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1.
Child Care Health Dev ; 41(5): 712-21, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25623331

RESUMO

BACKGROUND: There is limited information involving population data about the role of maternal health, fetal growth and neonatal health on children's developmental status at ages 4-7 years. Our aim was to determine the contribution of maternal, fetal and neonatal health to developmental status at ages 4-7 years. METHODS: In this 7-year follow-up prospective cohort study, a sample of 26,803 mothers participated in the beginning. Among their children, 19,187 voluntarily completed the development screening test or the social life ability survey, which were designed for two different age groups (<6 or ≥ 6 years old, respectively). Logistic regression analysis was used to link the data with the prenatal outcome card and interview questionnaire applied to pregnant women in previous study, to the analysis of various related factors such as demographic, socio-economic, disease and menstrual history, marriage and pregnancy care. RESULT: Univariate and multivariate logistic regression analysis were used separately in two age groups [4-6 (n = 8439) and 6-7 (n = 10,748) years old] to analyse relative factors. Maternal age of 25-30 years, maternal education of high school and greater, family income and not drinking during pregnancy were associated with higher scores in development. CONCLUSION: Both preconception and pregnancy health education and health care are the important maternal factors closely associated with children's cognitive and social competence. Public health policies for preconception care and public welfare for high-quality childcare are essential for improving children's life.


Assuntos
Deficiências do Desenvolvimento/epidemiologia , Mães , Cuidado Pré-Concepcional/estatística & dados numéricos , Cuidado Pré-Natal/estatística & dados numéricos , Adulto , Desenvolvimento Infantil , Pré-Escolar , China/epidemiologia , Deficiências do Desenvolvimento/etiologia , Feminino , Seguimentos , Indicadores Básicos de Saúde , Humanos , Modelos Logísticos , Masculino , Mães/psicologia , Formulação de Políticas , Vigilância da População , Gravidez , Estudos Prospectivos , Saúde Pública , Medição de Risco , Fatores de Risco
2.
Int J Clin Pract ; 67(6): 576-84, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23679909

RESUMO

AIMS: The aim of this study was to explore the factors associated with the occurrence, subsequent prognoses and need for additional medications following cutaneous adverse drug reactions (ADRs) among inpatients. METHODS AND MEASURES: This is a case-control study, nested in a large cohort study of 473,446 inpatients hospitalised from 2005 to 2008, examined cutaneous ADRs. A 1 : 5 strategy of individually matching age and principal diagnosis was applied to the data of cases (n = 700) and corresponding controls (n = 3365).The severity of ADRs was evaluated using Naranjo algorithms by senior pharmacists in the medical centre. Medical chart reviews and claim data analyses were analysed to explore risk factors associated with the occurrence and impact of cutaneous ADRs. Economic impacts in terms of length of stay and medical expenses were also analysed. RESULTS: The number of drug prescriptions and secondary diagnoses, and the department to which the patient was admitted, significantly contributed to the risk of cutaneous ADRs and subsequent prognosis. In addition to physician's seniority, the Naranjo score was also positively associated with patients' prognosis. Medical expenses associated with cutaneous ADRs patients ($US 916) were more than 2.5-fold higher than those patients who were not afflicted ($US 318). CONCLUSION: The study identified risk factors for cutaneous ADRs in terms of both patient characteristics and drug complexity. The present analyses indicate characteristics and mechanisms of cutaneous ADRs among inpatients, which provide clues for future intervention strategies and management issues in healthcare settings.


Assuntos
Toxidermias/etiologia , Sistemas de Notificação de Reações Adversas a Medicamentos , Estudos de Casos e Controles , Toxidermias/economia , Interações Medicamentosas , Feminino , Financiamento Pessoal , Humanos , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Honorários por Prescrição de Medicamentos , Prognóstico , Fatores de Risco
3.
J Med Chem ; 41(22): 4224-31, 1998 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-9784097

RESUMO

A series of 15-mer oligodeoxynucleotide analogues were synthesized, and their thrombin inhibitory activities in vitro and in vivo were evaluated. These oligodeoxynucleotide analogues share the same sequence (GGTTGGTGTGGTTGG) but have one or more phosphodiester linkages replaced by a neutral formacetal group. The results obtained from monosubstitutions show that no single phosphodiester group is critical for the thrombin inhibitory activity, suggesting that the interaction between the oligodeoxynucleotide and thrombin is based on a multiple-site charge-charge interaction. Analysis of the effects of different phosphodiester replacements indicates that the backside and left side of the chairlike structure formed by the molecule may be involved in binding with thrombin, presumably by having direct contacts with the anion-binding exosite of the enzyme. For the oligodeoxynucleotides containing two noncontiguous formacetal groups, the effect of the disubstitution is the sum of the effects obtained from the corresponding two monosubstitutions. Infusion of an oligodeoxynucleotide containing four formacetal groups into monkeys showed an increased in vivo anticoagulant effect and an extended in vivo half-life compared to the unmodified oligodeoxynucleotide.


Assuntos
Acetais/química , Formiatos/química , Oligonucleotídeos/síntese química , Inibidores de Serina Proteinase/síntese química , Trombina/antagonistas & inibidores , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Humanos , Técnicas In Vitro , Infusões Intravenosas , Macaca fascicularis , Oligonucleotídeos/química , Oligonucleotídeos/farmacocinética , Oligonucleotídeos/farmacologia , Tempo de Protrombina , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade
4.
Biochemistry ; 34(46): 15328-33, 1995 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-7578149

RESUMO

Tissue factor (TF) is a transmembrane protein that functions in the initiation of blood coagulation in vivo. At sites of vascular injury, TF serves as a cell-surface receptor for the serine protease factor VIIa (FVIIa), forming an enzyme--cofactor complex and enhancing the catalytic activity of FVIIa. Tissue factor, along with the receptors for alpha- and gamma-interferons, is a member of the class 2 cytokine receptor superfamily. Crystallographic analysis demonstrated that the extracellular domain of TF consists of two immunoglobulin-like domains joined by a linker region. Each domain is comprised of two antiparallel beta-sheets containing seven conserved beta-strands separated by more variable loop regions. Extensive mutagenesis has been performed in order to map the FVIIa binding site on TF. Results indicated that the discontinuous binding site for FVIIa lies at the domain--domain interface and includes residues from extended loops and beta-strands within both the N- and C-terminal domains. Our previous study provided evidence that three consecutive residues (D44, W45, K46) within the TF loop region between beta-strands C and C' of the N-terminal domain were important for interactions with FVIIa. We have presently extended our alanine-scanning mutagenesis to include the residues within the flanking beta-strands. Thirteen sTF mutants were screened for their ability to enhance FVIIa activity. Three residues within strand C (Y34, Q37, I38) and two residues within C' (K48, Y51) were shown to be important for TF cofactor function.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Fator VIIa/antagonistas & inibidores , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacologia , Tromboplastina/antagonistas & inibidores , Tromboplastina/química , Alanina , Sequência de Aminoácidos , Sítios de Ligação , Ciclização , Escherichia coli/genética , Fator VIIa/metabolismo , Expressão Gênica , Dados de Sequência Molecular , Mutagênese , Conformação Proteica , Estrutura Secundária de Proteína , Proteínas Recombinantes de Fusão , Solubilidade
5.
Biochemistry ; 35(51): 16449-57, 1996 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-8987977

RESUMO

Previous alanine scanning mutagenesis of thrombin revealed that substitution of residues W50, K52, E229, and R233 (W60d, K60f, E217, and R221 in chymotrypsinogen numbering) with alanine altered the substrate specificity of thrombin to favor the anticoagulant substrate protein C. Saturation mutagenesis, in which residues W50, K52, E229, and R233 were each substituted with all 19 naturally occurring amino acids, resulted in the identification of a single mutation, E229K, that shifted the substrate specificity of thrombin by 130-fold to favor the activation of the anticoagulant substrate protein C over the procoagulant substrate fibrinogen. E229K thrombin was also less effective in activating platelets (18-fold), was resistant to inhibition by antithrombin III (33-fold and 22-fold in the presence and absence of heparin), and displayed a prolonged half-life in plasma in vitro (26-fold). Thus E229K thrombin displayed an optimal phenotype to function as a potent and specific activator of endogenous protein C and as an anticoagulant in vivo. Upon infusion in Cynomolgus monkeys E229K thrombin caused an anticoagulant effect through the activation of endogenous protein C without coincidentally stimulating fibrinogen clotting and platelet activation as observed with wild-type thrombin. In addition, E229K thrombin displayed enhanced potency in vivo relative to the prototype protein C activator E229A thrombin. This enhanced potency may be attributable to decreased clearance by antithrombin III, the principal physiological inhibitor of thrombin.


Assuntos
Anticoagulantes/farmacologia , Engenharia de Proteínas , Trombina/genética , Trombina/farmacologia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fibrinogênio/metabolismo , Meia-Vida , Humanos , Cinética , Macaca fascicularis , Modelos Moleculares , Mutagênese Sítio-Dirigida , Ativação Plaquetária/efeitos dos fármacos , Proteína C/metabolismo , Conformação Proteica , Especificidade por Substrato , Trombina/metabolismo
6.
Nature ; 378(6555): 413-6, 1995 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-7477382

RESUMO

At sites of vascular injury, thrombin interacts with multiple procoagulant substrates, to mediate both fibrin clotting and platelet aggregation. But upon binding to thrombomodulin on the vascular endothelium, thrombin instead activates protein C, thereby functioning as an anticoagulant and attenuating clot formation. Upon infusion in vivo, both the procoagulant and anticoagulant effects of thrombin were observed. Preliminary studies indicating that thrombin's protein C activating and fibrinogen clotting activities could be dissociated by mutagenesis suggested to us that a thrombin variant that lacked procoagulant activity while retaining anticoagulant function might be an attractive antithrombotic agent. Using protein engineering, we introduced a single substitution, E229A, that substantially shifted thrombin's specificity in favour of the anticoagulant substrate, protein C. In monkeys, this modified thrombin functioned as an endogenous protein C activator demonstrating dose-dependent, reversible anticoagulation without any indication of procoagulant activity. Notably, template bleeding times were not prolonged, suggesting a reduced potential for bleeding complications.


Assuntos
Anticoagulantes/farmacologia , Trombina/farmacologia , Sequência de Aminoácidos , Animais , Anticoagulantes/química , Tempo de Sangramento , Ativação Enzimática , Humanos , Macaca fascicularis , Dados de Sequência Molecular , Mutagênese , Proteína C/metabolismo , Conformação Proteica , Engenharia de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Especificidade por Substrato , Trombina/química , Trombina/genética
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