RESUMO
AIMS: This study examined the trajectory of alcohol use frequency among parents from April-2020 to May-2021 during the COVID-19 pandemic in the state of Victoria, Australia (who experienced one of the longest lockdowns in the world), compared to parents from the other states of Australia (who experienced relatively fewer restrictions). We further examined the extent to which baseline demographic factors were associated with changes in alcohol use trajectories among parents. METHOD: Data were from the COVID-19 Pandemic Adjustment Survey (2,261 parents of children 0-18 years). Alcohol use frequency was assessed over 13 waves. Baseline demographic predictors included parent gender, age, speaking a language other than English, number of children, partnership status, education, employment, and income. RESULTS: Overall, alcohol trajectories declined over time. Victorian parents, in comparison to parents from other states, reported a smaller reduction in alcohol use frequency across 2020, with a more notable decline during 2021. Female/other gender, speaking a language other than English at home, unemployment, and lower income (Victoria only) were associated with alcohol trajectories of less frequent use, and older age was associated with a trajectory of more frequent use. CONCLUSIONS: Results suggest subtle difference in alcohol trajectories reflecting COVID-19 restrictions, when comparing Victoria and other states in Australia. Socioeconomically advantaged groups were most at risk for elevated trajectories of alcohol use frequency. Population level support may beneficial to reduce drinking behaviours.
Assuntos
COVID-19 , Pandemias , Criança , Humanos , Feminino , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Pais , Vitória/epidemiologiaRESUMO
The COVID-19 pandemic presents significant risks to population mental health. Despite evidence of detrimental effects for adults, there has been limited examination of the impact of COVID-19 on parents and children specifically. We aim to examine patterns of parent and child (0-18 years) mental health, parent substance use, couple conflict, parenting practices, and family functioning during COVID-19, compared to pre-pandemic data, and to identify families most at risk of poor outcomes according to pre-existing demographic and individual factors, and COVID-19 stressors. Participants were Australian mothers (81%) and fathers aged 18 years and over who were parents of a child 0-18 years (N = 2365). Parents completed an online self-report survey during 'stage three' COVID-19 restrictions in April 2020. Data were compared to pre-pandemic data from four Australian population-based cohorts. Compared to pre-pandemic estimates, during the pandemic period parents reported higher rates of parent depression, anxiety, and stress (Cohen's d = 0.26-0.81, all p < 0.001), higher parenting irritability (d = 0.17-0.46, all p < 0.001), lower family positive expressiveness (d = - 0.18, p < 0.001), and higher alcohol consumption (22% vs 12% drinking four or more days per week, p < 0.001). In multivariable analyses, we consistently found that younger parent age, increased financial deprivation, pre-existing parent and child physical and mental health conditions, COVID-19 psychological and environmental stressors, and housing dissatisfaction were associated with worse parent and child functioning and more strained family relationships. Our data suggest wide-ranging, detrimental family impacts associated with the COVID-19 pandemic; and support policy actions to assist families with financial supports, leave entitlements, and social housing.
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COVID-19 , Adulto , Feminino , Criança , Humanos , Adolescente , COVID-19/epidemiologia , Pandemias , Saúde Mental , Austrália/epidemiologia , Pais/psicologia , Poder Familiar/psicologiaRESUMO
PURPOSE: To examine associations between anxiety and depressive symptoms across adolescence and young adulthood with subsequent maternal- and paternal-infant bonding at 1 year postpartum. METHODS: The data were from a prospective, intergenerational cohort study. Participants (381 mothers of 648 infants; 277 fathers of 421 infants) self-reported depression and anxiety at three adolescent waves (ages 13, 15 and 17 years) and three young adult waves (ages 19, 23 and 27 years). Subsequent parent-infant bonds with infants were reported at 1 year postpartum (parent age 29-35 years). Generalised estimating equations (GEE) separately assessed associations for mothers and fathers. RESULTS: Mean postpartum bonding scores were approximately half a standard deviation lower in parents with a history of persistent adolescent and young adult depressive symptoms (maternal ßadj = - 0.45, 95% CI - 0.69, - 0.21; paternal ßadj = - 0.55, 95% CI - 0.90, 0.20) or anxiety (maternal ßadj = - 0.42, 95% CI - 0.66, - 0.18; paternal ßadj = - 0.49, 95% CI - 0.95, 0.03). Associations were still mostly evident, but attenuated after further adjustment for postpartum mental health concurrent with measurement of bonding. CONCLUSIONS: Persistent symptoms of depression or anxiety spanning adolescence and young adulthood predict poorer emotional bonding with infants 1-year postbirth for both mothers and fathers.
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Depressão Pós-Parto , Saúde Mental , Adolescente , Adulto , Estudos de Coortes , Depressão/psicologia , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/psicologia , Pai/psicologia , Feminino , Humanos , Lactente , Masculino , Mães/psicologia , Período Pós-Parto/psicologia , Estudos Prospectivos , Adulto JovemRESUMO
AIMS: We examine the extent to which adolescent and young adult psychosocial factors are associated with variation in the experience of common types of harm (e.g., injuries, violence, sexual regrets) with respect to binge-drinking frequency - termed residual harm. METHODS: Data were from the Australian Temperament Project, a population-based cohort study that has followed a sample of young Australians from infancy to adulthood since 1983. The current sample comprised 1,081 (565 women). Residual harm was operationalised by saving residuals from models regressing number of alcohol harms onto binge-drinking frequency at each of 5 waves, two in adolescence (15-16 and 17-18 years) and three in young adulthood (19-20, 23-24, and 27-28 years). Psychosocial factors (mental health, social skills, quality of parent and peer relationships) were assessed prior to binge drinking in early adolescence (13-14 years) and then again in young adulthood (19-20 years). RESULTS: Adolescent predictors of decreased residual harm were lower depressive symptoms, and higher cooperation, self-control, and peer and parent attachment. Young adult predictors of decreased residual harm were lower depressive, anxiety, and stress symptoms and peer and parent negative appraisal, and higher responsibility, and peer and parent emotional support. Associations were evident in males and females, although the strength of some associations diminished with age. CONCLUSIONS: Adolescents and young adults with better mental health, social skills, and relationship quality experienced less harm with respect to their binge-drinking frequency. Future research should examine the potential of investment in strength-based interventions for young people.
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Consumo Excessivo de Bebidas Alcoólicas , Temperamento , Adolescente , Adulto , Transtornos de Ansiedade , Austrália/epidemiologia , Consumo Excessivo de Bebidas Alcoólicas/epidemiologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Adulto JovemRESUMO
AIMS: To explore the process of applying counterfactual thinking in examining causal determinants of substance use trajectories in observational cohort data. Specifically, we examine the extent to which quality of the parent-adolescent relationship and affiliations with deviant peers are causally related to trajectories of alcohol, tobacco, and cannabis use across adolescence and into young adulthood. METHODS: Data were drawn from the Australian Temperament Project, a population-based cohort study that has followed a sample of young Australians from infancy to adulthood since 1983. Parent-adolescent relationship quality and deviant peer affiliations were assessed at age 13-14 years. Latent curve models were fitted for past month alcohol, tobacco, and cannabis use (n = 1590) from age 15-16 to 27-28 years (5 waves). Confounding factors were selected in line with the counterfactual framework. RESULTS: Following confounder adjustment, higher quality parent-adolescent relationships were associated with lower baseline cannabis use, but not alcohol or tobacco use trajectories. In contrast, affiliations with deviant peers were associated with higher baseline binge drinking, tobacco, and cannabis use, and an earlier peak in the cannabis use trajectory. CONCLUSIONS: Despite careful application of the counterfactual framework, interpretation of associations as causal is not without limitations. Nevertheless, findings suggested causal effects of both parent-adolescent relationships and deviant peer affiliations on the trajectory of substance use. Causal effects were more pervasive (i.e., more substance types) and protracted for deviant peer affiliations. The exploration of causal relationships in observational cohort data is encouraged, when relevant limitations are transparently acknowledged.
Assuntos
Grupo Associado , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Adulto , Austrália/epidemiologia , Estudos de Coortes , Humanos , Estudos Longitudinais , Pais , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: In extending work on early life antecedents of parenting, we investigate associations between childhood family history of disadvantage, adolescent socioemotional wellbeing, and age at first parenthood and subsequent parenting behaviour. METHODS: Parent-child interactions were recorded when participants in the longitudinal Dunedin Multidisciplinary Health and Development Study (New Zealand) had a three-year-old child. Data were available for 358 mothers and 321 fathers, aged between 17.7 and 41.5 at the time of their child's birth. Associations between parenting and antecedent data on socioeconomic disadvantage, adolescent wellbeing and mental health, as well as current adult mental health and age at parenting, were tested for using structural equation modelling. RESULTS: Family disadvantage in childhood and lower adolescent wellbeing was associated with less positive future parenting, but only adult (not adolescent) anxiety/depression symptoms were directly associated with parenting behaviour. Childhood family disadvantage was associated with further disadvantage across the life course that included less positive parenting of the next generation. In contrast, socioemotional wellbeing during adolescence and later age of onset of parenting were associated with more positive parenting. CONCLUSIONS: Reducing childhood disadvantage and improving socioemotional wellbeing during childhood and adolescence is likely to have intergenerational benefits through better parenting of the next generation.
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Saúde do Adolescente , Poder Familiar , Adolescente , Adulto , Pré-Escolar , Feminino , Humanos , Saúde Mental , Mães , Relações Pais-Filho , Adulto JovemRESUMO
BACKGROUND: Modelling trajectories of substance use over time is complex and requires judicious choices from a number of modelling approaches. In this study we examine the relative strengths and weakness of latent curve models (LCM), growth mixture modelling (GMM), and latent class growth analysis (LCGA). DESIGN: Data were drawn from the Australian Temperament Project, a 36-year-old community-based longitudinal study that has followed a sample of young Australians from infancy to adulthood across 16 waves of follow-up since 1983. Models were fitted on past month alcohol use (nâ¯=â¯1468) and cannabis use (nâ¯=â¯549) across six waves of data collected from age 13-14 to 27-28 years. FINDINGS: Of the three model types, GMMs were the best fit. However, these models were limited given the variance of numerous growth parameters had to be constrained to zero. Additionally, both the GMM and LCGA solutions had low entropy. The negative binomial LCMs provided a relatively well-fitting solution with fewer drawbacks in terms of growth parameter estimation and entropy issues. In all cases, model fit was enhanced when using a negative binomial distribution. CONCLUSIONS: Substance use researchers would benefit from adopting a complimentary framework by exploring both LCMs and mixture approaches, in light of the relative strengths and weaknesses as identified. Additionally, the distribution of data should inform modelling decisions.
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Consumo de Bebidas Alcoólicas/epidemiologia , Uso da Maconha/epidemiologia , Modelos Estatísticos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Adulto , Austrália/epidemiologia , Feminino , Humanos , Análise de Classes Latentes , Estudos Longitudinais , Masculino , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: The aims of the study were to describe the patterning and persistence of anxiety and depressive symptoms from adolescence to young adulthood and to examine long-term developmental relationships with earlier patterns of internalizing behaviours in childhood. METHOD: We used parallel processes latent growth curve modelling to build trajectories of internalizing from adolescence to adulthood, using seven waves of follow-ups (ages 11-27 years) from 1406 participants of the Australian Temperament Project. We then used latent factors to capture the stability of maternal reported child internalizing symptoms across three waves of early childhood follow-ups (ages 5, 7 and 9 years), and examined relationships among these patterns of symptoms across the three developmental periods, adjusting for gender and socio-economic status. RESULTS: We observed strong continuity in depressive symptoms from adolescence to young adulthood. In contrast, adolescent anxiety was not persistent across the same period, nor was it related to later depressive symptoms. Anxiety was, however, related to non-specific stress in young adulthood, but only moderately so. Although childhood internalizing was related to adolescent and adult profiles, the associations were weak and indirect by adulthood, suggesting that other factors are important in the development of internalizing symptoms. CONCLUSIONS: Once established, adolescent depressive symptoms are not only strongly persistent, but also have the potential to differentiate into anxiety in young adulthood. Relationships with childhood internalizing symptoms are weak, suggesting that early adolescence may be an important period for targeted intervention, but also that further research into the childhood origins of internalizing behaviours is needed.
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Desenvolvimento do Adolescente/fisiologia , Ansiedade/epidemiologia , Depressão/epidemiologia , Comportamento Problema , Temperamento/fisiologia , Adolescente , Adulto , Austrália , Criança , Pré-Escolar , Humanos , Estudos Longitudinais , Adulto JovemRESUMO
AIM: To determine the period prevalence of needlestick injury (NSI) at the Massey University Veterinary Teaching Hospital (VTH) and to identify handling and disposal practices that may contribute to the risk of NSI. METHODS: Observations of personnel were conducted in the equine (EVH) and companion animal (CAH) clinics of the VTH during scheduled clinical activities over 9- and 10-day periods, respectively. The number and type of NSI incidents, needle uncapping, capping and disposal events were recorded for veterinarians, nurses and other personnel (visitors and students). The number of needle-related practices, as a proportion of observations, were compared between CAH and EVH, and veterinarians, nurses and others using χ(2) tests. RESULTS: Needlestick injury was not observed during 190 and 163 needle handling and disposal observations in the CAH and EVH, respectively. Uncapping of needles by mouth was observed and was practised more by veterinarians (15/119; 13%) than nurses (2/42; 5%) and others (6/193; 3%) (p=0.001). Two-handed needle recapping after use was observed 265/354 times, and the one handed scooping technique was rarely observed (8/352). In the case of needle disposal, EVH workers used a container that was not purpose built for disposal more than CAH staff (p=0.02), or placed them in a pocket more frequently (p=0.003). Needle disposal containers were available on adjacent bench tops for 65/190 (34%) CAH observations, but no EVH observations. For 51/163 (31%) EVH observations the needle disposal containers were located on the ground, whereas none were observed there in the CAH. No approved sharps containers were observed in the immediate EVH and CAH work areas for 47/163 (28.8%) and 1/191 (0.5%) needle-handling activities, respectively. CONCLUSIONS: Unsafe needle-handling practices must be reduced by policies and training programmes to encourage safe needle-related practices, and ensuring that approved sharps containers are available in close proximity to where needles are used.
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Acidentes de Trabalho/prevenção & controle , Hospitais Veterinários/normas , Ferimentos Penetrantes Produzidos por Agulha/prevenção & controle , Faculdades de Medicina Veterinária/normas , Universidades , Técnicos em Manejo de Animais , Animais , Humanos , Agulhas , Segurança , Médicos VeterináriosRESUMO
BACKGROUND: Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated protein kinase (ERK) and p38MAPK, are known regulators of smooth muscle contractility. The contraction of smooth muscle is mainly regulated by the phosphorylation of regulatory light chains of myosin II (LC20), which is driven by the balance between myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP). We hypothesized that one possible mechanism for MAPK-dependent modulation of intestinal smooth muscle contractility is via the regulation of MLCP activity. METHODS: Contractile responses to carbachol (CCh) and effects of MAPK inhibitors on CCh-induced contractions were assessed with isolated rat ileal longitudinal smooth muscle strips. Biochemical assessments of MLCP activity and myosin phosphatse targeting subunit (MYPT1) and CPI-17 phosphorylations were completed. KEY RESULTS: Treatment of ileal smooth muscle with PD98059 (10 µM; MEK inhibitor) or SB203580 (10 µM; p38MAPK inhibitor) significantly inhibited CCh-induced contractile force. Decreased MLCP activity was observed during sustained contractions induced by CCh; the MLCP activity was recovered by treatment with PD98059 and SB203580. However, MYPT1 (Thr697 and Thr855) and CPI-17 (Thr38) phosphorylations were not affected. Application of ML-7 (MLCK inhibitor) during CCh-induced sustained contraction elicited an MLCP-dependent relaxation, the rate of which was accelerated by application of PD98059 and SB203580 with proportional changes in LC20 phosphorylation levels but not MYPT1 phosphorylation (Thr697 or Thr855). CONCLUSIONS & INFERENCES: ERK and p38MAPK contribute to CCh-induced sustained contraction in a LC20 phosphorylation dependent manner. Moreover, both kinases inhibit MLCP activity possibly by a novel mechanism.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Íleo/metabolismo , Sistema de Sinalização das MAP Quinases , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Animais , Cálcio/metabolismo , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Íleo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Contração Muscular/efeitos dos fármacos , Proteínas Musculares , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Clostridium difficile (Cdf) releases toxins (TcdA and TcdB) that damage the intestinal epithelial barrier. Ecto-5'-nucleotidase (CD73) is expressed on intestinal epithelial cells, and it is hypothesized to protect against toxin-induced epithelial damage through the cleavage of 5'-AMP to adenosine (Ado) and subsequent activation of adenosine receptors (AdoRs). Herein, we sought to assess the potential protective effects of CD73 and AdoR signaling on the injurious effects of Cdf toxins. METHODS: Barrier function was assessed with T84 colonocytes. Transepithelial electrical resistance (TEER), paracellular fluorescein isothiocyanate (FITC)-dextran flux, and tight junction protein (ZO-1) integrity were monitored. Intrarectal installation of Cdf toxin was used to assess epithelial damage in vivo. KEY RESULTS: TcdA/B caused reduced TEER and increased paracellular flux in vitro. Concurrent treatment with 5'-AMP attenuated these responses to Cdf toxin; an effect that was blocked with ZM241385 (AdoRA2 antagonist). APCP, a CD73 inhibitor, also suppressed the protective effects of 5'-AMP on paracellular flux. 5'-AMP reduced toxin-induced disruption of ZO-1, an effect that was abolished by APCP and ZM241385. Inhibition of CD73 with APCP during Cdf toxin exposure led to increased intestinal barrier permeability and epithelial damage in vivo. Intrarectal instillation of 5'-AMP had no effect on toxin-induced intestinal injury. CONCLUSIONS & INFERENCES: Our data suggest that CD73 has a protective role against TcdA/B-induced damage. 5'-AMP treatment attenuated the damaging effects of Cdf toxin in vitro, and inhibitors of CD73 (APCP) and AdoRs (ZM241385) revealed that the cleavage of 5'-AMP to Ado was necessary for the protective effects. Inhibition of CD73 in vivo increases colonic tissue damage and epithelial permeability during Cdf toxin exposure.
Assuntos
5'-Nucleotidase/metabolismo , Proteínas de Bactérias/farmacologia , Toxinas Bacterianas/farmacologia , Enterotoxinas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Receptores Purinérgicos P1/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Permeabilidade , Transdução de Sinais , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismoRESUMO
BACKGROUND: Colonic smooth muscle contractility is altered in colitis, and several protein kinase pathways can mediate colonic smooth muscle contraction. In the present study, we investigated whether protein kinase C (PKC) pathways also play a role in colonic hypercontractility observed during T(H) 2 colitis in BALB/c mice. METHODS: Colitis was induced in BALB/c mice by provision of 5% dextran sodium sulfate (DSS) for 7 days. Changes in smooth muscle contractility were examined using dissected circular smooth muscle preparations from the distal colon. The contribution of conventional and novel PKC isozymes to the hypercontractile response was examined with pharmacological PKC inhibitors. Western blot analyses were used to examine protein expression and phosphorylation changes. KEY RESULTS: Colonic smooth muscle was associated with inflammation-induced hypercontractility and altered PKC expression. Carbachol-induced peak (phasic) and sustained (tonic) contractions were increased. Chelerythrine was the most effective PKC inhibitor of both phasic and tonic contractions. There was no general difference in the percent contribution of conventional and novel PKC isozymes toward the DSS-induced hypercontractility, but inhibition of sustained force with GF109203x was higher for inflamed muscle. The CPI-17 phosphorylation was equally suppressed in both normal and DSS conditions by Gö6976 and chelerythrine, but only for the phasic component of contraction. CONCLUSIONS & INFERENCES: The outcomes suggest that both conventional and novel PKC isozymes contribute to the phasic and tonic contractile components of BALB/c colonic circular smooth muscle under normal conditions, with novel PKC isozymes having a greater contribution to the tonic contraction. However, no effect of inflammation was observed on the relative contribution of PKC and CPI-17 toward the observed hypercontractility.
Assuntos
Colite/induzido quimicamente , Colite/fisiopatologia , Colo/fisiologia , Contração Muscular/fisiologia , Fosfoproteínas Fosfatases/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais/fisiologia , Animais , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Colo/anatomia & histologia , Feminino , Peptídeos e Proteínas de Sinalização Intracelular , Isoenzimas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Proteínas Musculares , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Salvinorin A (SA) is the principal active ingredient of Salvia divinorum, with an established inhibitory action on gastrointestinal (GI) transit and colonic ion transport in mice. Under normal conditions, the effects of SA are mediated by kappa opioid (KOR) and cannabinoid (CB1 and CB2) receptors. However, the role of SA in pathophysiological conditions remains unresolved. The aim of this study was to characterize the in vitro and in vivo effects of SA on mouse ileum after endotoxin challenge. METHODS: Changes in GI motility were studied in vitro, using smooth muscle preparations from the mouse ileum. In vivo, the fecal pellet output and small intestinal fluid content were measured. Neurogenic ion transport and intestinal permeability were examined using Ussing chambers. In addition, Western blot analysis of mucosa was performed and plasma nitrite/nitrate levels were determined. KEY RESULTS: Salvinorin A inhibited endotoxin-induced ileal hypercontractility via KOR, CB1, and CB2 receptors. Neurogenic ion transport, which was significantly reduced after endotoxin challenge, was normalized by SA through a nitric oxide synthase (NOS)-dependent mechanism. Western blot analysis and plasma nitrite/nitrate level quantitation confirmed the involvement of NOS in the regulatory action of SA. CONCLUSIONS & INFERENCES: This is the first report showing differential effects of SA on motor and secretory activity in mouse GI during endotoxemia. The outcomes of our study imply possible novel applications of SA and its analogs in the treatment of GI disorders.
Assuntos
Diterpenos Clerodânicos/farmacologia , Endotoxinas/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/fisiologia , Transporte de Íons/efeitos dos fármacos , Animais , Defecação/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismoRESUMO
Intestinal mucosal integrity is dependent on epithelial function and a regulated immune response to injury. Fucosyltransferase VII (Fuc-TVII) is an essential enzyme required for the expression of the functional ligand for E- and P-selectin. Trefoil factor 3 (TFF3) is involved in both protecting the intestinal epithelium against injury as well as aiding in wound repair following injury. The aim of the present study was to assess the interplay between barrier function and leukocyte recruitment in intestinal inflammation. More specifically, we aimed to examine how targeted disruption of Fuc-TVII either in wild-type or TFF3(-/-) mice would alter their susceptibility to colonic injury. TFF3 and Fuc-TVII double-knockout mice (TFF3/Fuc-TVII(-/-) mice) were generated by mating TFF3(-/-) and Fuc-TVII(-/-) mice. Colitis was induced by administration of dextran sodium sulfate (DSS) (2.5% wt/vol) in the drinking water. Changes in baseline body weight, diarrhea, and fecal blood were assessed daily. Upon euthanasia, extents of colonic inflammation were assessed macroscopically, microscopically, and through quantification of myeloperoxidase (MPO) activity. Colonic lymphocyte subpopulations were assessed at 6 days after administration of DSS by flow cytometry and immunohistochemistry. No baseline intestinal inflammation was found in TFF3/Fuc-TVII(-/-), TFF3(-/-), Fuc-TVII(-/-), or wild-type mice. Loss of Fuc-TVII resulted in a reduction in disease severity whereas TFF3(-/-) mice were markedly more susceptible to DSS-induced colitis. Remarkably, the loss of Fuc-TVII in TFF3(-/-) mice markedly decreased the severity of DSS-induced colitis as evidenced by reduced weight loss, diarrhea, decreased colonic MPO levels and improved survival. Furthermore, the loss of TFF3 resulted in increased severity of spontaneous colitis in IL-2/beta-microglobulin-deficient mice. These studies highlight the importance of the interplay between factors involved in the innate immune response, mucosal barrier function, and genes involved in regulating leukocyte recruitment and other aspects of the immune response.
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Quimiotaxia de Leucócito , Colite/enzimologia , Fucosiltransferases/metabolismo , Imunidade Inata , Mucosa Intestinal/enzimologia , Leucócitos/enzimologia , Mucinas/metabolismo , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Colite/patologia , Colite/prevenção & controle , Sulfato de Dextrana , Diarreia/enzimologia , Diarreia/genética , Diarreia/imunologia , Modelos Animais de Doenças , Fucosiltransferases/deficiência , Fucosiltransferases/genética , Interleucina-2/deficiência , Interleucina-2/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Leucócitos/imunologia , Leucócitos/patologia , Melena/enzimologia , Melena/genética , Melena/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/deficiência , Mucinas/genética , Peroxidase/metabolismo , Índice de Gravidade de Doença , Fatores de Tempo , Fator Trefoil-3 , Redução de Peso , Microglobulina beta-2/deficiência , Microglobulina beta-2/genéticaRESUMO
Analysis of parasite-host interactions can reveal the intricacies of immunity and identify ways to modulate immunopathological reactions. We assessed the ability of a phosphate-buffered saline-soluble extract of adult Hymenolepis diminuta to suppress macrophage (human THP-1 cell line, murine peritoneal macrophages) activity in vitro and the impact of treating mice with this extract on colitis induced by dinitrobenzene sulfonic acid (DNBS). A high-molecular-mass fraction of adult H. diminuta (HdHMW) or excretory/secretory products reduced macrophage activation: lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) and poly(I:C)-induced TNF-alpha and IL-6 were suppressed by HdHMW. The active component in the HdHMW extract was minimally sensitive to boiling and trypsin digestion, whereas the use of sodium metaperiodate, as a general deglycosylation strategy, indicated that the immunosuppressive effect of HdHMW was at least partially dependent on a glycan: treating the HdHMW with neuraminidase and alpha-mannosidase failed to inhibit its blockade of LPS-induced TNF-alpha production by THP-1 macrophages. Mice treated with DNBS developed colitis, as typified by wasting, shortening of the colon, macroscopic and microscopic tissue damage, and an inflammatory infiltrate. Mice cotreated with HdHMW (three intraperitoneal injections) displayed significantly less inflammatory disease, and this was accompanied by reduced TNF-alpha production and increased IL-10 and IL-4 production by mitogen-stimulated spleen cells. However, cotreatment of mice with neutralizing anti-IL-10 antibodies had only a minor impact on the anticolitic effect of the HdHMW. We speculate that purification of the immunosuppressive factor(s) from H. diminuta has the potential to lead to the development of novel immunomodulatory drugs to treat inflammatory disease.
Assuntos
Extratos Celulares/uso terapêutico , Colite/patologia , Hymenolepis diminuta/química , Hymenolepis diminuta/imunologia , Imunossupressores/uso terapêutico , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Animais , Extratos Celulares/química , Extratos Celulares/isolamento & purificação , Linhagem Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/imunologia , Colo/patologia , Humanos , Imunossupressores/química , Imunossupressores/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peso MolecularRESUMO
SUMMARY: Infection with parasitic helminths takes a heavy toll on the health and well-being of humans and their domestic livestock, concomitantly resulting in major economic losses. Analyses have consistently revealed bioactive molecules in extracts of helminths or in their excretory/secretory products that modulate the immune response of the host. It is our view that parasitic helminths are an untapped source of immunomodulatory substances that, in pure form, could become new drugs (or models for drug design) to treat disease. Here, we illustrate the range of immunomodulatory molecules in selected parasitic trematodes, cestodes and nematodes, their impact on the immune cells in the host and how the host may recognize these molecules. There are many examples of the partial characterization of helminth-derived immunomodulatory molecules, but these have not yet translated into new drugs, reflecting the difficulty of isolating and fully characterizing proteins, glycoproteins and lipid-based molecules from small amounts of parasite material. However, this should not deter the investigator, since analytical techniques are now being used to accrue considerable structural information on parasite-derived molecules, even when only minute quantities of tissue are available. With the introduction of methodologies to purify and structurally-characterize molecules from small amounts of tissue and the application of high throughput immunological assays, one would predict that an assessment of parasitic helminths will yield a variety of novel drug candidates in the coming years.
Assuntos
Helmintos/imunologia , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Animais , Bovinos , Cestoides/imunologia , Galectinas/metabolismo , Helmintíase/imunologia , Humanos , Enteropatias Parasitárias/imunologia , Lectinas/metabolismo , Lectinas Tipo C/metabolismo , Camundongos , Nematoides/química , Nematoides/imunologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Trematódeos/imunologiaRESUMO
Three events for the decay K+-->pi+ nunu have been observed in the pion momentum region below the K+-->pi+pi0 peak, 140 < Ppi < 199 MeV/c, with an estimated background of 0.93+/-0.17(stat.) -0.24+0.32(syst.) events. Combining this observation with previously reported results yields a branching ratio of B(K+-->pi+ nunu) = (1.73(-1.05)+1.15) x 10(-10) consistent with the standard model prediction.
RESUMO
Chronic, partial obstruction of the small intestine can dramatically alter peristaltic contractile properties. Morphological studies have revealed hypertrophy of the circular smooth muscle cells in the constricted part of the intestine. In this issue of Neurogastroenterology and Motility, Chen et al. show that hyperplasia and hypertrophy of intestinal smooth muscle cells occur at distinct times in response to partial obstruction of the ileum. Furthermore, the first evidence is provided to link intestinal smooth muscle remodelling during mechanical obstruction with changes in serum response factor and two of its co-regulating factors, myocardin and Elk-1.
Assuntos
Obstrução Intestinal , Intestino Delgado , Músculo Liso , Hipertrofia/patologia , Intestino Delgado/anatomia & histologia , Intestino Delgado/patologia , Intestino Delgado/fisiologia , Músculo Liso/citologia , Músculo Liso/fisiologia , Rede Nervosa/fisiologia , Proteínas Nucleares/metabolismo , Peristaltismo/fisiologia , Fator de Resposta Sérica/metabolismo , Transativadores/metabolismo , Proteínas Elk-1 do Domínio ets/metabolismoRESUMO
Blood samples were collected from a high density population of wild badgers in Woodchester Park, Gloucestershire, England, where animals were routinely captured and examined as part of a long-term ecological study, and a selection of haematological and biochemical variables were measured. The badger cubs had lower red blood cell counts and haemoglobin concentrations than the adults, consistent with physiological anaemia, and lower serum protein concentrations. Growth of muscle and active bone formation in the cubs probably accounted for their higher serum concentrations of creatinine and calcium, and higher activities of alkaline phosphatase. Only triglyceride concentrations varied between the sexes. The serum concentration of urea was higher than observed in other mustelids, consistent with a protein-rich diet and possibly related to the consumption of earthworms.
Assuntos
Contagem de Células Sanguíneas/veterinária , Mustelidae/sangue , Fatores Etários , Anemia/veterinária , Animais , Análise Química do Sangue/veterinária , Cálcio/sangue , Creatinina/sangue , Dieta/veterinária , Inglaterra , Feminino , Testes Hematológicos/veterinária , Masculino , Mustelidae/crescimento & desenvolvimento , Fatores Sexuais , Triglicerídeos/sangueRESUMO
The TWIST Collaboration has measured the Michel parameter rho in normal muon decay, mu(+)--> e(+)nu(e)nu (mu). In the standard model, rho = 3/4. Deviations from this value imply mixing of left- and right-handed muon and electron couplings. We find rho=0.750 80+/-0.000 32(stat) +/- 0.000 97(syst) +/- 0.000 23, where the last uncertainty represents the dependence of rho on the Michel parameter eta. This result sets new limits on the W(L)-W(R) mixing angle in left-right symmetric models.