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1.
Am J Psychiatry ; : appiajp201919060583, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32046535

RESUMO

OBJECTIVE: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. METHODS: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female). RESULTS: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. CONCLUSIONS: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31919950

RESUMO

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome. Parents of emerging adults with 22q11DS have an intense and ongoing involvement in their child's life. This study explores the lived experience of parents in relation to their child becoming independent and establishing intimate relationships. METHOD: Interpretative phenomenological analysis was used to explore the positive and negative experiences of five parents of emerging adults with 22q11DS. RESULTS: Supervised independence overarched four subordinate themes. These themes highlighted the difficulties experienced by parents attempting to relinquish control whilst still experiencing a need to keep their child safe as their child negotiated a complex stage of life. Parents waited for "signs" from their child before initiating conversations about intimate relationships. CONCLUSIONS: These findings provide insight into the lived experience of parenting a child through the transition into adulthood, providing a catalyst for further research with the aim of facilitating better services for families.

3.
Mol Psychiatry ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358905

RESUMO

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

4.
J Asthma ; : 1-13, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31148493

RESUMO

Objective: We aimed to examine the prevalence and severity of psychological distress of women with asthma in both the prenatal and postnatal periods, and to determine whether asthmatic women with and without mental health problems differ in self-management, medications knowledge, and asthma symptoms. Methods: We assessed spirometry performance and asthma symptoms in 120 women (mean age 29.8 years) before 23 weeks gestation, as part of the Breathing for Life Trial (Trial ID: ACTRN12613000202763). Prenatal depression data was obtained from medical records. At 6 weeks postpartum, we assessed general health, self-reported asthma control, depression symptoms (with the Edinburgh Postnatal Depression Scale) and adaptive functioning (with the Achenbach System of Empirically Based Assessment scales). Results: Twenty percent of our sample reported having a current mental health diagnosis, 14% reported currently receiving mental health care, while 47% reported having received mental health care in the past (and may/may not have received a diagnosis). The sample scored high on the Aggressive Behavior, Avoidant Personality, and Attention Deficit/Hyperactivity scales. Poorer self-reported postnatal asthma control was strongly correlated with elevated somatic complaints, externalizing problems, antisocial personality problems, and greater withdrawal. Prenatal spirometry or asthma severity and control were largely not associated with measures of psychopathology. Conclusions: These findings indicate that pregnant women with asthma frequently report issues with psychopathology during the prenatal and postnatal periods, and that the subjective perception of asthma control may be more related to psychopathology than objective asthma measures. However, due to sample bias, these findings are likely to be understated.Trial registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12613000202763.

5.
J Asthma ; 56(2): 130-141, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29482387

RESUMO

OBJECTIVE: Maternal asthma during pregnancy is associated with a higher risk of negative perinatal outcomes. However, little is known about the direct effects of maternal asthma on infant cognitive development. We examined the evidence for an impact of maternal asthma during pregnancy on cognitive and behavioral development of the child. DATA SOURCES: We conducted a MEDLINE, PsychINFO, and manual search of the databases for all available studies until January 9th, 2018. STUDY SELECTIONS: Studies were deemed relevant if they included child cognitive and behavioral development as the outcome, with maternal asthma as the determinant of interest. RESULTS: Ten articles matched selection criteria. Some studies report that maternal asthma is associated with increased risk for autism and intellectual disability in children. However, these effects are small and are often eliminated when controlling for confounding variables. Other studies have found no association. The only prospective study found that well-managed asthma during pregnancy was not associated with negative developmental outcomes in children. CONCLUSIONS: The evidence suggests that the relationship between maternal asthma during pregnancy and poor developmental and behavioral outcomes of children is weak. Children of mothers with well-managed asthma during pregnancy have similar developmental trajectories to those born to healthy mothers. Prospective, longitudinal studies are needed to confirm these conclusions. Optimal asthma management is important in pregnancy as it may have longer term benefits for the health of the offspring. As the rate of asthma increases in the population, the implications of maternal asthma on child development will be of greater importance.


Assuntos
Asma , Comportamento Infantil , Desenvolvimento Infantil , Cognição , Complicações na Gravidez , Criança , Feminino , Humanos , Gravidez
6.
Mol Psychiatry ; 2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29895892

RESUMO

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

7.
BMC Public Health ; 18(1): 742, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907101

RESUMO

BACKGROUND: People with psychosis die on average 25 years earlier than those in the general population, with cardiovascular disease (CVD) contributing to much of the excess mortality. This cross-sectional study aimed to identify the relationship between lifestyle risk factors for CVD - poor nutrition, smoking and low physical activity levels - and dyslipidaemia, hypertension and hyperglycaemia while controlling for potential confounders in 1825 people from the Survey of High Impact Psychosis (SHIP) in Australia. We also aimed to identify clustering patterns of lifestyle risk factors and associated demographic variables. METHODS: Three logistic regressions were used to predict the effect of nutrition, smoking and physical activity on dyslipidaemia, hypertension and hyperglycaemia while controlling for clozapine use, sex and age. Clustering patterns of nutrition, smoking and physical activity were examined using the two-step cluster method which is based on hierarchical cluster analysis. Demographic variables associated with different clusters were identified using measures of association. RESULTS: Smoking status had a positive association with dyslipidaemia (adjusted odds ratio = 0.50; 95% confidence interval = 0.32-0.78; p = 0.002). Other cardiovascular disease lifestyle risk factors did not have a significant relationship with dyslipidaemia, hypertension and hyperglycaemia. Clustering patterns of lifestyle risk factors showed that younger men, with low education levels, and relying on a government pension, were most likely to display the poorest lifestyle risk behaviours. The largest cluster (42%) of participants was characterised by a mixed demographic profile and were most likely to display poor nutrition and low physical activity levels but less likely to smoke. CONCLUSIONS: Only smoking status had a significant positive association with dyslipidaemia which could indicate that there are additional factors affecting the relationship between other cardiovascular lifestyle risk factors and dyslipidaemia, hypertension and hyperglycaemia in people with psychosis. Unknown confounders and traditional lifestyle risk factors may explain the high rates of CVD in this group. Clustering of lifestyle risk factors and their demographic profiles could help the design of intervention programs in people with psychosis.


Assuntos
Doenças Cardiovasculares/epidemiologia , Estilo de Vida , Transtornos Psicóticos/epidemiologia , Adulto , Austrália/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Aust N Z J Psychiatry ; 52(5): 435-445, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29103308

RESUMO

OBJECTIVE: Parenthood is central to the personal and social identity of many people. For individuals with psychotic disorders, parenthood is often associated with formidable challenges. We aimed to identify predictors of adequate parenting among parents with psychotic disorders. METHODS: Data pertaining to 234 parents with psychotic disorders living with dependent children were extracted from a population-based prevalence study, the 2010 second Australian national survey of psychosis, and analysed using confirmatory factor analysis. Parenting outcome was defined as quality of care of children, based on participant report and interviewer enquiry/exploration, and included level of participation, interest and competence in childcare during the last 12 months. RESULTS: Five hypothesis-driven latent variables were constructed and labelled psychosocial support, illness severity, substance abuse/dependence, adaptive functioning and parenting role. Importantly, 75% of participants were not identified to have any dysfunction in the quality of care provided to their child(ren). Severity of illness and adaptive functioning were reliably associated with quality of childcare. Psychosocial support, substance abuse/dependence and parenting role had an indirect relationship to the outcome variable via their association with either severity of illness and/or adaptive functioning. CONCLUSION: The majority of parents in the current sample provided adequate parenting. However, greater symptom severity and poorer adaptive functioning ultimately leave parents with significant difficulties and in need of assistance to manage their parenting obligations. As symptoms and functioning can change episodically for people with psychotic illness, provision of targeted and flexible support that can deliver temporary assistance during times of need is necessary. This would maximise the quality of care provided to vulnerable children, with potential long-term benefits.


Assuntos
Adaptação Psicológica , Educação Infantil , Filho de Pais Incapacitados , Poder Familiar , Pais , Transtornos Psicóticos , Índice de Gravidade de Doença , Adulto , Austrália , Criança , Análise Fatorial , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Apoio Social , Adulto Jovem
9.
Psychiatry Res ; 256: 130-143, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28633054

RESUMO

We aimed to examine and compare sex-differences in people receiving treatment for psychotic illnesses in community settings, based on long or short duration of illness; expecting association between longer illness-duration and worse outcomes in women and men. Clinical, demographic and service-use data from the Survey of High Impact Psychosis were analysed by sex and duration of illness (≤5 years; ≥6 years), using independent t-tests, chi-square tests, one-way ANOVA, and Cramer's V. Of the 1825 participants, 47% had schizophrenia, 17.5% bipolar and 16.1% schizo-affective disorders. More women than men had undertaken post-school education, maintained relationships, and been living in their own homes. Women with a shorter-illness-duration showed social functioning equivalent to non-ill women in the general population. Men tended to have an early illness onset, show premorbid dysfunction, be single, show severe disability, and to use illicit substances. Men with a longer-illness-duration were very socially disadvantaged and isolated, often experiencing homelessness and substance use. Men with a short-illness-duration were most likely to be in paid employment, but two-thirds earned less than $AUD500 per fortnight. Men with longer-illness-duration showed most disability, socially and globally. Interventions should be guided by diagnosis, but also by a person's sex and duration of illness.


Assuntos
Inquéritos Epidemiológicos/métodos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Caracteres Sexuais , Adulto , Idoso , Austrália/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/epidemiologia , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Ajustamento Social , Fatores de Tempo , Adulto Jovem
10.
Nutrients ; 9(1)2017 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-28106815

RESUMO

This analysis aimed to examine the association of social dysfunction with food security status, fruit intake, vegetable intake, meal frequency and breakfast consumption in people with psychosis from the Hunter New England (HNE) catchment site of the Survey of High Impact Psychosis (SHIP). Social dysfunction and dietary information were collected using standardised tools. Independent binary logistic regressions were used to examine the association between social dysfunction and food security status, fruit intake, vegetable intake, meal frequency and breakfast consumption. Although social dysfunction did not have a statistically significant association with most diet variables, participants with obvious to severe social dysfunction were 0.872 (95% CI (0.778, 0.976)) less likely to eat breakfast than those with no social dysfunction p < 0.05. Participants with social dysfunction were therefore, 13% less likely to have breakfast. This paper highlights high rates of social dysfunction, significant food insecurity, and intakes of fruits and vegetables below recommendations in people with psychosis. In light of this, a greater focus needs to be given to dietary behaviours and social dysfunction in lifestyle interventions delivered to people with psychosis. Well-designed observational research is also needed to further examine the relationship between social dysfunction and dietary behaviour in people with psychosis.


Assuntos
Cooperação do Paciente , Fobia Social/etiologia , Transtornos Psicóticos/fisiopatologia , Transtornos do Comportamento Social/etiologia , Adolescente , Adulto , Austrália , Desjejum , Estudos de Coortes , Estudos Transversais , /psicologia , Comportamento Alimentar/psicologia , Feminino , Abastecimento de Alimentos/economia , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Cooperação do Paciente/psicologia , Fobia Social/economia , Fobia Social/prevenção & controle , Fobia Social/psicologia , Transtornos Psicóticos/economia , Transtornos Psicóticos/psicologia , Transtornos Psicóticos/terapia , Estudos Retrospectivos , Transtornos do Comportamento Social/economia , Transtornos do Comportamento Social/prevenção & controle , Transtornos do Comportamento Social/psicologia , Isolamento Social/psicologia , Fatores Socioeconômicos , Estresse Psicológico/economia , Estresse Psicológico/etiologia , Estresse Psicológico/prevenção & controle , Estresse Psicológico/psicologia , Adulto Jovem
11.
Health Psychol ; 36(1): 45-54, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27657800

RESUMO

OBJECTIVES: 22q11.2 deletion syndrome (22q11DS), a complex genetic syndrome associated with more than 180 features, presents complex challenges for parents including gaining a diagnosis. This phenomenological study sought the "lived" interpretations of parents supporting an adult child with 22q11DS, a poorly researched area. METHOD: Interpretative phenomenological analysis informed a detailed and open exploration of parenting a child through to adult life with 22q11DS. Using in-depth semistructured interviews, 8 parents (2 male, 6 female) of adult children with 22q11DS were individually interviewed; providing the data set for transcription and thematic analysis. RESULTS: Losing "I" Finding "self," overarched 6 subordinate themes that emerged from participants' articulated descriptions of psychological distress and psychological growth. Distress in parenting a child with 22q11DS was experienced through stigma, loss, grief, and guilt. Progressively, stigma undermined independence, friendships, and instinctual judgement. Ill-informed hierarchical structures experienced as layers of obstruction and lack of awareness of the syndrome triggered angry advocacy for their child. Diagnosis brought opposing relief and grief. In time, they came to value their unique "accomplishments," collected on their journey with 22q11DS, and in turn, consciously valued authentic "self" expressed through empathy, humility, gratitude, and pride. CONCLUSION: Parental distress through societal, educational, and health care invalidation persisted for decades for all participants. Conversely, distress facilitated psychological growth for redefining "self" and role as parents over time. Building on this phenomenological cameo, future research can educate against the plight of 22q11DS families. It can enlighten health care professionals in buffering against associated stigma, blame, and self-doubt, and in fostering psychological well-being. (PsycINFO Database Record


Assuntos
Crianças Adultas/psicologia , Síndrome de DiGeorge/psicologia , Acontecimentos que Mudam a Vida , Relações Pais-Filho , Poder Familiar/psicologia , Estigma Social , Criança , Síndrome de DiGeorge/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
J Invest Dermatol ; 137(2): 385-393, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27769845

RESUMO

Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.


Assuntos
Calpaína/fisiologia , Ictiose/genética , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Calpaína/genética , Criança , Folículo Piloso/fisiologia , Humanos , Ictiose/patologia , Proteínas de Filamentos Intermediários/análise , Masculino , Camundongos , Mutação , Peixe-Zebra
13.
J Neurodev Disord ; 8: 30, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27536336

RESUMO

BACKGROUND: People with 22q11.2 deletion syndrome (22q11DS) have difficulty processing social information including facial identity and emotion processing. However, difficulties with visual and attentional processes may play a role in difficulties observed with these social cognitive skills. METHODS: A cross-sectional study investigated visual perception and processing as well as facial processing abilities in a group of 49 children and adolescents with 22q11DS and 30 age and socio-economic status-matched healthy sibling controls using the Birmingham Object Recognition Battery and face processing sub-tests from the MRC face processing skills battery. RESULTS: The 22q11DS group demonstrated poorer performance on all measures of visual perception and processing, with greatest impairment on perceptual processes relating to form perception as well as object recognition and memory. In addition, form perception was found to make a significant and unique contribution to higher order social-perceptual processing (face identity) in the 22q11DS group. CONCLUSIONS: The findings indicate evidence for impaired visual perception and processing capabilities in 22q11DS. In turn, these were found to influence cognitive skills needed for social processes such as facial identity recognition in the children with 22q11DS.

14.
J Allergy Clin Immunol ; 138(2): 509-16, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27241890

RESUMO

BACKGROUND: Domestic water hardness and chlorine have been suggested as important risk factors for atopic dermatitis (AD). OBJECTIVE: We sought to examine the link between domestic water calcium carbonate (CaCO3) and chlorine concentrations, skin barrier dysfunction (increased transepidermal water loss), and AD in infancy. METHODS: We recruited 1303 three-month-old infants from the general population and gathered data on domestic water CaCO3 (in milligrams per liter) and chlorine (Cl2; in milligrams per liter) concentrations from local water suppliers. At enrollment, infants were examined for AD and screened for filaggrin (FLG) skin barrier gene mutation status. Transepidermal water loss was measured on unaffected forearm skin. RESULTS: CaCO3 and chlorine levels were strongly correlated. A hybrid variable of greater than and less than median levels of CaCO3 and total chlorine was constructed: a baseline group of low CaCO3/low total chlorine (CaL/ClL), high CaCO3/low total chlorine (CaH/ClL), low CaCO3/high total chlorine (CaL/ClH) and high CaCO3/high total chlorine (CaH/ClH). Visible AD was more common in all 3 groups versus the baseline group: adjusted odds ratio (AOR) of 1.87 (95% CI, 1.25-2.80; P = .002) for the CaH/ClL group, AOR of 1.46 (95% CI, 0.97-2.21; P = .07) for the CaL/ClH, and AOR of 1.61 (95% CI, 1.09-2.38; P = .02) for the CaH/ClH group. The effect estimates were greater in children carrying FLG mutations, but formal interaction testing between water quality groups and filaggrin status was not statistically significant. CONCLUSIONS: High domestic water CaCO3 levels are associated with an increased risk of AD in infancy. The influence of increased total chlorine levels remains uncertain. An intervention trial is required to see whether installation of a domestic device to decrease CaCO3 levels around the time of birth can reduce this risk.


Assuntos
Cloro/efeitos adversos , Dermatite Atópica/epidemiologia , Dermatite Atópica/etiologia , Água/efeitos adversos , Adulto , Idade de Início , Carbonato de Cálcio/efeitos adversos , Carbonato de Cálcio/química , Cloro/química , Comorbidade , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Proteínas de Filamentos Intermediários/genética , Masculino , Exposição Materna , Pessoa de Meia-Idade , Mutação , Razão de Chances , Vigilância da População , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Prevalência , Fatores de Risco , Reino Unido/epidemiologia , Água/química , Adulto Jovem
15.
J Allergy Clin Immunol ; 138(2): 482-490.e7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26934939

RESUMO

BACKGROUND: Mutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%. OBJECTIVE: This study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells. METHODS: Epidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11). RESULTS: Epidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83(+) Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions. CONCLUSIONS: We show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.


Assuntos
Diferenciação Celular/genética , Proteínas de Filamentos Intermediários/genética , Células de Langerhans/citologia , Células de Langerhans/metabolismo , Mutação , Adulto , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Biomarcadores , Antígeno CD11c/metabolismo , Comunicação Celular , Técnicas de Cocultura , Dermatite Atópica/diagnóstico , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina E/imunologia , Células de Langerhans/imunologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
17.
J Allergy Clin Immunol ; 136(6): 1573-1580.e2, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26071937

RESUMO

BACKGROUND: Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status. OBJECTIVE: We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD. METHODS: We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anti-corneodesmosin antibody and visualized with scanning electron microscopy. RESULTS: We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r = -0.80 and -0.75, P < .001 and P = .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients. CONCLUSIONS: NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrin-deficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations.


Assuntos
Córnea/anormalidades , Dermatite Atópica/genética , Proteínas de Filamentos Intermediários/genética , Adolescente , Adulto , Criança , Pré-Escolar , Córnea/citologia , Córnea/ultraestrutura , Feminino , Genótipo , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Masculino , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Mutação , Adulto Jovem
18.
J Neurodev Disord ; 7(1): 1, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25972975

RESUMO

BACKGROUND: 22q11.2 deletion syndrome (22q11DS, velo-cardio-facial syndrome [VCFS]) is a genetic disorder associated with interstitial deletions of chromosome 22q11.2. In addition to high rates of neuropsychiatric disorders, children with 22q11DS have impairments of face processing, as well as IQ-independent deficits in visuoperceptual function and social and abstract reasoning. These face-processing deficits may contribute to the social impairments of 22q11DS. However, their neurobiological basis is poorly understood. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to examine neural responses when children with 22q11DS (aged 9-17 years) and healthy controls (aged 8-17 years) incidentally processed neutral expressions and mild (50%) and intense (100%) expressions of fear and disgust. We included 28 right-handed children and adolescents: 14 with 22q11DS and 14 healthy (including nine siblings) controls. RESULTS: Within groups, contrasts showed that individuals significantly activated 'face responsive' areas when viewing neutral faces, including fusiform-extrastriate cortices. Further, within both groups, there was a significant positive linear trend in activation of fusiform-extrastriate cortices and cerebellum to increasing intensities of fear. There were, however, also between-group differences. Children with 22q11DS generally showed reduced activity as compared to controls in brain regions involved in social cognition and emotion processing across emotion types and intensities, including fusiform-extrastriate cortices, anterior cingulate cortex (Brodmann area (BA) 24/32), and superomedial prefrontal cortices (BA 6). Also, an exploratory correlation analysis showed that within 22q11DS children reduced activation was associated with behavioural impairment-social difficulties (measured using the Total Difficulties Score from the Strengths and Difficulties Questionnaire [SDQ]) were significantly negatively correlated with brain activity during fear and disgust processing (respectively) in the left precentral gyrus (BA 4) and in the left fusiform gyrus (FG, BA 19), right lingual gyrus (BA 18), and bilateral cerebellum. CONCLUSIONS: Regions involved in face processing, including fusiform-extrastriate cortices, anterior cingulate gyri, and superomedial prefrontal cortices (BA 6), are activated by facial expressions of fearful, disgusted, and neutral expressions in children with 22q11DS but generally to a lesser degree than in controls. Hypoactivation in these regions may partly explain the social impairments of children with 22q11DS.

19.
J Allergy Clin Immunol ; 135(4): 930-5.e1, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25618747

RESUMO

BACKGROUND: Loss-of-function mutations in the skin barrier protein filaggrin (FLG) are a major risk for atopic dermatitis (AD). The pathogenic sequence of disturbances in skin barrier function before or during the early development of AD is not fully understood. A more detailed understanding of these events is needed to develop a clearer picture of disease pathogenesis. A robust, noninvasive test to identify babies at high risk of AD would be important in planning early intervention and/or prevention studies. OBJECTIVES: To ascertain whether a noninvasive measurement of skin barrier function at day 2 after birth and at 2 months predicts the development of AD at 1 year. Furthermore, to determine whether increases in transepidermal water loss (TEWL) predate the development of clinical AD. METHODS: A total of 1903 infants were enrolled in the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints Birth Cohort study from July 2009 to October 2011. Measurements of TEWL were made at birth (day 2) and at 2 and 6 months. The presence of AD was ascertained at 6 and 12 months, and disease severity was assessed by using the SCORing Atopic Dermatitis clinical tool at 6 months and by using both the SCORing Atopic Dermatitis clinical tool and Nottingham Severity Score at 12 months. A total of 1300 infants were genotyped for FLG mutations. RESULTS: At 6 months, 18.7% of the children had AD, and at 12 months, 15.53%. In a logistic regression model, day 2 upper quartile TEWL measurement was significantly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.81; P < .05). Lowest quartile day 2 TEWL was protective against AD at 12 months. An upper quartile 2 month TEWL was also strongly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.84; P < .05). At both ages, this effect was independent of parental atopy, FLG status, or report of an itchy flexural rash at 2 months. Associations were increased when parental atopy status or child FLG mutation status was added into the linear regression model. CONCLUSIONS: Impairment of skin barrier function at birth and at 2 months precedes clinical AD. In addition to providing important mechanistic insights into disease pathogenesis, these findings have implications for the optimal timing of interventions for the prevention of AD.


Assuntos
Dermatite Atópica/diagnóstico , Pele/fisiopatologia , Análise Mutacional de DNA , Dermatite Atópica/genética , Dermatite Atópica/fisiopatologia , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Masculino , Prognóstico , Risco , Pele/metabolismo , Fatores de Tempo
20.
Psychiatry Res ; 225(3): 723-33, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25524813

RESUMO

Research demonstrates that people living with serious mental illness (SMI) contend with widespread public stigma; however, little is known about the specific experiences of stigma that mothers, and in particular fathers, with SMI encounter as parents. This study aimed to explore and compare the experiences of stigma for mothers and fathers with SMI inferred not only by living with a mental illness but also potential compounding gender effects, and the associated impact of stigma on parenting. Telephone surveys were conducted with 93 participants with SMI who previously identified as parents in the Second Australian National Survey of Psychosis. Results indicated that mothers were more likely than fathers to perceive and internalise stigma associated with their mental illness. Conversely, fathers were more inclined to perceive stigma relating to their gender and to hold stigmatising attitudes towards others. Mental illness and gender stigma predicted poorer self-reported parenting experiences for both mothers and fathers. These findings may assist in tailoring interventions for mothers and fathers with SMI.


Assuntos
Pai/psicologia , Transtornos Mentais/psicologia , Mães/psicologia , Poder Familiar/psicologia , Estigma Social , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto Jovem
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