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1.
BMC Psychiatry ; 22(1): 516, 2022 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-35908052

RESUMO

BACKGROUND: The last decade has shown a remarkable increase in the rates of illicit opioid use in Canada and internationally, which is associated with large increases in opioid related morbidity and mortality. While the differences between methadone and buprenorphine/naloxone in terms of retention have been studied outside Canada, the unique location and design of this study, gives it a specific significance. OBJECTIVES: This study aims to describe the relative treatment retention rates for first episode opioid replacement treatment between methadone and buprenorphine/naloxone for patients receiving daily witnessed dispensed medications in Nova Scotia. METHODS: A longitudinal retrospective descriptive study analyzing secondary data from the Nova Scotia Prescription Monitoring Program on patients 18 years of age and older who started first episode opioid agonist therapy with methadone or buprenorphine/naloxone for opioid use disorder in Nova Scotia between 2014 and 2018. Treatment episode was defined as date of initial opioid agonist prescription until there is a gap of greater than 6 days without receiving opioid agonist medication at a pharmacy. RESULTS: One thousand eight hundred sixty-seven of whom were analyzed as they had at least 1 day in treatment. There was significant treatment dropout within the first 2 weeks of treatment, which did not show a significant difference between OAT medication (23.4% of buprenorphine/naloxone; 22.2% methadone). Median duration of retention in treatment was 58 days for those treated with buprenorphine/naloxone and 101 days for patients treated with methadone. Multivariate cox proportional hazards model showed that buprenorphine/naloxone use as compared to methadone lead to increased hazard of treatment dropout by 62% (HR = 1.62). Hazard rate of treatment dropout for patients below 25 years of age was calculated. (HR 1.53). Median duration of retention in treatment for this subgroup of patients younger than age 25 was 37.5 days for patients treated with buprenorphine/naloxone and 69 days for patients treated with methadone. CONCLUSIONS: Our data suggests that methadone is a numerically superior medication for opioid use disorder when the metric of treatment retention is viewed in isolation, for our population in Nova Scotia. However, the results should be interpreted carefully considering the number of limitations of this study. There are social/accessibility, pharmacologic/safety, and patient preference factors which are also key in decision making when prescribing opioid agonist therapy. These must all be considered when deciding on which medication to initiate for a patient beginning a new treatment episode with OAT for opioid use disorder. This study should stimulate further research into this important area in addiction medicine.


Assuntos
Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Buprenorfina/uso terapêutico , Combinação Buprenorfina e Naloxona/uso terapêutico , Canadá , Humanos , Metadona/uso terapêutico , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estudos Retrospectivos
2.
PLoS Genet ; 14(3): e1007244, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29529029

RESUMO

A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development. Here, we use a combination of genetic mouse models to demonstrate that Prss56 mutations leading to reduced ocular size and hyperopia act via a loss of function mechanism. Using a conditional gene targeting strategy, we show that PRSS56 derived from Müller glia contributes to ocular growth, implicating a new retinal cell type in ocular size determination. Importantly, we demonstrate that persistent activity of PRSS56 is required during distinct developmental stages spanning the pre- and post-eye opening periods to ensure optimal ocular growth. Thus, our mouse data provide evidence for the existence of a molecule contributing to both the prenatal and postnatal stages of human ocular growth. Finally, we demonstrate that genetic inactivation of Prss56 rescues axial elongation in a mouse model of myopia caused by a null mutation in Egr1. Overall, our findings identify PRSS56 as a potential therapeutic target for modulating ocular growth aimed at preventing or slowing down myopia, which is reaching epidemic proportions.


Assuntos
Olho/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Erros de Refração/genética , Serina Proteases/metabolismo , Animais , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Olho/citologia , Olho/embriologia , Feminino , Humanos , Hiperopia/genética , Masculino , Camundongos Mutantes , Camundongos Transgênicos , Miopia/genética , Miopia/patologia , Neuroglia/metabolismo , Refração Ocular/genética , Refração Ocular/fisiologia , Erros de Refração/prevenção & controle , Serina Proteases/genética
3.
JAMA ; 325(8): 753-764, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33620406

RESUMO

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.


Assuntos
Síndrome de Exfoliação/genética , Variação Genética , Esteroide Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Câmara Anterior/patologia , Estudos de Casos e Controles , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Humanos , Modelos Logísticos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Sequenciamento do Exoma
4.
Pediatr Rheumatol Online J ; 21(1): 30, 2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37013572

RESUMO

BACKGROUND: Kawasaki Disease (KD) is the leading cause of acquired heart disease in children in developed countries with a variable incidence worldwide. Previous studies reported an unexpectedly high incidence of KD in the Canadian Atlantic Provinces. The goals of our study were to validate this finding in the province of Nova Scotia and to carefully review patients' characteristics and disease outcomes. METHODS: This was a retrospective review of all children < 16 years old from Nova Scotia diagnosed with KD between 2007-2018. Cases were identified using a combination of administrative and clinical databases. Clinical information was collected retrospectively by health record review using a standardized form. RESULTS: Between 2007-2018, 220 patients were diagnosed with KD; 61.4% and 23.2% met the criteria for complete and incomplete disease, respectively. The annual incidence was 29.6 per 100,000 children < 5 years. The male to female ratio was 1.3:1 and the median age was 3.6 years. All patients diagnosed with KD in the acute phase received intravenous immunoglobulin (IVIG); 23 (12%) were refractory to the first dose. Coronary artery aneurysms were found in 13 (6%) patients and one patient died with multiple giant aneurysms. CONCLUSION: We have confirmed an incidence of KD in our population which is higher than that reported in Europe and other regions of North America despite our small Asian population. The comprehensive method to capture patients may have contributed to the detection of the higher incidence. The role of local environmental and genetic factors also deserves further study. Increased attention to regional differences in the epidemiology of KD may improve our understanding of this important childhood vasculitis.


Assuntos
Síndrome de Linfonodos Mucocutâneos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Aneurisma Coronário/epidemiologia , Aneurisma Coronário/etiologia , Aneurisma Coronário/diagnóstico , Imunoglobulinas Intravenosas/uso terapêutico , Incidência , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Estudos Retrospectivos , Nova Escócia/epidemiologia , Recém-Nascido
5.
Biotechnol Lett ; 25(9): 739-44, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12882176

RESUMO

Leaf spot disease caused by Cercospora is responsible for crop and profitability losses in sugar beet crops in the US and worldwide. The cfp gene that encodes a protein that exports phytotoxic cercosporins from Cercospora was conjugally transferred to sugar beet using Rhizobium radiobacter (Agrobacterium tumefaciens), to improve Cercospora-induced leafspot resistance. Conditions for shoot regeneration were optimized to increase regeneration/transformation efficiencies. Low-light and room-temperature conditions were favorable to sugar beet regeneration without callus when cytokinin had been added to the tissue culture medium. Using this procedure adventitious shoots from leaf pieces were obtained in a simple, one-step regeneration procedure. T7, a cfp-transgenic clone verified by PCR with gene-specific primers, is being propagated for leaf spot disease resistance evaluation.


Assuntos
Beta vulgaris/genética , Beta vulgaris/metabolismo , Proteínas Fúngicas , Proteínas de Membrana Transportadoras , Perileno/análogos & derivados , Perileno/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Transformação Genética , Ascomicetos/genética , Ascomicetos/metabolismo , Beta vulgaris/crescimento & desenvolvimento , Proteínas de Transporte , Diferenciação Celular , Conjugação Genética , Técnicas de Cultura/métodos , Doenças das Plantas/microbiologia , Brotos de Planta/genética , Brotos de Planta/crescimento & desenvolvimento , Brotos de Planta/metabolismo , Brotos de Planta/microbiologia , Plantas Geneticamente Modificadas/genética , Proteínas Recombinantes/biossíntese , Regeneração/fisiologia , Rhizobium/genética , Rhizobium/metabolismo
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