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1.
Am J Med Genet A ; 194(2): 337-345, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37850681

RESUMO

Seizures occur in up to 59% of boys with creatine transporter deficiency (CTD). While seizure phenotypes have been previously described, electroencephalogram (EEG) findings have only been reported in several case reports. In this prospective observational study, we report seizure characteristics and EEG findings in combination with neurobehavioral and SLC6A8 pathogenic variants in twenty males with CTD. Eighteen study participants (SP) underwent video-EEG, and seven had follow-up EEG recordings. Seizures typically occurred by age of 2 years. Thirteen (65%) had non-febrile seizures, requiring anti-seizure medications in nine. Four had febrile seizures. Seizures were bilateral tonic-clonic in 7 SP and focal impaired awareness in 5 SP; often responding to 1 to 2 antiseizure medications. EEG showed slowing in 5 SP, beta activity in 6 SP, and focal/multifocal, and/or generalized epileptiform activity in 9 SP. Follow-up EEGs in 7 SP showed emergence of epileptiform activity in 1 SP, and increased activity in 2 SP. In conclusion, seizures were frequent in our cohort but tended to respond to antiseizure medications. Longitudinal follow up provided further insight into emergence of seizures and EEG abnormalities soliciting future studies with long term follow up. Biomarkers of epileptogenicity in CTD are needed to predict seizures in this population.


Assuntos
Encefalopatias Metabólicas Congênitas , Creatina/deficiência , Eletroencefalografia , Deficiência Intelectual Ligada ao Cromossomo X , Masculino , Humanos , Pré-Escolar , Mutação , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/genética , Proteínas do Tecido Nervoso , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
2.
Am J Med Genet A ; 194(8): e63608, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38546160

RESUMO

Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD) and other neurocognitive measures, including assessment of IQ, executive and adaptive functioning, and health-related quality of life. Thirteen individuals (65%) were identified as having ASD, of which five were newly diagnosed during the study. Of those, ASD symptom severity was in the mild-moderate range for 77%. Overall, IQ was in the average range, with a mean of 92.61 (SD 24.45, p = 0.5), though there was a non-statistically significant trend toward individuals without ASD having a higher mean IQ (102.7 vs 82.3; p = 0.1). Subjects had significant impairment in processing speed (mean 75.38, SD 24.75, p < 0.05), decreased adaptive functioning skills across all domains, and a trend toward having more executive functioning problems. Individuals with PHTS are at increased risk of neurodevelopmental disorders, including ASD and impaired executive and adaptive functioning. Although clear guidelines exist for cancer surveillance for individuals with PHTS, additional guidelines and screening for neurodevelopmental disorders are warranted.


Assuntos
Transtorno do Espectro Autista , Síndrome do Hamartoma Múltiplo , PTEN Fosfo-Hidrolase , Fenótipo , Humanos , Masculino , Feminino , Criança , Adolescente , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Síndrome do Hamartoma Múltiplo/diagnóstico , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/diagnóstico , PTEN Fosfo-Hidrolase/genética , Pré-Escolar , Qualidade de Vida
3.
Bull Math Biol ; 84(3): 37, 2022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-35099649

RESUMO

Geographic ranges of communities of species evolve in response to environmental, ecological, and evolutionary forces. Understanding the effects of these forces on species' range dynamics is a major goal of spatial ecology. Previous mathematical models have jointly captured the dynamic changes in species' population distributions and the selective evolution of fitness-related phenotypic traits in the presence of an environmental gradient. These models inevitably include some unrealistic assumptions, and biologically reasonable ranges of values for their parameters are not easy to specify. As a result, simulations of the seminal models of this type can lead to markedly different conclusions about the behavior of such populations, including the possibility of maladaptation setting stable range boundaries. Here, we harmonize such results by developing and simulating a continuum model of range evolution in a community of species that interact competitively while diffusing over an environmental gradient. Our model extends existing models by incorporating both competition and freely changing intraspecific trait variance. Simulations of this model predict a spatial profile of species' trait variance that is consistent with experimental measurements available in the literature. Moreover, they reaffirm interspecific competition as an effective factor in limiting species' ranges, even when trait variance is not artificially constrained. These theoretical results can inform the design of, as yet rare, empirical studies to clarify the evolutionary causes of range stabilization.


Assuntos
Evolução Biológica , Modelos Biológicos , Ecossistema , Conceitos Matemáticos , Modelos Teóricos , Fenótipo , Dinâmica Populacional
4.
Genet Med ; 23(10): 1864-1872, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34050321

RESUMO

PURPOSE: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). CTD features include developmental delay, seizures, and autism spectrum disorder. This study was designed to investigate CTD cardiac phenotype and sudden death risk. METHODS: We performed a cross-sectional analysis of CTD males between 2017 and 2020. Subjects underwent evaluation with electrocardiogram (ECG), echocardiography, and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8-/y) using ECG, echocardiography, exercise testing, and indirect calorimetry. RESULTS: Eighteen subjects with CTD (18 males, age 7.4 [3.8] years) were evaluated: seven subjects (39%) had QTc ≥ 470 milliseconds: 510.3 ± 29.0 vs. 448.3 ± 15.9, P < 0.0001. The QTc ≥ 470 milliseconds cohort had increased left ventricular internal dimension (diastole) ([LVIDd] Z-score: 0.22 ± 0.74, n = 7 vs. -0.93 ± 1.0, n = 11, P = 0.0059), and diminished left ventricular posterior wall dimension (diastole) ([LVPWDd, in mm]: 5.0 ± 0.6, n = 7 vs. 5.7 ± 0.8, n = 11, P = 0.0183), when compared to subjects with normal or borderline QTc prolongation. Similar ECG and echocardiographic abnormalities were seen in Slc6a8-/y mice. Additionally, Slc6a8-/y mice had diminished survival (65%). CONCLUSION: Prolonged QTc and abnormal echocardiographic parameters consistent with developing cardiomyopathy are seen in some male subjects with CTD. Slc6a8-/y mice recapitulated these cardiac abnormalities. Male CTD subjects may be at increased risk for cardiac dysfunction and sudden death.


Assuntos
Transtorno do Espectro Autista , Creatina , Animais , Encefalopatias Metabólicas Congênitas , Creatina/deficiência , Estudos Transversais , Morte Súbita , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X , Camundongos , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência
5.
Foodborne Pathog Dis ; 18(7): 448-454, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33904765

RESUMO

In July 2019, we investigated a cluster of Yersinia enterocolitica cases affecting a youth summer camp and nearby community in northeastern Pennsylvania. After initial telephone interviews with camp owners and community members, we identified pasteurized milk from a small dairy conducting on-site pasteurization, Dairy A, as a shared exposure. We conducted site visits at the camp and Dairy A where we collected milk and other samples. Samples were cultured for Y. enterocolitica. Clinical and nonclinical isolates were compared using molecular subtyping. We performed case finding, conducted telephone interviews for community cases, and conducted a cohort study among adult camp staff by administering an online questionnaire. In total, we identified 109 Y. enterocolitica cases. Consumption of Dairy A milk was known for 37 (34%); of these, Dairy A milk was consumed by 31 (84%). Dairy A had shipped 214 gallons of pasteurized milk in 5 weekly shipments to the camp by mid-July. Dairy A milk was the only shared exposure identified between the camp and community. Y. enterocolitica was isolated from Dairy A unpasteurized milk samples. Five clinical isolates from camp members, two clinical isolates from community members, and nine isolates from unpasteurized milk were indistinguishable by whole-genome sequencing. The risk for yersinosis among camp staff who drank Dairy A milk was 5.3 times the risk for those who did not (95% confidence interval: 1.6-17.3). Because Dairy A only sold pasteurized milk, pasteurized milk was considered the outbreak source. We recommend governmental agencies and small dairies conducting on-site pasteurization collaborate to develop outbreak prevention strategies.


Assuntos
Doenças Transmitidas por Alimentos/epidemiologia , Leite/microbiologia , Yersiniose/epidemiologia , Yersinia enterocolitica/isolamento & purificação , Adolescente , Animais , Criança , Estudos de Coortes , Surtos de Doenças , Feminino , Doenças Transmitidas por Alimentos/microbiologia , Humanos , Masculino , Pennsylvania/epidemiologia , Yersiniose/microbiologia , Yersinia enterocolitica/genética
6.
Dev Neurosci ; 41(1-2): 123-131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280271

RESUMO

47,XYY syndrome (XYY) is one of the common forms of sex chromosome aneuploidy in males. XYY males tend to have tall stature, early speech, motor delays, social and behavioral challenges, and a high rate of language impairment. Recent studies indicate that 20-40% of males with XYY meet diagnostic criteria for autism spectrum disorder (ASD; the rate in the general population is 1-2%). Although many studies have examined the neural correlates of language impairment in ASD, few similar studies have been conducted on individuals with XYY. Studies using magnetoencephalography (MEG) in idiopathic ASD (ASD-I) have demonstrated delayed neurophysiological responses to changes in the auditory stream, revealed in the mismatch negativity or its magnetic counterpart, the mismatch field (MMF). This study investigated whether similar findings are observed in XYY-associated ASD and whether delayed processing is also present in individuals with XYY without ASD. MEG measured MMFs arising from the left and the right superior temporal gyrus during an auditory oddball paradigm with vowel stimuli (/a/ and /u/) in children/adolescents with XYY both with and without a diagnosis of ASD, as well as in those with ASD-I and in typically developing controls (TD). Ninety male participants (6-17 years old) were included in the final analyses (TD, n = 38, 11.50 ± 2.88 years; ASD-I, n = 21, 13.83 ± 3.25 years; XYY without ASD, n = 15, 12.65 ± 3.91 years; XYY with ASD, n = 16, 12.62 ± 3.19 years). The groups did not differ significantly in age (p > 0.05). There was a main effect of group on MMF latency (p < 0.001). Delayed MMF latencies were found in participants with XYY both with and without an ASD diagnosis, as well as in the ASD-I group compared to the TD group (ps < 0.001). Furthermore, participants with XYY (with and without ASD) showed a longer MMF latency than the ASD-I group (ps < 0.001). There was, however, no significant difference in MMF latency between individuals with XYY with ASD and those with XYY without ASD. Delayed MMF latencies were associated with severity of language impairment. Our findings suggest that auditory MMF latency delays are pronounced in this specific Y chromosome aneuploidy disorder, both with and without an ASD diagnosis, and thus may implicate the genes of the Y chromosome in mediating atypical MMF activity.


Assuntos
Potenciais Evocados Auditivos/fisiologia , Transtornos dos Cromossomos Sexuais/fisiopatologia , Cariótipo XYY/fisiopatologia , Estimulação Acústica , Adolescente , Transtorno do Espectro Autista/etiologia , Criança , Humanos , Magnetoencefalografia , Masculino , Transtornos dos Cromossomos Sexuais/complicações
7.
J Pediatr ; 206: 283-285, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30579583

RESUMO

Early identification is a goal for creatine transporter deficiency and will be critical for future treatment. Before their first birthday, one-half of this sample showed both a significant feeding/weight gain issue and delayed sitting or crawling. Combined, these early indicators could have alerted providers to conduct a urine screen.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Creatina/deficiência , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Adolescente , Fatores Etários , Encefalopatias Metabólicas Congênitas/complicações , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/complicações , Estudos Retrospectivos , Fatores de Risco , Avaliação de Sintomas , Urinálise , Adulto Jovem
8.
J Math Biol ; 78(1-2): 257-292, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30054672

RESUMO

The Kirkpatrick-Barton model, well known to invasion biologists, is a pair of reaction-diffusion equations for the joint evolution of population density and the mean of a quantitative trait as functions of space and time. Here we prove the existence of two classes of coherent structures, namely "bounded trait mean differential" traveling waves and localized stationary solutions, using geometric singular perturbation theory. We also give numerical examples of these (when they appear to be stable) and of "unbounded trait mean differential" solutions. Further, we provide numerical evidence of bistability and hysteresis for this system, modeling an initially confined population that colonizes new territory when some biotic or abiotic conditions change, and remains in its enlarged range even when conditions change back. Our analytical and numerical results indicate that the dynamics of this system are more complicated than previously recognized, and help make sense of evolutionary range dynamics predicted by other models that build upon it and sometimes challenge its predictions.


Assuntos
Evolução Biológica , Modelos Biológicos , Animais , Biologia Computacional , Simulação por Computador , Conceitos Matemáticos , Modelos Genéticos , Fenótipo , Densidade Demográfica , Dinâmica Populacional/estatística & dados numéricos
9.
Am J Med Genet B Neuropsychiatr Genet ; 180(7): 471-482, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31161682

RESUMO

We describe a unique male with a dicentric Y chromosome whose phenotype was compared to that of males with 47,XYY (XYY). The male Y-chromosome aneuploidy XYY is associated with physical, behavioral/cognitive phenotypes, and autism spectrum disorders. We hypothesize that increased risk for these phenotypes is caused by increased copy number/overexpression of Y-encoded genes. Specifically, an extra copy of the neuroligin gene NLGN4Y might elevate the risk of autism in boys with XYY. We present a unique male with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, evaluated his physical, behavioral/cognitive, and neuroimaging/magnetoencephalography (MEG) phenotypes, and measured blood RNA expression of Y genes. The proband had tall stature and cognitive function within the typical range, without autism features. His blood RNA showed twofold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y. The M100 latencies were similar to findings in typically developing males. In summary, the proband had overexpression of a subset of Yp genes, absent NLGN4Y expression, without ASD findings or XYY-MEG latency findings. These results are consistent with a role for NLGN4Y overexpression in the etiology of behavioral phenotypes associated with XYY. Further investigation of NLGN4Y as an ASD risk gene in XYY is warranted. The genotype and phenotype(s) of this subject may also provide insight into how Y chromosome genes contribute to normal male development and the male predominance in ASD.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Cromossomos Humanos Y/genética , Cariótipo XYY/fisiopatologia , Adolescente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Moléculas de Adesão Celular Neuronais/metabolismo , Criança , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Dosagem de Genes/genética , Genes Ligados ao Cromossomo Y/genética , Humanos , Cariotipagem , Masculino , Testes Neuropsicológicos , Fenótipo , Cariótipo XYY/genética
10.
Curr Psychiatry Rep ; 20(11): 103, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30238166

RESUMO

PURPOSE OF REVIEW: This article discusses common issues surrounding transition to adulthood in youth with autism spectrum disorder (ASD). We review recent evidence on co-occurring medical and mental health conditions and topics of education and employment, sexuality and relationships, independent living, and financial support. RECENT FINDINGS: Transitioning individuals with ASD have increased risk for several medical and behavioral health comorbidities and should be routinely screened for co-occurring conditions. Evidence on interventions for mental health disorders is limited but emerging, particularly with respect to mindfulness training and cognitive behavioral therapy. Many autistic adults or their families express a desire for independent living, participation in education/employment, and intimacy and social relationships, but they often lack skills and/or resources to successfully achieve these outcomes. The time of transition to adulthood for adolescents with ASD is an opportunity for physicians to provide anticipatory guidance and necessary supports around issues of community participation. To allow time for planning, these discussions should occur well before the child reaches adulthood. Clinicians should also routinely screen for and address medical and/or behavioral health comorbidities.


Assuntos
Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/psicologia , Adolescente , Criança , Comorbidade , Humanos , Adulto Jovem
11.
Int J Behav Nutr Phys Act ; 14(1): 81, 2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28637470

RESUMO

BACKGROUND: Slowing the decline in participation in physical activity among adolescent girls is a public health priority. This study reports the outcomes from a multi-component school-based intervention (Girls in Sport), focused on promoting physical activity among adolescent girls. METHODS: Group randomized controlled trial in 24 secondary schools (12 intervention and 12 control). Assessments were conducted at baseline (2009) and at 18 months post-baseline (2010). The setting was secondary schools in urban, regional and rural areas of New South Wales, Australia. All girls in Grade 8 in 2009 who attended these schools were invited to participate in the study (N = 1769). Using a Health Promoting Schools and Action Learning Frameworks, each school formed a committee and developed an action plan for promoting physical activity among Grade 8 girls. The action plan incorporated strategies in three main areas - i) the formal curriculum, ii) school environment, and iii) home/school/community links - based on the results of formative data from target girls and staff and on individual needs of the school. A member of the research team supported each school throughout the intervention. The main outcome measure was accelerometer-derived total physical activity (TPA) spent in physical activity. Data were analyzed from December 2011 to March 2012. RESULTS: 1518 girls (mean age 13.6y ±0.02) were assessed at baseline. There was a significant decline in TPA from baseline to 18-month follow-up with no differences between girls in the intervention and control schools. Only one-third of schools (4/12) implemented the intervention as per their action plan. Per-protocol analyses on these schools revealed a smaller decline in percentage of time spent in MVPA among girls in the intervention group (adjusted difference 0.5%, 95% CI = -0.01, 0.99, P = 0.05). CONCLUSIONS: The Girls in Sport intervention was not effective in reducing the decline in physical activity among adolescent girls. Lack of implementation by most intervention schools was the main reason for a null effect. Identifying strategies to enhance implementation levels is critical to determining the true potential of this intervention approach. TRIAL REGISTRATION: This study was retrospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12610001077055 . Date of registration: 7 December 2010.


Assuntos
Exercício Físico , Promoção da Saúde/métodos , Serviços de Saúde Escolar , Instituições Acadêmicas , Esportes , Acelerometria , Adolescente , Feminino , Humanos , New South Wales
12.
Regul Toxicol Pharmacol ; 82: 94-98, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27769827

RESUMO

Chronic (>3 months) preclinical toxicology studies are conducted to support the safe conduct of clinical trials exceeding 3 months in duration. We have conducted a review of 32 chronic toxicology studies in non-rodents (22 studies in dogs and 10 in non-human primates) and 27 chronic toxicology studies in rats dosed with Merck compounds to determine the frequency at which additional target organ toxicities are observed in chronic toxicology studies as compared to subchronic studies of 3 months in duration. Our review shows that majority of the findings are observed in the subchronic studies since additional target organs were not observed in 24 chronic non rodent studies and in 21 chronic rodent studies. However, 6 studies in non rodents and 6 studies in rodents yielded new findings that were not seen in studies of 3-month or shorter duration. For 3 compounds the new safety findings did contribute to termination of clinical development plans. Although the incidence of compound termination associated with chronic toxicology study observations is low (∼10%), the observations made in these studies can be important for evaluating human safety risk.


Assuntos
Testes de Toxicidade Crônica/métodos , Testes de Toxicidade Subcrônica/métodos , Animais , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Indústria Farmacêutica , Humanos , Modelos Animais , Reprodutibilidade dos Testes , Medição de Risco , Especificidade da Espécie , Fatores de Tempo
13.
Appl Nurs Res ; 29: 9-11, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26856481

RESUMO

PURPOSE: The purpose of this study was to determine perceived cognitive functioning, fatigue, depression and general well-being among women before and after the initiation of chemotherapy for breast cancer compared to a sample of healthy women. METHOD: This descriptive, repeated measures study compared women receiving chemotherapy and healthy women. Women completed measures of quality of life, fatigue, cognitive changes and depression. RESULTS: Before chemotherapy, women with cancer reported more fatigue and depression than healthy women. After chemotherapy, women with cancer reported decreased cognitive functioning accompanied by more fatigue and depressive symptoms than healthy women. CONCLUSION: This study is one of the first to use multiple symptom measures before and after starting chemotherapy. Understanding cognitive changes and related symptoms that occur before and during chemotherapy for breast cancer is the first step toward helping women cope with changes that occur with breast cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cognição , Neoplasias da Mama/fisiopatologia , Neoplasias da Mama/psicologia , Depressão/psicologia , Fadiga/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Percepção , Projetos Piloto
14.
Am J Physiol Renal Physiol ; 308(6): F535-40, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25587124

RESUMO

The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) through first-pass hepatic metabolism. Although usually benign, RAAS activation may have detrimental effects on renal and hemodynamic function in some women. Since combined hormonal contraception with the transdermal patch (EVRA) does not undergo first-pass hepatic metabolism, we hypothesized that the RAAS response would be different from that of OCP subjects. Thirty-five nonsmoking, premenopausal women (15 control subjects, 10 OCP subjects, and 10 contraceptive patch subjects) without evidence of cardiovascular disease, renal disease, or diabetes were studied. Baseline angiotensinogen, renin, angiotensin II, aldosterone, and plasma renin activity were assessed along with hormonal and hemodynamic responses to simulated orthostatic stress using incremental lower body negative pressure (LBNP; -15, -25, and -40 mmHg). Baseline levels of angiotensinogen, angiotensin II, and plasma renin activity were significantly higher in OCP subjects compared with normotensive control and contraceptive patch subjects (P < 0.05), whereas aldosterone was significantly higher in OCP versus control subjects only (P < 0.05). Plasma renin levels were significantly lower at baseline in contraceptive patch subjects compared with normotensive control and OCP subjects (P < 0.05). In response to LBNP, increases in renin, angiotensin II, and aldosterone were attenuated in contraceptive patch subjects in conjunction with an exaggerated decline in mean arterial pressure (P < 0.05 vs. control and OCP subjects). The contraceptive patch in healthy premenopausal women is associated with an impaired ability to maintain blood pressure in response to LBNP, possibly due to insensitivity of the endogenous RAAS. Further evaluation may be beneficial in women with kidney disease.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Sistema Renina-Angiotensina/efeitos dos fármacos , Administração Cutânea , Adulto , Angiotensina II/sangue , Estudos de Casos e Controles , Feminino , Humanos , Pré-Menopausa/efeitos dos fármacos , Renina/sangue , Adulto Jovem
15.
Nature ; 459(7246): 528-33, 2009 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-19404256

RESUMO

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos Par 5/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Encéfalo/metabolismo , Caderinas/genética , Estudos de Casos e Controles , Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Estudos de Coortes , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
16.
Nature ; 459(7246): 569-73, 2009 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-19404257

RESUMO

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.


Assuntos
Transtorno Autístico/genética , Dosagem de Genes/genética , Variação Genética/genética , Genoma Humano/genética , Neurônios/metabolismo , Ubiquitina/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Estudos de Coortes , Europa (Continente)/etnologia , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
17.
J Math Biol ; 68(1-2): 207-34, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23187678

RESUMO

In an influential paper, Kirkpatrick and Barton (Am Nat 150:1-23 1997) presented a system of diffusive partial differential equations modeling the joint evolution of population density and the mean of a quantitative trait when the trait optimum varies over a continuous spatial domain. We present a stability theorem for steady states of a simplified version of the system, originally studied in Kirkpatrick and Barton (Am Nat 150:1-23 1997). We also present a derivation of the system.


Assuntos
Evolução Biológica , Modelos Genéticos , Característica Quantitativa Herdável , Animais , Simulação por Computador , Densidade Demográfica
18.
Artigo em Inglês | MEDLINE | ID: mdl-38969925

RESUMO

The electronic health record (EHR) should contain information to support culturally responsive care and research; however, the widely used default "Asian" demographic variable in most US social systems (including EHRs) lacks information to describe the diverse experience within the Asian diaspora (e.g., ethnicities, languages). This has a downstream effect on research, identifying disparities, and addressing health equity. We were particularly interested in EHRs of autistic patients from the Asian diaspora, since the presence of a developmental diagnosis might call for culturally responsive care around understanding causes, treatments, and services to support good outcomes. The aim of this study is to determine the degree to which information about Asian ethnicity, languages, and culture is documented and accessible in the EHR, and whether it is differentially available for patients with or without autism. Using electronic and manual medical chart review, all autistic and "Asian" children (group 1; n = 52) were compared to a randomly selected comparison sample of non-autistic and "Asian" children (group 2; n = 50). Across both groups, manual chart review identified more specific approximations of racial/ethnic backgrounds in 54.5% of patients, 56% for languages spoken, and that interpretation service use was underestimated by 13 percentage points. Our preliminary results highlight that culturally responsive information was inconsistent, missing, or located in progress notes rather than a central location where it could be accessed by providers. Recommendations about the inclusion of Asian ethnicity and language data are provided to potentially enhance cultural responsiveness and support better outcomes for families with an autistic child.

19.
Kidney Int ; 84(6): 1246-53, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23760288

RESUMO

Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascular protective effects; however, this is not established in humans. Here we evaluated the long-term effects of prior RAS blockade on hemodynamic function, urinary measures of inflammation, and tissue antioxidant mRNA expression in patients with type 1 diabetes mellitus (T1DM) who participated in the 5-year Renin Angiotensin System Study (RASS). At 4 years after completing the RASS and discontinuing study medication, renal hemodynamic responses to clamped hyperglycemia were significantly greater in 18 patients in the RAS blockade group compared to 9 patients of the placebo-treated group. Individuals who had received RAS blockade also exhibited higher flow-mediated vasodilatation, reduced urinary cytokine excretion in response to hyperglycemia, and increased skin mRNA expression of superoxide dismutase-1 and catalase. Thus, patients with uncomplicated T1DM who received prior RAS blockade for 5 years maintain long-term effects on renal hemodynamic and systemic vascular function, inflammatory pathways in the kidney, and antioxidant enzyme expression in skin 4 years after discontinuation of therapy. Our findings suggest that sustained long-term protective effects of finite RAS inhibition requires further study.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Enalapril/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Losartan/administração & dosagem , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Quimiocinas/urina , Citocinas/urina , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Esquema de Medicação , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ontário , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/enzimologia , Fatores de Tempo , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos
20.
Semin Dial ; 26(2): 195-202, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23406283

RESUMO

New healthcare delivery models are needed to enhance the patient experience and improve quality of care for individuals with chronic conditions such as kidney disease. One potential avenue is to implement self-management strategies. There is growing evidence that self-management interventions help optimize various aspects of chronic disease management. With the increasing use of information technology (IT) in health care, chronic disease management programs are incorporating IT solutions to support patient self-management practices. IT solutions have the ability to promote key principles of self-management, namely education, empowerment, and collaboration. Positive clinical outcomes have been demonstrated for a number of chronic conditions when IT solutions were incorporated into self-management programs. There is a paucity of evidence for self-management in chronic kidney disease (CKD) patients. Furthermore, IT strategies have not been tested in this patient population to the same extent as other chronic conditions (e.g., diabetes, hypertension). Therefore, it is currently unknown if IT strategies will promote self-management behaviors and lead to improvements in overall patient care. We designed and developed an IT solution called My KidneyCare Centre to support self-management strategies for patients with CKD. In this review, we discuss the rationale and vision of incorporating an electronic self-management tool to support the care of patients with CKD.


Assuntos
Sistemas Computadorizados de Registros Médicos , Educação de Pacientes como Assunto , Insuficiência Renal Crônica/terapia , Autocuidado , Coleta de Dados/métodos , Gerenciamento Clínico , Grupos Focais , Humanos , Modelos Teóricos , Interface Usuário-Computador
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