women, and to explore changes in relationship functioning. DESIGN: Participants were assigned randomly to an alcohol-focused treatment or to a waiting-list control group. The waiting-list control group began the intervention at 1-month follow-up. SETTING: The intervention took place at a research and training centre offering outpatient psychology services to the community. PARTICIPANTS: A sample of 32 women with alcohol and marital problems were recruited through the media. Participants reported protracted alcohol problems, moderate to severe impact of alcohol on social and occupational functioning, and moderate to severe marital distress. MEASUREMENTS: Measures of average alcohol consumption, marital distress, relational efficacy and depression were administered at pre- and post-therapy, and at 1, 6 and 12-month follow-up. INTERVENTION: The intervention involved six 1-hour sessions, consisting of clinical assessment, motivational interviewing, cognitive-behavioural strategies and relapse prevention. RESULTS: At 1-month follow-up, the intervention was associated with statistically significant improvements in alcohol consumption, marital satisfaction, relational efficacy and depression, and these effects were sustained at 12-month follow-up. CONCLUSIONS: At 1-month follow-up the intervention was associated with decreased alcohol consumption and depression, and increased marital satisfaction and relational efficacy, with evidence of maintained effects at 12-month follow-up. However, it is unlikely that reduced problem drinking and improved confidence in resolving problems were the only factors producing low marital quality in these couples. Further research is needed to identify those individuals who might benefit from marital interventions.
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Alcoholismo/terapia , Terapia Cognitivo-Conductual/métodos , Relaciones Interpersonales , Matrimonio , Psicoterapia Breve/métodos , Adulto , Alcoholismo/complicaciones , Análisis de Varianza , Depresión/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esposos , Estrés Psicológico/terapia , Resultado del TratamientoRESUMEN
AIM: To evaluate the effectiveness of three approaches to assisting the female partners of male problem drinkers with the stress imposed by the male's drinking. DESIGN: Participants were assigned randomly via random number tables to one of three treatment conditions: supportive counselling, stress management or alcohol-focused couples therapy. SETTING: The intervention took place at the Behaviour Research and Therapy Centre (BRTC), The University of Queensland. This research and training centre offers outpatient psychology services to the community. PARTICIPANTS: Sixty-one married women whose husbands drank heavily. Participants reported protracted alcohol problems, severe impact of alcohol on social functioning and severe marital distress. MEASUREMENT: The women's stress, alcohol consumption by the male, and relationship functioning were assessed at pre- and post-treatment and at 6-month follow-up. INTERVENTIONS: All three treatments involved 15 1-hour sessions with the woman. In the alcohol-focused couple therapy, attempts were made to engage the man in these sessions. RESULTS: Contrary to our predictions, there were few differences between the treatments. All three treatments were associated with reductions in the women's reported stress, with trends for somewhat greater reduction in the women's stress in the stress management and alcohol-focused couples therapy conditions than for supportive counselling. None of the treatments produced clinically significant reductions in men's drinking or relationship distress. CONCLUSION: The treatments ease stresses and burden but do not improve drinking or relationships. Limited power in the design restricted the capacity to detect differential treatment effects.
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Alcoholismo/psicología , Consejo/métodos , Esposos/psicología , Estrés Psicológico/terapia , Adulto , Análisis de Varianza , Femenino , Humanos , Masculino , Estrés Psicológico/etiología , Resultado del TratamientoRESUMEN
The results of CT and MR imaging were reviewed retrospectively and compared in 100 patients who experienced clinically significant head trauma. The findings were analyzed on the basis of several parameters in an attempt to establish objective clinical guidelines for the use of each diagnostic technique. CT remains the screening method of choice in evaluating acute severe head trauma; however, MR revealed additional clinically relevant findings in all four cases in which the patient's clinical symptoms were disproportionate to the CT findings. MR was equal or superior to CT in the evaluation of all patients with acute minor head trauma and in 94 of 95 patients examined in the subacute, chronic, or remote phase of injury, irrespective of the severity or pathologic nature of their injuries. All subacute contusions (21 lesions) and white-matter shearing lesions (18 cases) were demonstrated to particular advantage on MR compared with CT, as were all subdural hematomas (of 52 small subdural collections, 58% were detected only by MR). Although surgical management was not altered by the additional information provided by MR, the implications regarding the medical management and disposition of the patients with head trauma were significant.
Asunto(s)
Lesiones Encefálicas/diagnóstico , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Conmoción Encefálica/diagnóstico , Conmoción Encefálica/diagnóstico por imagen , Lesiones Encefálicas/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/diagnóstico por imagen , Femenino , Humanos , MasculinoRESUMEN
Haloperidol, administered to mice in their drinking water, produced a 21% increase in striatal D2 dopamine receptor density after seven days of continuous exposure. The steady-state D2 receptor RNA prevalence was unaffected by this treatment, yet the RNA coding for preproenkephalin was elevated, as expected. These data indicate that the homologous up-regulation of dopamine receptor density by antipsychotic drugs proceeds by mechanisms other than changes in RNA abundance.
Asunto(s)
Haloperidol/farmacología , ARN/metabolismo , Receptores Dopaminérgicos/metabolismo , Animales , Northern Blotting , Regulación de la Expresión Génica/efectos de los fármacos , Haloperidol/metabolismo , Masculino , Ratones , Ratones Endogámicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Dopaminérgicos/genética , Factores de Tiempo , Transcripción Genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
To investigate the pathophysiological process of transient ischaemic events in a clinically relevant model, we produced transient focal cerebral ischaemia in five baboons using endogenously generated platelet microemboli. Thrombogenic segments of Dacron vascular graft were incorporated as unilateral carotid arterio-arterial shunts to produce endogenous platelet microemboli. The embolized microparticles were quantified by isotopic imaging using 111In-platelets and by transcranial Doppler ultrasonography. Platelet microemboli accumulated rapidly in the shunted carotid territory and reached a maximum value of 3.2 +/- 0.8 x 10(9) in the embolized hemisphere 20 min after initiating blood flow through the graft segment. Sixty min after removing the grafts 111In-platelets were largely cleared from hemispheric vasculature. Recovered animals exhibited mild contralateral hemiparesis which disappeared completely within 24 h. We conclude that endogenously generated platelet microemboli accumulate transiently in the dependent cerebral circulation and produce corresponding transient focal neurological dysfunction. This model may be useful in the evaluation of new therapeutic strategies in acute stroke.
Asunto(s)
Ataque Isquémico Transitorio/fisiopatología , Tromboembolia/complicaciones , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Circulación Cerebrovascular , Ecoencefalografía , Radioisótopos de Indio , Ataque Isquémico Transitorio/sangre , Ataque Isquémico Transitorio/etiología , Masculino , Compuestos Organometálicos , Oxiquinolina/análogos & derivados , Papio , Recuento de Plaquetas , Tromboembolia/sangre , Tromboembolia/fisiopatología , Tomografía Computarizada de EmisiónRESUMEN
We tested the ability of ultrasound radiofrequency (RF) signal analysis to characterize thrombus accumulation in a Dacron graft incorporated into the exteriorized arteriovenous shunt in 3 baboons with constant blood flow for 60 min. Thrombus formation was quantified by sequential measurements of 111Indium-labeled platelet deposition. RF signals were acquired every 15 min at 2 sites in the graft, using a 2.9 Fr intravascular ultrasound catheter-based transducer (30 MHz) and digitized at 250 MHz in 8-bit resolution. Regions of interest were placed within a 0.5-mm perimeter adjacent to the graft wall. Integrated backscatter increased significantly (p < 0.001) with increasing platelet deposition. However, mean-to-standard deviation ratio of the RF envelope showed no significant change and the distribution pattern of the RF probability function remained constant and consistent with a Rayleigh scattering process. These results provide a basis for using RF analysis to monitor the time-course of thrombus formation.
Asunto(s)
Modelos Animales de Enfermedad , Trombosis/diagnóstico por imagen , Ultrasonografía Intervencional/métodos , Análisis de Varianza , Animales , Derivación Arteriovenosa Quirúrgica , Prótesis Vascular , Progresión de la Enfermedad , Arteria Femoral , Vena Femoral , Oclusión de Injerto Vascular/diagnóstico por imagen , Papio , Tereftalatos Polietilenos , Factores de Tiempo , Ultrasonografía Intervencional/instrumentación , Ultrasonografía Intervencional/estadística & datos numéricosRESUMEN
Cardiovascular and respiratory functions were serially evaluated in ten healthy, fasting, spontaneously breathing, laterally recumbent adult horses during five hours of constant 1.06% alveolar halothane (equivalent to 1.2 times the minimum alveolar concentration for horses). Mean carotid arterial pressure was about 25% higher after one hour of constant-dose halothane than after 30 minutes of constant-dose (P less than 0.05), and remained increased throughout the study. Mean carotid arterial pressure peaked after 90 minutes, and was about 30% higher than at 30 minutes. Total peripheral vascular resistance initially increased (20% at one hour), then gradually returned to the 0.5-hour value over the next four hours. Cardiac output progressively increased with time (P less than 0.05; 20% by two hours; nearly 40% by five hours) because of an increase in stroke volume. An increase (P less than 0.05) in mixed venous PO2 accompanied the increase in cardiac output. Heart rate did not change significantly (P greater than 0.05). Some measures of ventilation changed significantly with time (P less than 0.05). After four and five hours of constant alveolar halothane, the PaCO2, inspired gas flow, and ratio of inspired vs expired gas flow were significantly higher than the 0.5-hour values. Inspiratory time significantly decreased, beginning at three hours. All horses recovered from anesthesia and recumbency without complications.