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1.
Cereb Cortex ; 31(2): 933-948, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33009551

RESUMO

A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles. HFPRM revealed a latent measure of white matter microstructure that explained approximately 50% of variation in our tractography-based measures and accounted for a large proportion of heritable variation in each individual bundle. An intronic SNP in PSMF1 on chromosome 20 exceeded the conventional GWAS threshold of 5 x 10-8 (p = 4.61 x 10-8). Additional loci nearing genome-wide significance were located near genes with known roles in axon growth and guidance, fasciculation, and myelination.


Assuntos
Estudo de Associação Genômica Ampla , Substância Branca/ultraestrutura , Axônios/fisiologia , Cromossomos Humanos Par 20/genética , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Recém-Nascido , Masculino , Bainha de Mielina/fisiologia , Fibras Nervosas/fisiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Complexo de Endopeptidases do Proteassoma/genética , Análise de Regressão
2.
Br J Dermatol ; 184(6): 1047-1058, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32880909

RESUMO

BACKGROUND: Significantly more patients with moderate-to-severe plaque psoriasis treated with the interleukin (IL)-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab in the IXORA-R head-to-head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at week 12. OBJECTIVES: To compare skin and nail clearance and patient-reported outcomes for ixekizumab vs. guselkumab, up to week 24. METHODS: IXORA-R enrolled adults with moderate-to-severe plaque psoriasis, defined as static Physician's Global Assessment ≥ 3, PASI ≥ 12 and involved body surface area ≥ 10%. Statistical comparisons were performed using the Cochran-Mantel-Haenszel test stratified by pooled site. Time-to-first-event comparisons were performed using Kaplan-Meier analysis, and P-values were generated using adjusted log-rank tests stratified by treatment group. Cumulative days at clinical and patient-reported responses were compared by ancova. The trial was registered with ClinicalTrials.gov (NCT03573323). RESULTS: Of the 1027 patients randomly assigned, 90% completed the trial (465 of 520 ixekizumab and 459 of 507 guselkumab). As early as week 2 and through week 16, more patients on ixekizumab achieved PASI 100 (P < 0·01). At week 24, ixekizumab was noninferior to guselkumab (50% vs. 52%, difference -2·3%), with no statistically significant difference in PASI 100 (P = 0·41). More patients receiving ixekizumab showed completely clear nails at week 24 (52% vs. 31%, P = 0·007). The median time to first PASI 50/75/90 and PASI 100 were 2 and 7·5 weeks shorter, respectively, for patients on ixekizumab vs. guselkumab (P < 0·001). Patients on ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, with Dermatology Life Quality Index of 0 or 1, and itch free (P < 0·05). The frequency of serious adverse events was 3% for each group, with no new safety signals. CONCLUSIONS: Ixekizumab was noninferior to guselkumab in complete skin clearance and superior in clearing nails at week 24. Ixekizumab cleared skin more rapidly in patients with moderate-to-severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, the safety findings were consistent with the known safety profile for ixekizumab.


Assuntos
Psoríase , Adulto , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Humanos , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Cereb Cortex ; 30(2): 587-596, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-31216015

RESUMO

Turner syndrome (TS) is a genetic disorder affecting approximately 1:2000 live-born females. It results from partial or complete X monosomy and is associated with a range of clinical issues including a unique cognitive profile and increased risk for certain behavioral problems. Structural neuroimaging studies in adolescents, adults, and older children with TS have revealed altered neuroanatomy but are unable to identify when in development differences arise. In addition, older children and adults have often been exposed to years of growth hormone and/or exogenous estrogen therapy with potential implications for neurodevelopment. The study presented here is the first to test whether brain structure is altered in infants with TS. Twenty-six infants with TS received high-resolution structural MRI scans of the brain at 1 year of age and were compared to 47 typically developing female and 39 typically developing male infants. Results indicate that the typical neuroanatomical profile seen in older individuals with TS, characterized by decreased gray matter volumes in premotor, somatosensory, and parietal-occipital cortex, is already present at 1 year of age, suggesting a stable phenotype with origins in the prenatal or early postnatal period.


Assuntos
Encéfalo/patologia , Síndrome de Turner/patologia , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Tamanho do Órgão , Síndrome de Turner/diagnóstico por imagem
4.
J Eur Acad Dermatol Venereol ; 34(6): 1302-1308, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31800124

RESUMO

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory, skin condition associated with many comorbidities and often has a substantial impact on patients' lives. OBJECTIVES: To evaluate symptom burden and health-related quality of life (HRQoL) at baseline in patients with HS in an observational, real-world, clinical setting using several tools including a validated HS-specific instrument. METHODS: This study evaluated HRQoL data from the international UNITE HS disease registry. Administration of patient-reported outcome (PRO) instruments and collection of data were executed per local regulations. All data were assessed using descriptive statistical methods. RESULTS: PRO data from 529 adults and 65 adolescents were evaluated. Most adults (64.5%) and adolescents (73.8%) were classified as Hurley Stage II with substantial disease burden at baseline. HS had a large effect (mean DLQI = 12.6) and moderate effect (mean CDLQI = 6.9) on the lives of adults and adolescents, respectively. Approximately 58% of adults and 41% of adolescents had anxiety scores beyond the normal range; 30% of adults and 16% of adolescents exhibited symptoms of depression. Based on HSSA and HSIA scores, approximately 30% of adults reported a substantial burden of multiple HS clinical symptoms and more than 45% reported a significant emotional impact of HS that adversely affected their intimate relationships. Only 60% of adults were employed and of those, 64% reported at least some degree of impairment while working because of HS. CONCLUSIONS: Based on PROs collected from patients enrolled in the UNITE registry, a real-world, clinical setting, HS has a significant negative impact on the everyday lives of patients affected by this disease.


Assuntos
Hidradenite Supurativa , Adolescente , Adulto , Hidradenite Supurativa/epidemiologia , Humanos , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Sistema de Registros , Índice de Gravidade de Doença
5.
Mol Psychiatry ; 23(1): 15-23, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29158581

RESUMO

There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results. Here, we review the return of results debate in genomics research and propose that, as for genomic studies of other medical conditions, psychiatric genomics researchers should offer findings that meet the minimum criteria stated above. Additionally, if resources allow, psychiatry researchers could consider offering to return pre-specified 'clinically valuable' findings even if not medically actionable-for instance, findings that help corroborate a psychiatric diagnosis, and findings that indicate important health risks. Similarly, we propose offering 'likely clinically valuable' findings, specifically, variants of uncertain significance potentially related to a participant's symptoms. The goal of this Perspective is to initiate a discussion that can help identify optimal ways of managing the return of results from psychiatric genomics research.


Assuntos
Comitês de Ética em Pesquisa/normas , Pesquisa em Genética/ética , Genômica/métodos , Guias como Assunto , Transtornos Mentais/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Genômica/ética , Humanos , Masculino , Transtornos Mentais/diagnóstico
6.
Mol Psychiatry ; 23(7): 1652-1658, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29133949

RESUMO

The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.


Assuntos
Doenças Autoimunes/epidemiologia , Transtorno Obsessivo-Compulsivo/imunologia , Síndrome de Tourette/imunologia , Adolescente , Adulto , Idoso , Doenças Autoimunes/fisiopatologia , Estudos de Casos e Controles , Criança , Análise por Conglomerados , Comorbidade , Família , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/genética , Linhagem , Fatores de Risco , Irmãos , Suécia/epidemiologia , Transtornos de Tique/epidemiologia , Síndrome de Tourette/complicações , Síndrome de Tourette/genética
7.
Mol Psychiatry ; 23(3): 708-712, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28555076

RESUMO

Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic.


Assuntos
Corpo Estriado/efeitos dos fármacos , Haloperidol/metabolismo , Esquizofrenia/genética , Animais , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Haloperidol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco , Psicologia do Esquizofrênico , Análise de Sequência de RNA
8.
J Eur Acad Dermatol Venereol ; 33(9): 1676-1684, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31054215

RESUMO

Psoriasis is a chronic disease that requires long-term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)-23. This article reviews published data on the safety of these IL-23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo- and active-controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk-benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL-23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL-23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long-term extension studies and patient registries will further establish the safety profile of IL-23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/uso terapêutico , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/efeitos adversos , Produtos Biológicos/efeitos adversos , Humanos
9.
J Eur Acad Dermatol Venereol ; 33(11): 2168-2178, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31304993

RESUMO

BACKGROUND: Few clinical trials have evaluated long-term treatment of nail psoriasis with biologics. OBJECTIVE: Safety and efficacy of adalimumab [ADA; Humira AbbVie Inc, North Chicago, IL, USA)] long-term treatment (52 weeks) was evaluated in a phase-3, randomized trial in patients with moderate-to-severe plaque psoriasis and concomitant moderate-to-severe fingernail psoriasis. Results from the first 26 weeks (Period A) have been reported. METHODS: Patients receiving 40 mg ADA every other week or placebo in Period A, continued with or switched to 40 mg ADA every-other-week treatment in the subsequent 26-week open-label extension (OLE) period. Main efficacy evaluations were ≥75% improvement in total-fingernail modified Nail Psoriasis Severity Index (mNAPSI 75) and achievement of Physician's Global Assessment for Fingernail Psoriasis of clear or minimal disease (PGA-F 0/1) with a ≥2-grade improvement from baseline, across the trial for patients who continued ADA from Period A through the OLE (Continuous-ADA Population). Safety was evaluated during the OLE and for patients receiving ADA at any time during the study (All-ADA Population). RESULTS: Of the 217 patients initially randomized in Period A, 188 (86.6%; 94 in each treatment group) entered the OLE after completion of or early escape from Period A. For the Continuous-ADA Population (N = 109), endpoint achievement rates improved from OLE entry (Week 26) to Week 52, including total-fingernail mNAPSI 75 (47.4-54.5%); PGA-F 0/1 (51.1-55.6%) and total-fingernail mNAPSI = 0 (6.6-17.9%). Serious adverse event and serious infection rates for the All-ADA Population (N = 203) were 6.9% and 3.4%, respectively. CONCLUSIONS: In this population of psoriasis patients with concomitant, moderate-to-severe nail psoriasis, long-term efficacy and improvement in signs and symptoms of nail disease were demonstrated after every-other-week ADA treatment, including incremental improvements in rate of total clearance of nail disease. No new safety risks were identified for patients receiving at least one ADA dose across 52 weeks.


Assuntos
Adalimumab/uso terapêutico , Doenças da Unha/tratamento farmacológico , Psoríase/tratamento farmacológico , Adalimumab/efeitos adversos , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Unha/complicações , Psoríase/complicações , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
10.
Mol Psychiatry ; 19(7): 762-73, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24776740

RESUMO

Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , População Branca/genética , Adulto , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Suécia
12.
J Eur Acad Dermatol Venereol ; 28(7): 882-90, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23790018

RESUMO

BACKGROUND: The Randomized Controlled Evaluation of Adalimumab in Treatment of Chronic Plaque Psoriasis of the Hands and Feet (REACH) trial demonstrated that adalimumab was efficacious and well-tolerated for the treatment of hand and/or foot psoriasis through 28 weeks. OBJECTIVE: To evaluate the effects of patient baseline characteristics on efficacy of adalimumab treatment of hand and/or foot psoriasis. METHODS: Patients with moderate-to-severe chronic plaque psoriasis of the hands and/or feet were randomized 2 : 1 to adalimumab or placebo during the 16 week, double-blind period of REACH. Primary endpoint was percentage of patients achieving Physician's Global Assessment of the hands and/or feet of clear/almost clear at week 16. Post hoc analyses evaluated effects of baseline patient characteristics on the primary endpoint. Patients with nail psoriasis at baseline were assessed for association of Nail Psoriasis Severity Index (NAPSI) 50 response with efficacy outcomes at week 16. RESULTS: Seventy-two patients (49 adalimumab : 23 placebo) were analysed. Greater percentages of adalimumab-treated patients achieved the primary endpoint vs. placebo across all subgroups. Among 31 patients with nail psoriasis, a greater percentage of adalimumab-treated patients achieved NAPSI 50 (56.5%) vs. placebo (12.5%) at week 16. In adalimumab-treated patients, greater percentages of NAPSI 50 Responders vs. Non-responders achieved the primary endpoint, and had greater improvements in erythema, scaling, induration and fissuring, Dermatology Life Quality Index, and pain scores. CONCLUSIONS: Adalimumab was efficacious in treating chronic plaque psoriasis of the hands and/or feet over 16 weeks, regardless of baseline characteristics. Marked improvement in nail psoriasis among adalimumab-treated patients correlated with significant improvements in skin disease and patient-reported outcomes.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , , Mãos , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Adalimumab , Adulto , Idoso , Doença Crônica , Relação Dose-Resposta a Droga , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Fatores de Tempo , Resultado do Tratamento
13.
J Dairy Sci ; 97(6): 3894-905, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24731627

RESUMO

Feed represents a large proportion of the variable costs in dairy production systems. The omission of feed intake measures explicitly from national dairy cow breeding objectives is predominantly due to a lack of information from which to make selection decisions. However, individual cow feed intake data are available in different countries, mostly from research or nucleus herds. None of these data sets are sufficiently large enough on their own to generate accurate genetic evaluations. In the current study, we collate data from 10 populations in 9 countries and estimate genetic parameters for dry matter intake (DMI). A total of 224,174 test-day records from 10,068 parity 1 to 5 records of 6,957 cows were available, as well as records from 1,784 growing heifers. Random regression models were fit to the lactating cow test-day records and predicted feed intake at 70 d postcalving was extracted from these fitted profiles. The random regression model included a fixed polynomial regression for each lactation separately, as well as herd-year-season of calving and experimental treatment as fixed effects; random effects fit in the model included individual animal deviation from the fixed regression for each parity as well as mean herd-specific deviations from the fixed regression. Predicted DMI at 70 d postcalving was used as the phenotype for the subsequent genetic analyses undertaken using an animal repeatability model. Heritability estimates of predicted cow feed intake 70 d postcalving was 0.34 across the entire data set and varied, within population, from 0.08 to 0.52. Repeatability of feed intake across lactations was 0.66. Heritability of feed intake in the growing heifers was 0.20 to 0.34 in the 2 populations with heifer data. The genetic correlation between feed intake in lactating cows and growing heifers was 0.67. A combined pedigree and genomic relationship matrix was used to improve linkages between populations for the estimation of genetic correlations of DMI in lactating cows; genotype information was available on 5,429 of the animals. Populations were categorized as North America, grazing, other low input, and high input European Union. Albeit associated with large standard errors, genetic correlation estimates for DMI between populations varied from 0.14 to 0.84 but were stronger (0.76 to 0.84) between the populations representative of high-input production systems. Genetic correlations with the grazing populations were weak to moderate, varying from 0.14 to 0.57. Genetic evaluations for DMI can be undertaken using data collated from international populations; however, genotype-by-environment interactions with grazing production systems need to be considered.


Assuntos
Bovinos/fisiologia , Indústria de Laticínios , Comportamento Alimentar , Genótipo , Animais , Austrália , Cruzamento , Bovinos/genética , Europa (Continente) , Feminino , Lactação , América do Norte , Fenótipo , Análise de Regressão
14.
Pharmacogenomics J ; 12(2): 147-55, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21079646

RESUMO

Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (TD) (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci, which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. In all, 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg kg(-1) per day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs; the mouse analog of TD) and other movement phenotypes derived from open-field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90 and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS). Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.


Assuntos
Antipsicóticos/efeitos adversos , Haloperidol/efeitos adversos , Mastigação/efeitos dos fármacos , Animais , Masculino , Mastigação/genética , Camundongos , Camundongos Endogâmicos
15.
Br J Dermatol ; 167(3): 658-67, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22564148

RESUMO

BACKGROUND: The clinical utility of increasing to weekly adalimumab therapy in patients with psoriasis with inadequate response to every other week (eow) dosing is unknown. OBJECTIVES: (i) To determine the effectiveness of escalating adalimumab dosage from 40 mg eow to 40 mg weekly in patients with < PASI 50 response following ≥ 24 weeks treatment. (ii) To identify retrospectively characteristics of patients likely to benefit from dose escalation using classification and regression tree analysis. (iii) To assess cost implications for allowing dose escalation from the private payers' perspective. METHODS: Patients with moderate-to-severe psoriasis who had received blinded adalimumab 40 mg eow or placebo in antecedent phase II/III studies could enrol in an open-label extension (OLE) and initially receive open-label adalimumab 40 mg eow (EOW population). On/after week 24 (OLE), patients with < PASI 50 response relative to baseline of antecedent study could increase to 40 mg weekly. The dosage escalation population continued on weekly dosing until achieving PASI 75 response, then resumed eow dosing. Study visits were 6/12 weeks after dosage escalation, and every 12 weeks thereafter. The percentage of patients who achieved PASI 75 response following dosage escalation was determined (missing PASI scores imputed as nonresponse). Safety was assessed for the dosage escalation population and for all adalimumab exposure that did not follow dosage escalation in the EOW set. RESULTS: In total, 349/1256 (27·8%) patients underwent dosage escalation (OLE). At 12/24 weeks after dosage escalation, 93/349 (26·6%)/133/349 (38·1%) were PASI 75 responders or resumed eow dosing. Secondary nonresponders, patients weighing ≤ 102 kg, and those with disease duration < 8·3 years were most likely to benefit from dose escalation. Rates of serious/serious infectious/malignant (excluding nonmelanoma skin cancers or lymphoma) adverse events were 6·8/0·9/1·4 events per 100 patient-years (dosage escalation population); comparable rates in the EOW set were 6·5/1·2/0·5 events per 100 patient-years. CONCLUSIONS: Most patients did not require dose escalation. By 12 weeks after dose escalation, one-quarter achieved substantial clinical improvement. Safety results were similar between patients who dosage-escalated and those who did not.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Adalimumab , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/economia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/economia , Relação Dose-Resposta a Droga , Esquema de Medicação , Custos de Medicamentos , Feminino , Humanos , Injeções , Masculino , Psoríase/economia , Resultado do Tratamento
16.
J Dermatolog Treat ; 33(1): 219-228, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32349565

RESUMO

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.


Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento
17.
Br J Dermatol ; 165(3): 661-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21574984

RESUMO

BACKGROUND: The tumour necrosis factor-α antagonist etanercept and the interleukin (IL)-12/23p40 antagonist ustekinumab have been shown to be effective psoriasis therapies. The IL-12/23p40 antagonist briakinumab was shown to be effective psoriasis treatment in a phase II study. OBJECTIVES: To assess the efficacy, safety and tolerability of briakinumab compared with etanercept and placebo in patients with moderate to severe psoriasis. METHODS: Three hundred and fifty patients were enrolled in this phase III, 12-week study (M10-315, NCT00710580) and randomized in the following 2:2:1 ratio: 139 patients received 200 mg briakinumab at weeks 0 and 4 followed by 100 mg briakinumab at week 8; 139 patients received 50 mg of etanercept twice weekly 3-4 days apart at weeks 0-11; 72 patients received placebo injections matching active treatment. The co-primary efficacy endpoints were the proportion of patients achieving a Physician's Global Assessment (PGA) of 0/1 at week 12, and the proportion of patients achieving a Psoriasis Area and Severity Index (PASI) 75 response at week 12. RESULTS: Of the briakinumab-treated patients, 72·7% achieved a PGA of 0/1 at week 12 as compared with 29·5% of etanercept-treated patients and 4·2% of placebo-treated patients (P < 0·001, for both comparisons). Of the briakinumab-treated patients, 80·6% achieved a PASI 75 response at week 12 as compared with 39·6% of etanercept-treated and 6·9% of placebo-treated patients (P < 0·001, for both comparisons). Serious adverse events were reported in two (1·4%) briakinumab-treated patients, one (0·7%) etanercept-treated patient and two (2·8%) placebo-treated patients. CONCLUSIONS: In patients with moderate to severe psoriasis, briakinumab had superior efficacy to both placebo and etanercept at 12 weeks as administered in this study.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Imunoglobulina G/uso terapêutico , Psoríase/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Doença Crônica , Método Duplo-Cego , Etanercepte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
J Anim Sci ; 96(2): 375-397, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29390120

RESUMO

The objective of this study was to develop and validate a customized cost-effective single nucleotide polymorphism (SNP) panel for genetic improvement of feed efficiency in beef cattle. The SNPs identified in previous association studies and through extensive analysis of candidate genomic regions and genes, were screened for their functional impact and allele frequency in Angus and Hereford breeds used as validation candidates for the panel. Association analyses were performed on genotypes of 159 SNPs from new samples of Angus (n = 160), Hereford (n = 329), and Angus-Hereford crossbred (n = 382) cattle using allele substitution and genotypic models in ASReml. Genomic heritabilities were estimated for feed efficiency traits using the full set of SNPs, SNPs associated with at least one of the traits (at P ≤ 0.05 and P < 0.10), as well as the Illumina bovine 50K representing a widely used commercial genotyping panel. A total of 63 SNPs within 43 genes showed association (P ≤ 0.05) with at least one trait. The minor alleles of SNPs located in the GHR and CAST genes were associated with decreasing effects on residual feed intake (RFI) and/or RFI adjusted for backfat (RFIf), whereas minor alleles of SNPs within MKI67 gene were associated with increasing effects on RFI and RFIf. Additionally, the minor allele of rs137400016 SNP within CNTFR was associated with increasing average daily gain (ADG). The SNPs genotypes within UMPS, SMARCAL, CCSER1, and LMCD1 genes showed significant over-dominance effects whereas other SNPs located in SMARCAL1, ANXA2, CACNA1G, and PHYHIPL genes showed additive effects on RFI and RFIf. Gene enrichment analysis indicated that gland development, as well as ion and cation transport are important physiological mechanisms contributing to variation in feed efficiency traits. The study revealed the effect of the Jak-STAT signaling pathway on feed efficiency through the CNTFR, OSMR, and GHR genes. Genomic heritability using the 63 significant (P ≤ 0.05) SNPs was 0.09, 0.09, 0.13, 0.05, 0.05, and 0.07 for ADG, dry matter intake, midpoint metabolic weight, RFI, RFIf, and backfat, respectively. These SNPs contributed to genetic variation in the studied traits and thus can potentially be used or tested to generate cost-effective molecular breeding values for feed efficiency in beef cattle.


Assuntos
Bovinos/genética , Metabolismo Energético/genética , Polimorfismo de Nucleotídeo Único/genética , Ração Animal , Animais , Peso Corporal/genética , Bovinos/fisiologia , Ingestão de Alimentos/genética , Metabolismo Energético/fisiologia , Genoma , Genômica , Genótipo , Fenótipo
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