RESUMO
ISSUE ADDRESSED: Women are 'at-risk' population for failing to meet muscle strengthening guidelines. Health benefits specific to this exercise mode include maintenance of muscle mass, which is associated with reduced risk of chronic disease and falls. Of significance is the progressive decline in muscle strength exercise participation in women aged 35-54 in Australia. This period is critical for maintaining muscle strength as it establishes foundations for older women's engagement. This integrative review examined available evidence regarding factors influencing muscle strength exercise participation, specifically in women aged 35-54. METHODS: Seven databases were searched. Study inclusion criteria were: (1) peer reviewed, (2) English language, (3) sample populations of healthy female adults or general adult sample population differentiating females from males, (4) mean age between 35 and 54 years, (5) focused on muscle strength exercise and measured as the primary outcome factors of participation in muscle strength exercise. FINDINGS: Five of 1895 studies met inclusion criteria. Five key factors were associated with participation in muscle strength exercise of women aged 35-54 years: perceived time constraints; knowledge and education; modality and intensity; social support and behavioural strategies. CONCLUSIONS: Focused education on strength exercise and guidelines, plus initiatives and strategies that suit the needs of this cohort, are necessary to achieve health and wellbeing benefits. Responsive approaches by health professionals to these women's circumstances can potentially address current low participation levels. SO WHAT?: Creating conditions where health professionals respect a woman's exercise preferences can positively impact these women's musculoskeletal health into older age.
RESUMO
BACKGROUND: Limited epidemiological evidence suggests that low maternal iron status and anaemia in pregnancy may increase the risk of childhood respiratory and allergic outcomes. OBJECTIVES: To investigate the relation between maternal haemoglobin concentrations in pregnancy and childhood respiratory and allergic outcomes. METHODS: In the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined associations of maternal haemoglobin concentrations (g/dL) in pregnancy with hayfever, eczema, wheezing, doctor-diagnosed asthma, allergic sensitisation and total IgE at 7 years, and with lung function at 8-9 years in the offspring, after controlling for potential confounders (N = 3234-5335). RESULTS: Maternal haemoglobin was not associated with offspring hayfever, eczema, wheezing or asthma. However, the first haemoglobin measurement in pregnancy (<18 weeks' gestation) and the last measurement (>28 weeks' gestation) were negatively associated with allergic sensitisation (adjusted odds ratio [95% CI] per g/dL 0.91 [0.83 to 0.99] and 0.90 [0.83 to 0.98], respectively). The last haemoglobin measurement was also negatively associated with total IgE (adjusted geometric mean ratio 0.94 [0.88 to 0.99]). Anaemia (haemoglobin <11 g/dL) in late pregnancy was negatively associated with forced vital capacity (difference in standard deviation score -0.07 [-0.13 to -0.01]). CONCLUSIONS AND CLINICAL RELEVANCE: Lower maternal haemoglobin in pregnancy may be a risk factor for allergic sensitisation, elevated IgE and lower FVC in childhood, which may reflect effects of lower prenatal iron status. However, maternal haemoglobin was not associated with risk of childhood asthma or other allergic disorders.
Assuntos
Hemoglobinas , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Doenças Respiratórias/epidemiologia , Doenças Respiratórias/etiologia , Anemia/complicações , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina E/imunologia , Estudos Longitudinais , Masculino , Razão de Chances , Avaliação de Resultados da Assistência ao Paciente , Gravidez , Complicações Hematológicas na GravidezRESUMO
Maternal smoking during pregnancy increases childhood asthma risk, but health effects in children of nonsmoking mothers passively exposed to tobacco smoke during pregnancy are unclear. We examined the association of maternal passive smoking during pregnancy and wheeze in children aged ≤2â years.Individual data of 27â993 mother-child pairs from 15 European birth cohorts were combined in pooled analyses taking into consideration potential confounders.Children with maternal exposure to passive smoking during pregnancy and no other smoking exposure were more likely to develop wheeze up to the age of 2â years (OR 1.11, 95% CI 1.03-1.20) compared with unexposed children. Risk of wheeze was further increased by children's postnatal passive smoke exposure in addition to their mothers' passive exposure during pregnancy (OR 1.29, 95% CI 1.19-1.40) and highest in children with both sources of passive exposure and mothers who smoked actively during pregnancy (OR 1.73, 95% CI 1.59-1.88). Risk of wheeze associated with tobacco smoke exposure was higher in children with an allergic versus nonallergic family history.Maternal passive smoking exposure during pregnancy is an independent risk factor for wheeze in children up to the age of 2â years. Pregnant females should avoid active and passive exposure to tobacco smoke for the benefit of their children's health.
Assuntos
Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Sons Respiratórios/etiologia , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Gravidez , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. OBJECTIVE: We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. METHODS: We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. RESULTS: We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. CONCLUSIONS AND CLINICAL RELEVANCE: This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.
Assuntos
Estudos de Associação Genética , Variação Genética , Óxido Nítrico , Proteínas rab de Ligação ao GTP/genética , Adulto , Alelos , Asma/genética , Asma/imunologia , Asma/metabolismo , Biomarcadores , Mapeamento Cromossômico , Expiração , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Adulto Jovem , Proteínas rab27 de Ligação ao GTPRESUMO
BACKGROUND: It has been suggested that maternal vitamin D status in pregnancy influences the risk of asthma and atopy in the offspring. The epidemiological evidence to support these claims is conflicting and may reflect chance findings and differences in how vitamin D was assessed. OBJECTIVE: To examine the association between blood total maternal 25-hydroxy vitamin D (25(OH)D) concentrations in pregnancy and offspring asthma, atopy and lung function in the largest birth cohort study to date. METHODS: Participants were largely of white European origin and resident in the South West of England. We examined the associations of maternal 25(OH)D concentrations in pregnancy with the following outcomes in the offspring: wheeze, asthma, atopy, eczema, hayfever, at mean age 7.5 years (n = 3652-4696 depending on outcome), IgE at 7 years (n = 2915) and lung function and bronchial responsiveness at mean age 8.7 years (n = 3728-3784). RESULTS: Sixty-eight per cent of mothers had sufficient (> 50 nmol/L) concentrations of 25(OH)D, 27% were insufficient (27.5-49.99 nmol/L) and 5% were deficient (< 27.5 nmol/L). There was no evidence to suggest that maternal 25(OH)D concentration in pregnancy was associated with any respiratory or atopic outcome in the offspring. These findings remained after adjustment for season of measurement and for potential confounders. There was also no evidence that these relationships followed a non-linear form and no evidence that either deficient or high concentrations of maternal 25(OH)D were associated with atopic or respiratory outcomes. CONCLUSIONS: We found no evidence that maternal blood 25(OH)D concentration in pregnancy is associated with childhood atopic or respiratory outcomes.
Assuntos
Asma/epidemiologia , Asma/etiologia , Hipersensibilidade Imediata/epidemiologia , Hipersensibilidade Imediata/etiologia , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Vitamina D/análogos & derivados , Adulto , Asma/fisiopatologia , Criança , Feminino , Humanos , Hipersensibilidade Imediata/fisiopatologia , Vigilância da População , Gravidez , Estudos Prospectivos , Testes de Função Respiratória , Vitamina D/sangue , Deficiência de Vitamina D/sangueRESUMO
BACKGROUND: Antibiotic use in infancy disrupts gut microflora during a critical period for immune system development. It is hypothesized that this could predispose to the development of allergic diseases. We investigated the associations of antibiotic use in the first 2 yr of life with the development of asthma, eczema or hay fever by age 7.5 yr in a longitudinal birth cohort. METHODS: Subjects were 4952 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Child antibiotic use and asthma, eczema and hay fever symptoms were maternally reported. Atopy was assessed by skin prick tests at age 7.5 yr. The total number of antibiotic courses was considered as the main exposure. Data were analysed using multivariate logistic regression. RESULTS: Children reported to have taken antibiotics during infancy (0-2 yr) were more likely to have asthma at 7.5 yr (OR 1.75, 95% CI 1.40-2.17), and the odds (OR, [95% CI]) increased with greater numbers of courses: once 1.11 [0.84-1.48]; twice 1.50 [1.14-1.98]; three times 1.79 [1.34-2.40]; four times or more 2.82 [2.19-3.63]. Increased antibiotic use was also associated with higher odds of eczema and hay fever but not atopy. The effect appeared to be associated with cumulative rather than a critical period of exposure during the first 2 yr. CONCLUSIONS: A robust and dose-dependent association was found between antibiotic use in the first 2 yr of life and asthma at age 7.5 yr but did not appear to be mediated through an association with atopy.
Assuntos
Antibacterianos/imunologia , Asma/imunologia , Eczema/imunologia , Fatores Etários , Antibacterianos/uso terapêutico , Criança , Estudos de Coortes , Relação Dose-Resposta Imunológica , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Risco , Testes CutâneosRESUMO
OBJECTIVE: To test the feasibility of a pragmatic trial design with economic evaluation and nested qualitative study, comparing usual care (UC) with UC plus individualised homeopathy, in children requiring secondary care for asthma. This included recruitment and retention, acceptability of outcome measures patients' and health professionals' views and experiences and a power calculation for a definitive trial. METHODS: In a pragmatic parallel group randomised controlled trial (RCT) design, children on step 2 or above of the British Thoracic Society Asthma Guidelines (BTG) were randomly allocated to UC or UC plus a five visit package of homeopathic care (HC). Outcome measures included the Juniper Asthma Control Questionnaire, Quality of Life Questionnaire and a resource use questionnaire. Qualitative interviews were used to gain families' and health professionals' views and experiences. RESULTS: 226 children were identified from hospital clinics and related patient databases. 67 showed an interest in participating, 39 children were randomised, 18 to HC and 21 to UC. Evidence in favour of adjunctive homeopathic treatment was lacking. Economic evaluation suggests that the cost of additional consultations was not offset by the reduced cost of homeopathic remedies and the lower use of primary care by children in the homeopathic group. Qualitative data gave insights into the differing perspectives of families and health care professionals within the research process. CONCLUSIONS: A future study using this design is not feasible, further investigation of a potential role for homeopathy in asthma management might be better conducted in primary care with children with less severe asthma.
Assuntos
Asma/terapia , Homeopatia/métodos , Materia Medica/uso terapêutico , Medicina de Precisão/métodos , Índice de Gravidade de Doença , Asma/economia , Criança , Serviços de Saúde da Criança/organização & administração , Estudos de Viabilidade , Feminino , Homeopatia/economia , Humanos , Masculino , Materia Medica/economia , Avaliação de Resultados em Cuidados de Saúde , Medicina de Precisão/economia , Garantia da Qualidade dos Cuidados de Saúde/métodos , Resultado do Tratamento , Reino UnidoRESUMO
BACKGROUND: Maternal smoking during pregnancy has detrimental effects on the respiratory health of infants and children. Polymorphisms of antioxidant genes including glutathione-S-transferases (GSTs) have been proposed as candidates for asthma and reduced lung function in children. METHODS: Women enrolled in the Avon Longitudinal Study of Parents and Children reported smoking habits during pregnancy. Asthma status in their children was established at age 7.5 years from parental reports and lung function was measured by spirometry at age 8.5â years. Maternal and child DNA were genotyped for deletions of GSTM1 and GSTT1 and functional polymorphisms of GSTP1 and Nrf2 genes. Associations of prenatal tobacco smoke exposure with asthma and lung function in children were stratified by maternal genotype. RESULTS: In 6606 children, maternal smoking during pregnancy was negatively associated with maximal mid expiratory flow (FEF(25-75)) (-0.05 SD units, 95% CI -0.07 to -0.03, p<0.001). There was little evidence for interactions between maternal smoking and any maternal genotype considered on children's asthma or lung function. Maternal smoking was associated with reduced childhood FEF(25-75) only in mother-child pairs (n=1227) with both copies of GSTM1 deleted (-0.08 SD units, 95% CI -0.14 to -0.02, p=0.01) or (n=2313) at least one copy of GSTT1 present (-0.05 SD units, 95% CI -0.09 to 0, p=0.03). CONCLUSION: This study confirms a detrimental effect of intrauterine tobacco smoke exposure on childhood lung function but no strong evidence of modification by maternal genotype for important antioxidant genes. Adverse effects of fetal exposure to tobacco smoke on the respiratory health of children may be mediated by pathways other than oxidative stress.
Assuntos
Asma/embriologia , Glutationa Transferase/genética , Fator 2 Relacionado a NF-E2/genética , Efeitos Tardios da Exposição Pré-Natal , Poluição por Fumaça de Tabaco/efeitos adversos , Asma/epidemiologia , Asma/genética , Asma/fisiopatologia , Criança , Inglaterra/epidemiologia , Feminino , Seguimentos , Genótipo , Humanos , Fluxo Máximo Médio Expiratório , Polimorfismo Genético , Gravidez , Fatores de Risco , Fumar/epidemiologia , Fumar/genéticaRESUMO
BACKGROUND: Studies of the relation between maternal diet in pregnancy and respiratory and atopic outcomes in the offspring have focused on the effects of individual nutrients and foods rather than dietary patterns. A study was undertaken to determine whether dietary patterns in pregnancy are related to childhood asthma and related outcomes. METHODS: In a population-based birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), dietary patterns in pregnancy previously identified using principal components analysis ("health conscious", "traditional", "processed", "vegetarian" and "confectionery") were related to early wheezing phenotypes and eczema; wheezing, hay fever, eczema, doctor-diagnosed asthma, atopy and total IgE at 7 years; lung function and bronchial responsiveness at 8-9 years. In regression models, confounders were controlled for using propensity scores. RESULTS: Univariately, the "health conscious" pattern was positively associated with eczema, total IgE, forced expiratory volume in 1 s and forced expiratory flow and negatively associated with early wheezing and asthma (unadjusted odds ratios per standard deviation increase in pattern score for early persistent wheeze and asthma: 0.78 (95% CI 0.70 to 0.87), p = 7.3x10(-6), N = 8886 and 0.90 (95% CI 0.84 to 0.97), p = 0.007, N = 7625, respectively). The "processed" pattern was positively associated with early wheezing and negatively associated with atopy and forced vital capacity. On controlling for confounders, the effects were substantially attenuated and became non-significant (adjusted odds ratios for the associations of the "health conscious" pattern with early persistent wheeze and asthma: 1.00 (0.86 to 1.16), p = 0.99 and 0.95 (0.86 to 1.04), p = 0.27, respectively). CONCLUSIONS: In this cohort, dietary patterns in pregnancy did not predict asthma and related outcomes in the offspring after controlling for confounders.
Assuntos
Asma/epidemiologia , Dieta/efeitos adversos , Eczema/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Transtornos Respiratórios/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Eczema/fisiopatologia , Inglaterra/epidemiologia , Comportamento Alimentar , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Lactente , Estudos Longitudinais , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Prevalência , Transtornos Respiratórios/fisiopatologia , Sons Respiratórios/fisiopatologia , Rinite Alérgica Sazonal/epidemiologia , Capacidade Vital/fisiologiaRESUMO
OBJECTIVE: To investigate whether duration of television (TV) viewing in young children is associated with subsequent development of asthma. METHODS: Children taking part in the Avon Longitudinal Study of Parents and Children (ALSPAC) with no wheeze up to the age of 3.5 years and follow-up data at 11.5 years of age took part in a prospective longitudinal cohort study. The main outcome measure was asthma, defined as doctor-diagnosed asthma by 7.5 years of age with symptoms and/or treatment in the previous 12 months at 11.5 years of age. Parental report of hours of TV viewing per day by the children was ascertained at 39 months. RESULTS: In children with no symptoms of wheeze at 3.5 years of age and follow-up data at 11.5 years of age, the prevalence of asthma was 6% (185/3065). Increased TV viewing at 3.5 years was associated with increased prevalence of asthma at 11.5 years of age (p for linear trend = 0.0003). Children who watched television for >2 h/day were almost twice as likely to develop asthma by 11.5 years of age as those watching TV for 1-2 h/day (adjusted odds ratio 1.8 (95% CI 1.2 to 2.6)). CONCLUSION: Longer duration of TV viewing in children with no symptoms of wheeze at 3.5 years of age was associated with the development of asthma in later childhood.
Assuntos
Asma/etiologia , Televisão/estatística & dados numéricos , Asma/epidemiologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/etiologia , Criança , Pré-Escolar , Inglaterra/epidemiologia , Exercício Físico/fisiologia , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Prevalência , Estudos Prospectivos , Distribuição por Sexo , Fatores de TempoRESUMO
Immunoconjugates (BR96-DOX) were prepared between chimeric monoclonal antibody BR96 and the anticancer drug doxorubicin. The monoclonal antibody binds an antigen related to Lewis Y that is abundantly expressed at the surface of cells from many human carcinomas; it has a high degree of tumor selectivity and is internalized after binding. BR96-DOX induced complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and cured 70 percent of mice bearing extensive metastases of a human lung carcinoma. Also, BR96-DOX cured 94 percent of athymic rats with subcutaneous human lung carcinoma, even though the rats, like humans and in contrast to mice, expressed the BR96 target antigen in normal tissues.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doxorrubicina/uso terapêutico , Imunotoxinas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Superfície/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/administração & dosagem , Humanos , Imunotoxinas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Ratos NusRESUMO
Three high-affinity binding sites for the GATA family of transcriptional regulators have been identified within the T-cell receptor beta-chain (TCR beta) transcriptional enhancer, and their functional significance has been determined in an effort to understand the T-cell specificity of the enhancer more fully. One site, TE4, is important for activity of the enhancer in T cells. Neither site TE1 nor site TE2 can functionally replace a mutated TE4 site in T cells; however, the same protein, probably GATA-3, binds all three sites, as judged by electrophoretic mobility shift, oligonucleotide competition, and proteolytic clipping assays. These data suggest that additional proteins are critical for the ability of GATA-3 to activate the TCR beta enhancer. In fibroblasts, the GATA sequence at site TE1 appears to bind a negative regulator. Since this is not true in B cells, B cells and fibroblasts appear to have different mechanisms for negative regulation of the TCR beta enhancer.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos , Expressão Gênica , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Núcleo Celular/metabolismo , Cloranfenicol O-Acetiltransferase/biossíntese , Cloranfenicol O-Acetiltransferase/metabolismo , Primers do DNA , Fator de Transcrição GATA3 , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Oligodesoxirribonucleotídeos , Reação em Cadeia da Polimerase , Linfócitos T/imunologia , Transcrição Gênica , TransfecçãoRESUMO
Macrophages adapt both phenotypically and functionally to the cytokine balance in host tissue microenvironments. Recent studies established that macrophages contribute an important yet poorly understood role in the development of infection-elicited oral bone loss. We hypothesized that macrophage adaptation to inflammatory signals encountered before pathogen interaction would significantly influence the subsequent immune response of these cells to the keystone oral pathobiont Porphyromonas gingivalis. Employing classically activated (M1) and alternatively activated (M2) murine bone-marrow-derived macrophage (BMDMø), we observed that immunologic activation of macrophages before P. gingivalis challenge dictated phenotype-specific changes in the expression of inflammation-associated molecules important to sensing and tuning host response to bacterial infection including Toll-like receptors 2 and 4, CD14, CD18 and CD11b (together comprising CR3), major histocompatibility complex class II, CD80, and CD86. M2 cells responded to P. gingivalis with higher expression of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, regulated on activation normal T cell expressed and secreted, and KC than M1 cells. M1 BMDMø expressed higher levels of interleukin-10 to P. gingivalis than M2 BMDMø. Functionally, we observed that M2 BMDMø bound P. gingivalis more robustly than M1 BMDMø. These data describe an important contribution of macrophage skewing in the subsequent development of the cellular immune response to P. gingivalis.
Assuntos
Imunidade Celular , Ativação de Macrófagos , Macrófagos/imunologia , Porphyromonas gingivalis/imunologia , Animais , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígeno B7-2/genética , Antígeno B7-2/imunologia , Aderência Bacteriana , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Antígenos CD18/genética , Antígenos CD18/imunologia , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/genética , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Inflamação , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Macrófagos/fisiologia , Camundongos , Doenças Periodontais/imunologia , Doenças Periodontais/microbiologia , Porphyromonas gingivalis/patogenicidade , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaRESUMO
The anticarcinoma antibody BR64 was conjugated to a doxorubicin derivative, doxorubicin 13-[3-(2-pyridyldithio)propionyl]hydrazone, and the resulting conjugates (BR64-DOX) were evaluated for activity and immunological specificity in vitro and in human tumor xenograft models. The BR64-DOX immunoconjugates retained immunoreactivity and cytotoxicity and demonstrated antigen-specific cytotoxicity in vitro. The potency of BR64-DOX immunoconjugates in vitro was related to the drug:monoclonal antibody mole ratio of the conjugates. The antitumor activity of BR64-DOX conjugates was consistently superior to the maximal activity obtained with the parent drug, doxorubicin (DOX), in established human lung and human breast carcinoma xenograft models. The superior antitumor activity of BR64-DOX conjugates was reflected both in tumor growth inhibition and in regressions and cures of established tumors following the administration of tolerated doses of BR64-DOX. The antitumor activity of BR64-DOX conjugates was not the result of synergism between monoclonal antibody BR64 and DOX, because mixtures consisting of monoclonal antibody and optimized DOX were not more active than an equivalent dose of DOX administered alone. The antitumor activity of BR64-DOX conjugates was antigen specific; equivalent doses of nonbinding isotype-matched conjugates were not active against established tumor xenografts.
Assuntos
Antígenos de Neoplasias/imunologia , Doxorrubicina/uso terapêutico , Epitopos/imunologia , Imunotoxinas/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Testes Imunológicos de Citotoxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Epitopos/análise , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
BMS-275291 is an p.o. bioavailable, sulfhydryl-based matrix metalloproteinase (MMP) inhibitor currently in clinical development for the treatment of cancer. This inhibitor was designed to potently inhibit MMP activities while minimally affecting those of other metalloproteases (e.g., sheddases) involved in the release of cell-associated molecules such as tumor necrosis factor-alpha, tumor necrosis factor-alpha receptor, interleukin-6 receptor, or L-selectin. In vitro, BMS-275291 is a potent inhibitor (nM) of the activities of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastasis, and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated that the plasma concentrations of parent BMS-275291 in mice exceeds the in vitro IC(50) values for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. Taken together, these data demonstrate that BMS-275291 inhibits MMP activities that contribute to tumor metastasis and angiogenesis.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Inibidores de Metaloproteinases de Matriz , Melanoma Experimental/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Compostos Orgânicos , Animais , Antineoplásicos/farmacocinética , Colágeno , Combinação de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Imidazóis , Laminina , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , ProteoglicanasRESUMO
The internalizing anti-Le(y) monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific activity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-SS-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-intensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/imunologia , Doxorrubicina/farmacologia , Imunoconjugados/farmacologia , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacocinética , Ensaios de Seleção de Medicamentos Antitumorais , Epitopos/imunologia , Feminino , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
BACKGROUND: Respiratory function testing is important for detecting and monitoring illness, however, it is difficult for some patients, such as the young and severely ill, to perform conventional tests that require cooperation and/or patient contact. METHOD: A new method was developed for non-contact breathing measurement, employing photometric stereo to capture the surface topography of the torso of an unconstrained subject. The surface is integrated to calculate time-dependent volume changes during respiration. RESULTS: The method provides a useful means of continuously measuring volume changes during respiration with high spatial and temporal resolution. The system was tested by comparison with pneumotachometry equipment and a clear periodic signal, of a frequency corresponding to the reference data, was observed. CONCLUSION: The approach is unique in performing breathing monitoring (with potential diagnostic capability) for unconstrained patients in virtually any lighting conditions (including darkness during sleep) and in a non-contact, unobtrusive (i.e. using imperceptible light) fashion. Copyright © 2015 John Wiley & Sons, Ltd.
Assuntos
Imageamento Tridimensional/métodos , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Respiração , Algoritmos , Desenho de Equipamento , Humanos , Luz , Movimento , Testes de Função RespiratóriaRESUMO
The effects of colchicine and vincristine on the concentration of glucose and its metabolites in milk were studied following intramammary injection of the alkaloids into one mammary gland of lactating goats. Both alkaloids decreased the rate of milk secretion from the treated gland and produced similar changes in the concentrations of various metabolites in milk. The concentrations of glucose, UDP-galactose, galactose, pyruvate and lactate increased, while those of glucose 6-phosphate and phosphoenolpyruvate decreased in milk from treated glands. The rate of milk secretion from the untreated gland increased, along with the concentrations of glucose in the milk. The changes in the concentrations of the metabolites in milk are discussed in relation to possible biochemical changes occurring in the mammary gland during the suppression of milk secretion by the alkaloids. It is suggested that, before alkaloid treatment, the rate of milk secretion was limited by intracellular glucose supply.
Assuntos
Colchicina/farmacologia , Glucose/análise , Leite/análise , Vincristina/farmacologia , Animais , Feminino , Galactose/análise , Glicólise , Cabras , Lactose/análise , Glândulas Mamárias Animais/efeitos dos fármacos , Fatores de Tempo , Uridina Difosfato Galactose/análiseRESUMO
The efficacy of chemotherapy has been improved by regimens that combine several cytotoxic drugs with different mechanisms of action and/or different dose-limiting toxicities. Here we demonstrate clearly, and for the first time, that combined therapy using an anticarcinoma immunoconjugate, BR96-doxorubicin, and the cytotoxic drug paclitaxel results in a significant increase in antitumor activity over that of either agent alone. Synergistic activity was seen at doses of BR96-doxorubicin that were minimally active as single agents. A dramatic increase in regression rates was seen when a regimen that combined BR96-doxorubicin and paclitaxel was used to treat both paclitaxel-sensitive and paclitaxel-insensitive carcinomas. Importantly, combined therapy resulted in increased antitumor activity against lung, colon, and breast tumors xenografted in athymic mice and large, paclitaxel-insensitive colon tumors xenografted in athymic rats that also express the Lewis(y) target antigen in normal tissues.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Neoplasias/patologia , Paclitaxel/administração & dosagem , Ratos , Ratos Nus , Fatores de Tempo , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
The ability to function as an effective member of a dental care team is a highly desirable--frequently mandated--attribute of dental technology (DT) graduates. Currently, there is little rigorous examination of how the learning of team-working skills might best be structured in a DT curriculum. This research compares DT curricula, and students' attitudes and perceptions regarding collaboration in practice, from four countries. Students (n=376) were invited to complete an education profile questionnaire, and the standardised measure--the shared learning scale. There were 196 (52%) responses. Students given opportunities to engage with others had better perceptions of inter-professional learning (IPL). Most believed that team-work and collaborative skills were best acquired by learning together with other dental care professionals, preferably sharing cases for real patients. Curricula should maximise opportunities for dental technology students to experience authentic IPL. Collaboration and team-work needs to be embedded through the whole undergraduate programme.