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1.
Antarct Sci ; 30(1): 67-78, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32818010

RESUMO

The Antarctic Dry Valleys represent a unique environment where it is possible to study dry permafrost overlaying an ice-rich permafrost. In this paper, two opposing mechanisms for ice table stability in University Valley are addressed: i) diffusive recharge via thin seasonal snow deposits andii) desiccation via salt deposits in the upper soil column. A high-resolution time-marching soil and snow model was constructed and applied to University Valley, driven by meteorological station atmospheric measurements. It was found that periodic thin surficial snow deposits (observed in University Valley) are capable of drastically slowing (if not completely eliminating) the underlying ice table ablation. The effects of NaCl, CaCl2 and perchlorate deposits were then modelled. Unlike the snow cover, however, the presence of salt in the soil surface (but no periodic snow) results in a slight increase in the ice table recession rate, due to the hygroscopic effects of salt sequestering vapour from the ice table below. Near-surface pore ice frequently forms when large amounts of salt are present in the soil due to the suppression of the saturation vapour pressure. Implications for Mars high latitudes are discussed.

2.
Acta Psychol (Amst) ; 181: 51-61, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29049936

RESUMO

Retrieval of target information can cause forgetting for related, but non-retrieved, information - retrieval-induced forgetting (RIF). The aim of the current studies was to examine a key prediction of the inhibitory account of RIF - interference dependence - whereby 'strong' non-retrieved items are more likely to interfere during retrieval and therefore, are more susceptible to RIF. Using visual objects allowed us to examine and contrast one index of item strength -object typicality, that is, how typical of its category an object is. Experiment 1 provided proof of concept for our variant of the recognition practice paradigm. Experiment 2 tested the prediction of the inhibitory account that the magnitude of RIF for natural visual objects would be dependent on item strength. Non-typical objects were more memorable overall than typical objects. We found that object memorability (as determined by typicality) influenced RIF with significant forgetting occurring for the memorable (non-typical), but not non-memorable (typical), objects. The current findings strongly support an inhibitory account of retrieval-induced forgetting.


Assuntos
Inibição Psicológica , Rememoração Mental , Sinais (Psicologia) , Feminino , Humanos , Masculino , Reconhecimento Visual de Modelos , Adulto Jovem
3.
Child Care Health Dev ; 43(3): 441-450, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27739085

RESUMO

BACKGROUND: Playgroups are a relatively unique form of family support programme that is common in Australia which has high community acceptance and significant government investment. However, limited evidence exists regarding the effectiveness of playgroups to achieve better outcomes for children and their parents. This study describes patterns of playgroup participation for Aboriginal and Torres Strait Islander families with young children and examines the extent to which participation from birth to three years is associated with subsequent child, parent and community outcomes. METHODS: This study uses three years of longitudinal data for 622 Aboriginal and Torres Strait Islander children who were participants in the Longitudinal Study of Indigenous Children (LSIC). Longitudinal associations between playgroup attendance when children were age 2 and 3 years and outcome measures for child vocabulary, motor skills, behaviour problems, prosocial development, parent home learning engagement, resilience, advice-seeking and health service use, and community trustworthiness were examined using path analysis. RESULTS: Rates of playgroup participation in this sample group were generally lower than for Australian children overall. Playgroup attendance when children were age 2 to 3 years was associated with higher parental engagement in home learning activities when children were aged 4 years which, in turn, was associated with stronger expressive vocabulary scores for children. CONCLUSION: The findings from this study suggest that playgroup participation can enhance the home learning environments for Aboriginal and Torres Strait Islander children. Playgroups as a parent support programme hold strong potential to reach and engage families, particularly in areas of high geographic isolation, which can realize improved outcomes for children, parents and communities.


Assuntos
Participação da Comunidade/psicologia , Promoção da Saúde/organização & administração , Havaiano Nativo ou Outro Ilhéu do Pacífico , Pais/psicologia , Jogos e Brinquedos/psicologia , Adulto , Austrália/epidemiologia , Pré-Escolar , Pesquisa Participativa Baseada na Comunidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Avaliação de Programas e Projetos de Saúde
4.
Ann Oncol ; 26(5): 1019-1025, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25678586

RESUMO

BACKGROUND: Molecular phenotypes of invasive breast cancer predict early recurrence. Ductal carcinoma in situ (DCIS) exhibits similar phenotypes, but their frequency and significance remain unclear. To determine whether DCIS molecular phenotypes predict recurrence, 314 women (median age 57.7 years) with primary DCIS who were screened or entered DCIS trials in a specialist breast unit from 1990 to 2010 were studied. PATIENTS AND METHODS: Expression of Ki67, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) within primary DCIS was established using immunohistochemistry (IHC). Patients were subdivided into molecular phenotypes using IHC surrogates [Luminal A (ER/PR+HER2-), Luminal B (ER/PR+/HER2+), HER2 type (ER and PR-/HER2+) or triple negative (ER/PR/HER2)] and recurrence rates compared. RESULTS: Overall, there were 57 (18.2%) recurrences, 35 (11.2%) DCIS and 22 (7%) invasive cancer. A low rate of recurrence at 5 years was seen in Luminal A DCIS (7.6%), compared with 15.8%-36.1% in other phenotypes. Independent predictors of overall recurrence on multivariate analysis were involved (<1 mm) surgical margins (HR 4.31, P < 0.001), high-grade lesions (HR 2.28, P < 0.024) and molecular phenotype (HR 5.14, P = 0.001 for Luminal B; HR 6.46, P < 0.001 for HER2 type and HR 3.27, P = 0.028 for triple-negative disease compared with Luminal A DCIS). Independent predictors for invasive recurrence were high Ki67 expression (HR 1.04, P = 0.021) and molecular phenotype (HR 13.4, P = 0.014 for Luminal B; HR 11.4, P = 0.027 for HER2 type and HR 10.3, P = 0.031 for triple negative compared with Luminal A DCIS). CONCLUSIONS: DCIS molecular phenotype predicts for both overall and invasive recurrence. HER2 testing of DCIS could help clinicians individualise the treatment of patients with DCIS.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Carcinoma Intraductal não Infiltrante/química , Imuno-Histoquímica , Técnicas de Diagnóstico Molecular , Recidiva Local de Neoplasia , Neoplasias de Mama Triplo Negativas/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/terapia , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Inglaterra , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
5.
Eur J Surg Oncol ; 40(3): 249-54, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24433818

RESUMO

INTRODUCTION: DCIS accounts for 20% of screen-detected breast cancers, but also presents symptomatically. Historically, approximately 5% of DCIS was thought to be symptomatic, but accurate evaluation of the presentation of symptomatic DCIS is needed to determine its incidence and tumour biology. METHODS: Clinico-pathological details of a consecutive series of patients presenting to a single breast-unit, with a pre-operative diagnosis of DCIS, were selected. Data included age, mode of presentation, pre-operative clinical and radiographical findings. The final tumour histology, operation, size, grade, ER status (and HER2 expression in invasive cases) were recorded. RESULTS: 375 patients had a pre-operative histological diagnosis of DCIS. 308 (82%) screen-detected (median age 59), 67 (18%) presented via symptomatic clinics (median age 50). At final histology 286 (74%) were pure DCIS, and 67 (23%) had an invasive focus. 43% (29/67) of symptomatic cases had an invasive focus at final histology versus 19% (60/308) screen-detected (p ≤ 0.001). 31% (9/29) of symptomatic, versus 10% (6/60) of screen-detected cases with invasion were node positive (p = 0.05). 45% (28/62) intermediate/high-grade symptomatic cases had an invasive focus at final histology, compared to 19% (57/297) intermediate/high-grade screen-detected cases. 86% (212/248) screen-detected pure DCIS was ER positive compared to 68% (26/38) symptomatically presenting pure DCIS (p ≤ 0.001). Overall, 13% (38/248) pure DCIS presented symptomatically (p = 0.001). CONCLUSIONS: Overall, thirteen percent of pure DCIS present symptomatically. Nearly half of symptomatically presenting DCIS at core biopsy has an occult invasive focus and is more frequently ER negative. Symptomatic DCIS with an invasive focus is more likely to have lymph node involvement.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/epidemiologia , Carcinoma Intraductal não Infiltrante/patologia , Detecção Precoce de Câncer/métodos , Adulto , Distribuição por Idade , Idoso , Biópsia por Agulha , Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Incidência , Mamografia/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida
7.
Br J Pharmacol ; 160(2): 334-45, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20331614

RESUMO

BACKGROUND AND PURPOSE: Smoking cessation trials with three high-affinity partial agonists of alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human alpha4beta2 nAChRs. EXPERIMENTAL APPROACH: Rat plasma and brain pharmacokinetics were characterized and used to predict human steady-state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human alpha4beta2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn-over. KEY RESULTS: A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate alpha4beta2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at alpha4beta2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect alpha4beta2 nAChRs. CONCLUSIONS AND IMPLICATIONS: The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other alpha4beta2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy.


Assuntos
Agonistas Nicotínicos/farmacologia , Abandono do Hábito de Fumar/métodos , Tabagismo/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Alcaloides/farmacocinética , Alcaloides/farmacologia , Animais , Azepinas/farmacocinética , Azepinas/farmacologia , Azocinas/farmacocinética , Azocinas/farmacologia , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Encéfalo/metabolismo , Dopamina/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/metabolismo , Masculino , Camundongos , Camundongos Knockout , Agonistas Nicotínicos/farmacocinética , Quinolizinas/farmacocinética , Quinolizinas/farmacologia , Quinoxalinas/farmacocinética , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Distribuição Tecidual , Tabagismo/fisiopatologia , Vareniclina , Xenopus laevis , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
8.
Acta Neurol Scand ; 119(3): 172-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18705678

RESUMO

BACKGROUND: To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer's disease (AD) using a built-in control for the genetic risk factor for AD (apoE-epsilon4 status). METHODS: A prospective, open-label, 6-month pilot medication trial with memantine and follow-up after discontinuance conducted at the Center for Neuroscience in Women's Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community-dwelling postmenopausal women (11 apoE-epsilon4 carriers and 11 apoE-epsilon4 non-carriers) with at least one putative risk factor for AD. RESULTS: ApoE-epsilon4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend-level improvements were seen in motor dexterity of the non-dominant hand and maintained even after drug discontinuance. CONCLUSIONS: Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE-epsilon4 carrier status did not account for observed changes in cognition.


Assuntos
Cognição/efeitos dos fármacos , Demência/prevenção & controle , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Nootrópicos/uso terapêutico , Pós-Menopausa , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Apolipoproteína E4/genética , Demência/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Predisposição Genética para Doença , Humanos , Hipotireoidismo/epidemiologia , Memantina/farmacologia , Transtornos da Memória/prevenção & controle , Pessoa de Meia-Idade , Transtornos do Humor/epidemiologia , Transtornos do Humor/genética , Testes Neuropsicológicos , Nootrópicos/farmacologia , Projetos Piloto , Estudos Prospectivos , Risco , Resultado do Tratamento
9.
Haemophilia ; 14(5): 939-44, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18540889

RESUMO

While factor replacement treatments allow children with haemophilia to lead near normal lives, these treatments can be difficult to administer, especially to younger children. The intervenous infusions required by these treatments can be painful and result in children attempting to avoid treatment by exhibiting a range of inappropriate behaviours. Their children's uncooperative behaviour during prophylaxis was cited by parents as a significant barrier to treatment adherence. This study provides a case illustration of the use of psychological interventions to increase adherence during factor administration. Single-case methodology was used to demonstrate the effectiveness of the psychological interventions including counterconditioning, distraction, and positive differential reinforcement. The intervention resulted in increased adherence across several months of intervention. Psychological interventions can be effectively used by caregivers and care providers to increase adherence in the treatment of haemophilia.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Cooperação do Paciente , Atenção , Terapia Comportamental/métodos , Transtornos do Comportamento Infantil/etiologia , Transtornos do Comportamento Infantil/prevenção & controle , Pré-Escolar , Hemofilia A/psicologia , Humanos , Masculino , Filmes Cinematográficos , Estresse Psicológico/prevenção & controle
10.
Thorax ; 63(8): 717-24, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18263663

RESUMO

BACKGROUND: Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). A study was undertaken to compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation. METHODS: In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, The Netherlands, UK and USA, participants were randomly assigned (1:1) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to week 52. The primary outcome was the biochemically confirmed (exhaled carbon monoxide < or = 10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment. Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction. RESULTS: A total of 376 and 370 participants assigned to varenicline and NRT, respectively, were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; OR 1.70, 95% CI 1.26 to 2.28, p<0.001). The week 52 CAR (NRT, weeks 8-52; varenicline, weeks 9-52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI 0.99 to 1.99, p = 0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) compared with NRT. The most frequent adverse event was nausea (varenicline, 37.2%; NRT, 9.7%). CONCLUSIONS: The outcomes of this trial established that abstinence from smoking was greater and craving, withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT. TRIAL REGISTRATION NUMBER: NCT00143325.


Assuntos
Benzazepinas/administração & dosagem , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Quinoxalinas/administração & dosagem , Abandono do Hábito de Fumar/métodos , Prevenção do Hábito de Fumar , Administração Cutânea , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Reforço Psicológico , Síndrome de Abstinência a Substâncias/etiologia , Resultado do Tratamento , Vareniclina
12.
Neuropharmacology ; 52(3): 985-94, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17157884

RESUMO

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.


Assuntos
Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Agonistas Nicotínicos/farmacologia , Quinoxalinas/farmacologia , Abandono do Hábito de Fumar/métodos , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Linhagem Celular Transformada , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Nicotina/administração & dosagem , Técnicas de Patch-Clamp/métodos , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Autoadministração , Transfecção , Vareniclina
13.
Pharmacol Biochem Behav ; 84(2): 282-93, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16828151

RESUMO

Following active service during the 1990/1991 Gulf conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans' Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that long-term health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated using a non-human primate model, the common marmoset. This paper reports the results from two aspects of the study, brain electrical activity (EEG, collected during performance of a touchscreen mediated discrimination task) and sleep. There were no marked long-term changes in EEG or sleep patterns that could be attributed to vaccines and/or PB administration. The changes that were detected were predominantly time related and independent of treatment. Where statistical differences were detected between treatments, the magnitudes of the difference were relatively minor and therefore not regarded as having long term biological significance.


Assuntos
Discriminação Psicológica/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Brometo de Piridostigmina/farmacologia , Sono/efeitos dos fármacos , Vacinas/farmacologia , Animais , Callithrix , Interações Medicamentosas , Feminino , Masculino , Síndrome do Golfo Pérsico/etiologia , Sono REM/efeitos dos fármacos
14.
Lab Anim ; 39(2): 169-77, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15901360

RESUMO

Patterns of spontaneous activity are valuable reflections of well-being in animals and humans and, because of this, investigations have frequently incorporated some form of activity monitoring into their studies. It is widely believed that activity monitoring, alongside assessments of general behaviour, should be included in initial CNS safety pharmacology screening. As the number of marmoset studies having actimetry as their focus, or as an adjunct, is increasing, we wished to evaluate an alternative approach to those commonly used. The method is based on miniaturized accelerometer technologies, currently used for human activity monitoring.Actiwatch-Minis were used to monitor the activity of two groups of differently housed marmosets for 14 consecutive days. Group A consisted of four mixed-sex pairs of animals and group B comprised eight group-housed males. Activity profiles were generated for weekday and weekend periods. The devices captured quantifiable data which showed differences in total activity between the two differently housed groups and revealed intragroup variations in the temporal spread of activity between weekdays and weekends. The Actiwatch-Mini has been shown to generate retrospective, data-logged activity counts recorded from multiple animals in a single arena by means of non-invasive monitoring.


Assuntos
Ciclos de Atividade/fisiologia , Callithrix/fisiologia , Atividade Motora/fisiologia , Animais , Feminino , Masculino , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Monitorização Fisiológica/veterinária
15.
Eur J Appl Physiol ; 92(1-2): 211-8, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15045505

RESUMO

Magnetic stimulation of the motor cortex with electromyographic recordings from exercising muscles has shown corticospinal excitability to be depressed following exercise. We now investigate whether this depression spreads to non-exercising muscles and its influence on performance. Healthy volunteers made unilateral biceps curls to exhaustion and, in another later session, for 25% of the time to exhaustion. Bilateral motor-evoked potentials (MEPs) in biceps brachii and first dorsal interosseus muscles were measured at 2-min intervals before and after exercise. In another experiment, subjects performed exhaustive curls and, in addition to MEP areas, force production in biceps, hand-grip force, simple reaction times and movement times were measured bilaterally. MEPs were depressed after exhaustive exercise in the exercising biceps for over 60 min; depression was also observed 10-15 min after exercise in the non-exercising biceps but not in the first dorsal interosseus of either hand. The shorter exercise period produced depression of MEPs only in the exercising muscle. After exhaustive exercise maximum voluntary contraction fell in the exercising biceps and this correlated with MEP areas. No reduction in force was seen in the non-exercising biceps but hand-grip force fell slightly in both arms. There was no change in reaction times or movement times. Depression of MEPs can occur in non-exercising homonymous muscles but not in heteronymous muscles and only when exercise levels are high. There was no measurable functional deficit in the non-exercising limb, so we conclude that the reduced corticospinal excitability observed in this limb has little or no consequence on the performance parameters measured.


Assuntos
Potencial Evocado Motor/fisiologia , Exercício Físico/fisiologia , Córtex Motor/fisiologia , Contração Muscular/fisiologia , Fadiga Muscular/fisiologia , Músculo Esquelético/fisiologia , Tempo de Reação/fisiologia , Adaptação Fisiológica/fisiologia , Adolescente , Adulto , Braço/fisiologia , Feminino , Humanos , Masculino , Músculo Esquelético/inervação , Inibição Neural/fisiologia , Sensibilidade e Especificidade
16.
EMBO J ; 20(13): 3473-83, 2001 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-11432834

RESUMO

To survive ionic, pH and pheromone stress, the yeast Saccharomyces cerevisiae activates signaling through the Ca2+-activated phosphatase calcineurin to the transcription factor Crz1p/Tcn1p. We show that the overexpression of SKN7, a response-regulator transcription factor, activates transcription from a calcineurin/Crz1p-dependent response element (CDRE). Ca2+-induced, calcineurin/Crz1p-dependent activation of several genes is reduced in skn7 mutants. Skn7p modulates CDRE-dependent transcription by affecting Crz1p protein levels. Specifically, the rate of Crz1p turnover is increased in skn7 mutants. Calcineurin, but not its phosphatase activity, is required for Skn7p-mediated Crz1p stabilization. Skn7p binds to both calcineurin and Crz1p in vitro, and we suggest that this interaction is required for Skn7p regulation of Crz1p. The DNA-binding and internal coiled-coil domains, but not the response- regulator phosphorylation of Skn7p, are necessary for Crz1p-dependent transcriptional activation and Crz1p stabilization by Skn7 in vivo. The DNA-binding domain of Skn7p is also required for binding to Crz1p and calcineurin in vitro. Thus, we propose that Skn7p protects Crz1p from degradation by binding to it and calcineurin through its DNA-binding domain.


Assuntos
Calcineurina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Fúngica da Expressão Gênica , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/fisiologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , beta-Galactosidase/genética , Proteínas de Ligação a DNA/genética , Genes Reporter , Genótipo , Modelos Biológicos , Plasmídeos , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Transdução de Sinais , Transativadores/genética , Fatores de Transcrição/genética , Dedos de Zinco
17.
Cancer ; 91(8): 1437-43, 2001 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11301390

RESUMO

BACKGROUND: The role of adjuvant therapy in the management of patients with malignant mixed Müllerian tumors (MMMT) of the uterus has not been defined. The outcome of planned multimodality therapy for patients with apparent early stage disease was assessed. METHODS: A pilot study was performed on 38 patients with clinical Stage I or II MMMTs of the uterus who were offered treatment according to a standard protocol. The protocol consisted of removal of the uterus, fallopian tubes, and ovaries and surgical staging followed by tailored radiation therapy and chemotherapy, consisting of cisplatin and epirubicin. RESULTS: The overall survival was 74% (28 of 38 patients), with a mean duration of follow-up for survivors of 55 months (range, 17-121 months). The mean time to death from disease was 26 months (range, 7-87 months). The survival rate for those patients who completed treatment according to the multimodality protocol was 95% (20 of 21 patients), with a disease free survival rate of 90% (19 of 21 patients). The overall survival of patients who did not receive the recommended treatment protocol for various reasons was 47% (8 of 17 patients). An analysis of survival curves demonstrated that there was a significant survival advantage for those patients who completed the treatment according to the multimodality protocol (P = 0.01). CONCLUSIONS: In this pilot study, patients with clinical Stage I or II MMMTs who underwent surgical staging and aggressive adjuvant radiation and chemotherapy had an excellent survival rate. The results justify a randomized prospective study of this approach.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tumor Mulleriano Misto/radioterapia , Tumor Mulleriano Misto/cirurgia , Neoplasias Uterinas/radioterapia , Neoplasias Uterinas/cirurgia , Adulto , Idoso , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Epirubicina/administração & dosagem , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Tumor Mulleriano Misto/tratamento farmacológico , Ovariectomia , Radioterapia Adjuvante , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Uterinas/tratamento farmacológico
18.
Genetics ; 153(3): 1091-103, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10545444

RESUMO

Mitogen-activated protein kinase (MAPK) cascades are frequently used signal transduction mechanisms in eukaryotes. Of the five MAPK cascades in Saccharomyces cerevisiae, the high-osmolarity glycerol response (HOG) pathway functions to sense and respond to hypertonic stress. We utilized a partial loss-of-function mutant in the HOG pathway, pbs2-3, in a high-copy suppressor screen to identify proteins that modulate growth on high-osmolarity media. Three high-copy suppressors of pbs2-3 osmosensitivity were identified: MSG5, CAK1, and TRX1. Msg5p is a dual-specificity phosphatase that was previously demonstrated to dephosphorylate MAPKs in yeast. Deletions of the putative MAPK targets of Msg5p revealed that kss1delta could suppress the osmosensitivity of pbs2-3. Kss1p is phosphorylated in response to hyperosmotic shock in a pbs2-3 strain, but not in a wild-type strain nor in a pbs2-3 strain overexpressing MSG5. Both TEC1 and FRE::lacZ expressions are activated in strains lacking a functional HOG pathway during osmotic stress in a filamentation/invasion-pathway-dependent manner. Additionally, the cellular projections formed by a pbs2-3 mutant on high osmolarity are absent in strains lacking KSS1 or STE7. These data suggest that the loss of filamentation/invasion pathway repression contributes to the HOG mutant phenotype.


Assuntos
Glicogênio/genética , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/fisiologia , Clonagem Molecular , Genótipo , Glicerol/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Concentração Osmolar , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Transdução de Sinais , Sorbitol/farmacologia , Supressão Genética/efeitos dos fármacos , Transcrição Gênica
19.
J Lab Clin Med ; 133(2): 161-70, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9989768

RESUMO

Preliminary in vivo studies suggested that oral dextran sulfate was poorly absorbed, but investigations were limited by inadequate methods for measuring the drug in the body. To determine absorption in HIV-positive subjects, hydrogenated dextran sulfate, average molecular weight 8000 (Usherdex 8), was orally administered in a short-term (single dose, 4 g/day for 5 days, 7 subjects) and in a long-term study (1 g, 4 times per day for 29 to 335 days, 8 subjects), which was a continuation of the short-term study with the inclusion of an additional subject. When an agarose gel electrophoresis technique with toluidine blue staining was used, the drug was recovered from plasma (67%, peak 2.2 microg/mL) and circulating peripheral blood lymphocyte (PBL) samples (50%, peak 333 microg/L blood) obtained at 5 and 15 minutes and 1, 3, 6, and 24 hours after the first day's dose and from plasma (56%) and PBL samples (38%) obtained 5 minutes after administration on 4 subsequent days in the short-term study. In the long-term study, the drug was found in plasma (67%, peak 2.4 microg/mL) and PBL samples (25%, peak 126 microg/L blood) obtained at monthly visits within 4 hours of the last dose. The drug was found in all urine samples from all subjects in both studies (short-term study, 24-hour samples up to 4 days after the final dose; long-term study, monthly samples within 4 hours of the last dose). In the long-term study, bone marrow preparations from 3 subjects showed metachromatic inclusions present in reticular cells when the cells were stained with toluidine blue, indicating the presence of sulfated polyanions. A significant rise in activated partial thromboplastin time and a drop in platelet count (P < .025) were demonstrated, with thrombocytopenia developing in 3 patients. Mild-to-moderate gastrointestinal disturbances were experienced by 6 subjects in the short-term study and by all subjects in the long-term study. One subject experienced mild central nervous system symptoms in the short-term study. These results indicate that dextran sulfate is absorbed after oral administration; therefore, further studies on its efficacy, particularly in the early stages of the disease, along with additional observations on its toxicity, are warranted.


Assuntos
Antivirais/farmacocinética , Sulfato de Dextrana/farmacocinética , Soropositividade para HIV/metabolismo , HIV-1/imunologia , Absorção , Administração Oral , Adulto , Antivirais/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Relação CD4-CD8/efeitos dos fármacos , Sulfato de Dextrana/uso terapêutico , Eletroforese em Gel de Ágar , Soropositividade para HIV/imunologia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino
20.
Gynecol Oncol ; 71(1): 59-63, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9784320

RESUMO

Uterine papillary serous carcinoma (UPSC) is an uncommon but aggressive type of endometrial cancer associated with rapid progression of disease and poor prognosis. We investigated 23 cases of UPSC. p53 expression was studied in archival paraffin-embedded tissue by immunohistochemistry. Eleven tumors (47.8%) showed p53 overexpression whereas 12 tumors (52.2%) were p53 negative. One of 8 stage I/II (12.5%) and 10/15 stage III/IV (66.6%) tumors revealed p53 staining (P = 0.027). The median overall survival was 43.3 months. Patients with advanced-stage (III, IV) disease had a 5-year overall survival probability (5-year OS%) of 24% compared to 100% in those in stages I and II (log-rank, P = 0.018). Myometrial invasion, lymphatic space invasion, or lymph node involvement did not correlate with the 5-year OS of these patients. Patients whose tumors overexpressed p53 had a significantly shorter survival than those whose tumors did not (P = 0.033). This study confirms the influence of p53 overexpression on survival in UPSC patients.


Assuntos
Cistadenocarcinoma Papilar/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Uterinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cistadenocarcinoma Papilar/diagnóstico , Cistadenocarcinoma Papilar/mortalidade , Cistadenocarcinoma Papilar/patologia , Intervalo Livre de Doença , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia
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