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The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases. Here we found that MSK1 and MSK2 were needed to limit the production of proinflammatory cytokines in response to stimulation of primary macrophages with lipopolysaccharide. By inducing transcription of the mitogen-activated protein kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10, MSK1 and MSK2 exerted many negative feedback mechanisms. Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1. Mice doubly deficient in MSK1 and MSK2 were hypersensitive to lipopolysaccharide-induced endotoxic shock and showed prolonged inflammation in a model of toxic contact eczema induced by phorbol 12-myristate 13-acetate. Our results establish MSK1 and MSK2 as key components of negative feedback mechanisms needed to limit Toll-like receptor-driven inflammation.
Assuntos
Lipopolissacarídeos/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/enzimologia , Proteínas Quinases Ativadas por Mitógeno/deficiência , Receptores Toll-Like/imunologia , Fatores de Transcrição/metabolismo , Animais , Lipopolissacarídeos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/imunologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , Receptores Toll-Like/efeitos dos fármacos , Transcrição GênicaRESUMO
Feedbacks between surface and deep Earth processes in collisional mountain belts depend on how erosion and topographic relief vary in space and time. One outstanding unknown lies in how rock strength influences bedrock river morphology and thus mountain relief. Here, we quantify boulder cover and channel morphology using uncrewed aerial vehicle surveys along 30 kilometers of bedrock-bound river corridors throughout the Taiwan Central Range where regional gradients in rock properties relate to tectonic history. We find that boulder size systematically increases with increasing metamorphic grade and depth of exhumation. Boulder size correlates with reach-scale channel steepness but does not explain observations of highly variable channel width. Transport thresholds indicate that rivers are adjusted to mobilize boulders and are well in excess of the threshold to transport gravel and cobbles, as previously assumed. The linkage between metamorphic history, boulder size, and channel steepness reveals how rock properties can influence feedbacks between tectonics and topography throughout the life span of a mountain range.
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Background: People who enter and leave places of incarceration experience considerable health inequities and are at increased risk of premature death compared to the general population. Causes of premature death in this population vary markedly between countries and so country-specific information is needed. Additionally, there is a lack of large population-based studies which can disaggregate mortality risk based on person and incarceration factors. This study is the first examination of mortality in the period following release from incarceration in New Zealand. Methods: We linked deidentified administrative data on incarceration and release between 1 January 1998 and 31 December 2016 with national mortality data for the same period to examine mortality after release in those who had been incarcerated for at least 1 day. Age standardised mortality rates and mortality ratios compared to the general New Zealand population were calculated separately for men and women, for releases from remand compared with prison, and by cause of death and time since release. Results: 90,195 individuals (13% women, 49% Maori) were followed up for 9.4 years after release from incarceration, with 4,764 deaths over the follow-up period. The overall standardised mortality ratio was 3.3 (95% CI 3.2, 3.4) compared to the general population, and higher for women (3.8) than men (2.7). The most common causes of death were cardiovascular disease, cancer and suicide. Rates of death were similar following release from remand versus prison, however suicide rates were highest following release from remand. Regardless of the type of incarceration, mortality was highest in the first month after release. Conclusion: Experience of incarceration in New Zealand is associated with high rates of mortality from both chronic conditions and external causes. There are urgent policy imperatives to recognise and actively address the increased health and mortality risks faced by people released from New Zealand prisons.
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Phosphorylation of Ser133 in the transcription factor CREB is an important mechanism for regulating its transcriptional activity, however recent work has suggested significant roles for other regulatory inputs into CREB. To allow study of this in vivo, we have generated a Ser133 to alanine knockin mutation in the mouse CREB locus. As CREB knockout is perinatal lethal, a minigene strategy was used to allow conditional knockin of the Ser133Ala mutation in adult mice using Cre recombinase. While some expression of the mutated protein was observed prior to Cre expression, following Cre expression in either T cells or neurons only the mutated CREB protein was detected.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Técnicas de Introdução de Genes/métodos , Mutação , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Integrases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
We draw upon two recent reports from the Chief Ombudsman that describe the prison management of people assessed at risk of self-harm or suicide, as cruel, inhuman or degrading treatment or punishment. People were mechanically restrained on 'tie-down' beds by their legs, arms and chest or placed in waist restraints with their hands cuffed behind their backs over prolonged periods. These practices occurred at the direction of, or were approved by, health professionals. We highlight ethical issues for health professionals party to 'tie down' and examine the current guidance and regulatory framework for health professionals working in coercive environments. This article is timely in the context of current Government Inquiries into the criminal justice system and mental health and addictions, the review of the health and disability system, the Correction's Amendment Bill before parliament, and Government plans to expand Waikeria prison to include a 100-bed mental health facility. We call for the use of 'tie down' to be abolished in New Zealand prisons, and for all health professionals to refuse to participate in this practice. Government must make provision for sufficient forensic mental health capacity and capability in the health sector, and ensure timely, equitable access to high-quality, trauma-informed and culturally safe services.
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Serviços de Saúde Mental/legislação & jurisprudência , Prisioneiros/legislação & jurisprudência , Prisões/legislação & jurisprudência , Restrição Física/legislação & jurisprudência , Internação Compulsória de Doente Mental/legislação & jurisprudência , Humanos , Avaliação das Necessidades/legislação & jurisprudência , Nova Zelândia , PuniçãoRESUMO
p38 mitogen-activated protein kinases (MAPKs) are activated primarily in response to inflammatory cytokines and cellular stress, and inhibitors which target the p38alpha and p38beta MAPKs have shown potential for the treatment of inflammatory disease. Here we report the generation and initial characterization of a knockout of the p38beta (MAPK11) gene. p38beta-/- mice were viable and exhibited no apparent health problems. The expression and activation of p38alpha, ERK1/2, and JNK in response to cellular stress was normal in embryonic fibroblasts from p38beta-/- mice, as was the activation of p38-activated kinases MAPKAP-K2 and MSK1. The transcription of p38-dependent immediate-early genes was also not affected by the knockout of p38beta, suggesting that p38alpha is the predominant isoform involved in these processes. The p38beta-/- mice also showed normal T-cell development. Lipopolysaccharide-induced cytokine production was also normal in the p38beta-/- mice. As p38 is activated by tumor necrosis factor, the p38beta-/- mice were crossed onto a TNFDeltaARE mouse line. These mice overexpress tumor necrosis factor, which results in development symptoms similar to rheumatoid arthritis and inflammatory bowel disease. The progression of these diseases was not however moderated by knockout of p38beta. Together these results suggest that p38alpha, and not p38beta, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p38beta during the development of p38 inhibitors.
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Deleção de Genes , Proteína Quinase 11 Ativada por Mitógeno/deficiência , Proteína Quinase 11 Ativada por Mitógeno/metabolismo , Animais , Artrite/genética , Artrite/metabolismo , Artrite/patologia , Diferenciação Celular , Células Cultivadas , Doença Crônica , Doença de Crohn/genética , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Citocinas/biossíntese , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Isoenzimas/genética , Isoenzimas/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Transgênicos , Proteína Quinase 11 Ativada por Mitógeno/genética , Transdução de Sinais/genética , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
It has been proposed that p38 mitogen-activated protein kinase (MAPK) isoforms sensitive to the pyridinylimidazole compounds SB 203580 and SB 202190 may participate in the acute insulin-dependent activation of glucose transporters recruited to the plasma membrane of adipocytes and skeletal muscle. Here, we explore whether these kinases support the insulin stimulation of glucose uptake in these tissues by investigating the effects of a genetic loss in p38beta and that of the p38 MAPK inhibitor SB 203580. Glucose uptake in adipocytes and soleus muscle was stimulated by insulin by up to fourfold irrespective of whether tissues were isolated from wild-type or p38beta-null mice. Consistent with this finding, mice lacking p38beta exhibited normal glucose tolerance, insulinemia, and glycemia compared with their wild-type counterparts. Insulin-stimulated glucose uptake was not inhibited by SB 203580 when adipocytes were preincubated with the drug at a cytocrit of 50%, but intriguingly, uptake was suppressed (by 35%) when the cytocrit was reduced by one-half. Despite the activation of glucose uptake at the higher cytocrit, insulin failed to induce any detectable activation of p38 MAPK, whereas p38 signaling was robustly activated by anisomycin in a SB 203580-sensitive manner. Although insulin also failed to induce any detectable activation of p38 MAPK in muscle, insulin-dependent glucose uptake was reduced by SB 203580 (approximately 44%) in muscle of both wild-type and p38beta-null mice. Our results indicate that p38beta is not required for insulin-stimulated glucose uptake in adipocytes or muscle. Moreover, given that insulin fails to promote any significant activation of p38 MAPK in these tissues and the finding that sensitivity of glucose uptake, but not that of the kinase, to SB 203580 can be influenced by cytocrit, we suggest that p38 signaling is unlikely to participate in any putative activation of transporters recruited to the cell surface by insulin and that SB 203580 suppresses insulin-stimulated glucose transport by a mechanism unrelated to its inhibitory effect on p38 MAPK.
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Tecido Adiposo/enzimologia , Glucose/metabolismo , Insulina/farmacologia , Músculo Esquelético/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Anisomicina/farmacologia , Transporte Biológico/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal , Deleção de Genes , Imidazóis/farmacologia , Insulina/sangue , Insulina/metabolismo , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Piridinas/farmacologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Collegiate recreation student employment opportunities are found in such areas as facilities, intramurals, aquatics, fitness, and outdoor adventure. Recreation is one of the largest providers of student employment opportunities on campuses across the country with an important role in student employee leadership development.
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Emprego/psicologia , Liderança , Recreação , Estudantes/psicologia , Universidades , HumanosRESUMO
AIMS: This article explores how primary health care policy changes in New Zealand over the last decade have impacted on primary care access equity and avoidable hospital admissions. METHODS: The national Ambulatory Sensitive Hospitalisations (ASH) data trends by age, ethnicity and area level deprivation were analysed in relation to the Primary Health Care policy initiatives for the period 2002 to 2014. RESULTS AND CONCLUSIONS: Changes in primary care access over the decade have led to improvement in ASH indicators for parts of the population, but not for others. ASH rates decreased very significantly for children, especially in the 0-4 age group. These trends began in 2004, with decreases most marked for Pacific children, and those from the most deprived neighbourhoods. Inequalities in ASH rates for children between ethnic groups and levels of deprivation have substantially decreased. On the other hand, there has been a significant increase in ASH rates and inequalities for Pacific peoples in the 45 to 64 age group. Maori in the same age band show a modest reduction in ASH rates, with inequalities compared with the rest of the population remaining unchanged. Inequalities in ASH rates between 45-65 year olds living in different levels of deprivation remain large and unchanged, indicative of the recalcitrant nature of inequalities in primary care access for the adult population. Major policy initiatives undertaken by the government during this period have significantly affected primary care access. These include the New Zealand Health Strategy, the Primary Health Care Strategy, the creation of District Health Boards and Primary Health Organisations, and free care to under 6-year-olds. In the latter part of the decade, high-level target setting by successive Ministers is also affecting system performance. We conclude that the success in reducing inequality in access to primary care for children needs to be intensified, and the same principles applied to the adult population groups.
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Etnicidade/estatística & dados numéricos , Política de Saúde , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Atenção Primária à Saúde , Atenção Secundária à Saúde , Classe Social , Cobertura Universal do Seguro de Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Nova Zelândia , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
BACKGROUND: ERK5 is a member of the mitogen activated protein kinase family activated by certain mitogenic or stressful stimuli in cells, but whose physiological role is largely unclear. RESULTS: To help determine the function of ERK5 we have used gene targeting to inactivate this gene in mice. Here we report that ERK5 knockout mice die at approximately E10.5. In situ hybridisation for ERK5, and its upstream activator MKK5, showed strong expression in the head and trunk of the embryo at this stage of development. Between E9.5 and E10.5, multiple developmental problems are seen in the ERK5-/- embryos, including an increase in apoptosis in the cephalic mesenchyme tissue, abnormalities in the hind gut, as well as problems in vascular remodelling, cardiac development and placental defects. CONCLUSION: Erk5 is essential for early embryonic development, and is required for normal development of the vascular system and cell survival.
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Embrião de Mamíferos/anormalidades , Proteínas Quinases Ativadas por Mitógeno/deficiência , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Placenta/anormalidades , Abdome/anormalidades , Abdome/embriologia , Animais , Cruzamentos Genéticos , Embrião de Mamíferos/irrigação sanguínea , Embrião de Mamíferos/enzimologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Genes Letais/fisiologia , Cabeça/anormalidades , Cabeça/embriologia , Extremidade Inferior/embriologia , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Proteína Quinase 7 Ativada por Mitógeno , Quinases de Proteína Quinase Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Neovascularização Fisiológica/fisiologia , Placenta/embriologia , Placenta/enzimologiaRESUMO
Echovirus type 33 (E33) is a relatively uncommon enterovirus. An E33 outbreak during the winter of 2000 in New Zealand led to 75 virologically-confirmed cases of E33 infection (2.6 cases per 100,000 individuals). Sixty-six (88%) of the 75 patients were aged <30 years, with the highest rates of infection recorded in Maori and Pacific ethnic groups. Overall, 47 (84%) of 56 patients whose cases were analyzed had either aseptic meningitis or encephalitis. Central nervous system involvement was more common after infancy (43 of 45 non-infant patients vs. 4 of 11 infants [relative risk, 2.6; 95% CI, 1.5-4.3]). Two infants died, including a neonate with fulminant hepatitis. Independent of symptom duration, neutrophil-predominant pleocytosis was detected in 17 (41%) of 41 cerebrospinal fluid specimens. Virus isolates could not be definitively typed by antibody neutralization testing but were identified as E33 by partial sequencing of the VP-1 capsid gene. The isolates were closely related to strains from Australia and Oman. Molecular typing, together with a serotype-specific E33 PCR, improved the speed and effectiveness of the outbreak investigation.
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Surtos de Doenças , Enterovirus Humano B/isolamento & purificação , Infecções por Enterovirus/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/mortalidade , Enterovirus Humano B/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/mortalidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Sorotipagem/métodosRESUMO
AIMS: To compare heart failure outcomes for Mäori and non-Mäori New Zealanders. METHODS: Restrospective analysis of New Zealand mortality (1988-97) and hospital admissions (1989-98) due to heart failure for Mäori and non-Mäori, aged 45 years and over. RESULTS: Mortality from heart failure was more than 8.8 times higher among Mäori males aged 45-64 years than non-Mäori (95% confidence interval 7.6 to 10.1), and 3.5 (3.1 to 4.1) times higher among Mäori aged 65 years and over. Mortality ratios for females were similar. Hospital admissions with a primary diagnosis of heart failure averaged eight times higher among Mäori males aged 45-64 and nine times higher among Mäori females compared to non-Mäori. Mäori males and females aged 65 years and over had three and four times the non-Mäori rate of admission. CONCLUSIONS: Disparities between Mäori and non-Mäori in outcomes for heart failure are high in New Zealand. Effective, evidence-based interventions have not yet impacted on populations most 'at risk'.
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Insuficiência Cardíaca/etnologia , Insuficiência Cardíaca/mortalidade , População Branca , Idoso , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Estudos RetrospectivosRESUMO
AIMS: This paper provides New Zealand evidence on the effectiveness of primary care investment, measured through the Capital and Coast District Health Board's (DHB) Primary Health Care Framework. The Framework was developed in 2002/2003 to guide funding decisions at a DHB level, and to provide a transparent basis for evaluation of the implementation of the Primary Health Care Strategy in this district. METHODS: The Framework used a mixed method approach; analysis was based on quantitative and qualitative data. RESULTS AND CONCLUSIONS: This article demonstrates the link between investment in primary health care, increased access to primary care for high-need populations, workforce redistribution, and improved health outcomes. Over the study period, ambulatory sensitive hospitalisations and emergency department use reduced for enrolled populations and the District's immunisation coverage improved markedly. Funding and contracting which enhanced both 'mainstream' and 'niche' providers combined with community-based health initiatives resulted in a measurable impact on a range of health indicators and inequalities. Maori primary care providers improved access for Maori but also for their enrolled populations of Pacific and Other ethnicity. Growth and redistribution of primary care workforce was observed, improving the availability of general practitioners, nurses, and community workers in poorer communities.
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Administração Financeira/estatística & dados numéricos , Promoção da Saúde/economia , Acessibilidade aos Serviços de Saúde/economia , Serviços de Saúde do Indígena/economia , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Atenção Primária à Saúde/economia , Centros Comunitários de Saúde/organização & administração , Eficiência Organizacional , Reforma dos Serviços de Saúde/economia , Promoção da Saúde/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Serviços de Saúde do Indígena/estatística & dados numéricos , Humanos , Investimentos em Saúde/estatística & dados numéricos , Nova Zelândia , Atenção Primária à Saúde/estatística & dados numéricos , Indicadores de Qualidade em Assistência à Saúde , Populações Vulneráveis/estatística & dados numéricosRESUMO
AIM: To determine whether health promotion activities in March-August 2009 increased sore throat swabbing rates among Flaxmere (Hawke's Bay, New Zealand) children aged 5-14 years, and in particular among Maori and Pacific children. METHOD: Monthly totals of Hawke's Bay bacterial throat swabs for the period March-October 2008 and March-October 2009 were obtained. Using Poisson regression, the 2008 and 2009 test rates for Flaxmere children residing in the target area during the intervention were compared with non-Flaxmere children. Flaxmere test rates were determined for Maori or Pacific children and non-Maori non-Pacific children separately. RESULTS: Flaxmere children had a higher pre-intervention bacterial throat swab rate, compared to non-Flaxmere children (6.0% vs 3.2%; p<0.001). The throat swab rate increased significantly for Flaxmere children during the intervention period, compared to both the previous year (1.6; 1.3-2.0) and compared to the increase observed among non-Flaxmere children (1.4; 1.1-1.8). Subanalysis among Flaxmere children found a significant increase in the throat swab rate of Maori and Pacific children (1.8; 1.4-2.4). CONCLUSIONS: A demonstrable increase in throat swabbing rates among high-risk Flaxmere children was observed following a combination of health promotion interventions. The increase in throat swabbing rates observed among Maori and Pacific children suggest that the intervention was effective for children with the highest risk.
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Promoção da Saúde , Faringite/microbiologia , Prevenção Primária , Febre Reumática/prevenção & controle , Manejo de Espécimes/estatística & dados numéricos , Infecções Estreptocócicas/diagnóstico , Adolescente , Criança , Pré-Escolar , Etnicidade/estatística & dados numéricos , Educação em Saúde , Humanos , Nova Zelândia/epidemiologiaRESUMO
Activation of the p38 MAP kinase pathways is crucial for the adaptation of mammalian cells to changes in the osmolarity of the environment. Here we identify SAP97/hDlg, the mammalian homologue of the Drosophila tumour suppressor Dlg, as a physiological substrate for the p38gamma MAP kinase (SAPK3/p38gamma) isoform. SAP97/hDlg is a scaffold protein that forms multiprotein complexes with a variety of proteins and is targeted to the cytoskeleton by its association with the protein guanylate kinase-associated protein (GKAP). The SAPK3/p38gamma-catalysed phosphorylation of SAP97/hDlg triggers its dissociation from GKAP and therefore releases it from the cytoskeleton. This is likely to regulate the integrity of intercellular-junctional complexes, and cell shape and volume in response to osmotic stress.