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1.
Women Health ; 64(2): 94-108, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38151762

RESUMO

We examined the association between postdiagnostic aspirin use and recurrence and disease-specific mortality among women with breast cancer in a meta-analysis. The PubMed, Embase, and Web of Science databases were searched to identify observational studies with longitudinal follow-ups according to the aim of the meta-analysis. Combining the results was achieved using a random-effects model that included inter-study heterogeneity. Fifteen cohort studies with 131,636 women with breast cancer were included. Based on a meta-analysis, women who took aspirin after being diagnosed with breast cancer had a lower risk of breast cancer recurrence (adjusted risk ratio [RR]: 0.77, 95 percent confidence interval [CI]: 0.63 to 0.95, P = .02; I2 = 72 percent) and breast cancer specific mortality (adjusted RR: 0.73, 95 percent CI: 0.60 to 0.90, P = .004; I2 = 80 percent) than those who did not use aspirin. The certainty of the evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluations scoring system showed moderate certainty for both the outcomes because significant inconsistency was observed. In conclusion, aspirin use after diagnosis might be associated with reduced recurrence and disease-specific mortality in women with breast cancer.


Assuntos
Aspirina , Neoplasias da Mama , Feminino , Humanos , Aspirina/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Estudos de Coortes , Mama
2.
Nutrition ; 116: 112189, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37689015

RESUMO

OBJECTIVES: Future primary prevention strategies may benefit from understanding the connection between mortality in individuals with central obesity and modifiable lifestyle factors like dietary intake. This study sought to determine whether there was a separate relationship between folate, vitamin B6, and vitamin B12 intake and all-cause and cause-specific mortality in the US population with central obesity. METHODS: The study analyzed data from the National Health and Nutrition Examination Survey between 1999 and 2016. Using the Cox proportional hazards model, the association between dietary intake of B vitamins and all-cause and cause-specific mortality was examined. A total of 7718 adults with central obesity were enrolled, with a mean age of 49.87 (SD = 0.25) y at baseline. RESULTS: Folate intake was independently associated with a decreased incidence of all-cause mortality (adjusted hazard ratio = 0.71; 95% CI, 0.58-0.87). Furthermore, higher intake of vitamin B6 and vitamin B12 was inversely correlated with cardiovascular disease mortality (adjusted hazard ratio = 0.63; 95% CI, 0.40-0.98; and adjusted hazard ratio = 0.44; 95% CI, 0.29-0.65, respectively) and the finding reveal an interaction between homocysteine and vitamin B12 and folate on All-cause mortality CONCLUSIONS: The findings of this study suggest that vitamin B12 and folate intake may be protective factors in individuals with central obesity. It is important to consider both their total homocysteine level and body mass index in conjunction with these nutrients. Further research is needed to validate these findings.


Assuntos
Complexo Vitamínico B , Adulto , Humanos , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade Abdominal , Causas de Morte , Ácido Fólico , Vitamina B 12 , Vitamina B 6 , Piridoxina , Homocisteína
3.
Epilepsia ; 56(7): 1081-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26032891

RESUMO

OBJECTIVE: Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of γ-aminobutyric acid (GABA) B receptor (GABA(B)R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans. The G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) gene, KCNJ6, is overexpressed in Ts mice, and the GABA(B)R-mediated GIRK2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK2 channel plays a significant role in the behavioral (measured by acute extensor spasms quantification) and EEG (measured by the electrodecremental response duration) phenotype induced in the Ts mice by GABA(B)R agonists. METHODS: GIRK2(-/-), (+/-), and (+/+) mice were treated with γ-butyrolactone (GBL), a pro-drug of the GABA(B)R agonist γ-hydroxybutyric acid, and the specific GABA(B)R agonist baclofen (BAC) under continuous EEG monitoring. These drugs induce epileptiform bursts, extensor spasms, and an electrodecremental response (EDR) in Ts mice at low doses, and in wild-type mice at high doses. A dose-response curve was ascertained with two treatment groups: GBL (100, 200, and 400 mg/kg) and BAC (4, 8, 12, and 16 mg/kg). We determined the baseline, the presence and duration of electrodecremental epochs (EDEs), and quantified acute epileptic extensor spasms. RESULTS: Analysis of EEG and behavior of GIRK2(-/-), (+/-), and (+/+) mice after treatment with GABA(B)R agonists and antagonists, indicate that GIRK2(-/-) mice are highly resistant to GABA(B)R agonist-induced EEG and behavioral changes. SIGNIFICANCE: These data increase the possibility that GIRK2 channel function plays a major role in the genesis of infantile spasms.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/biossíntese , Agonistas GABAérgicos/toxicidade , Subunidades Proteicas/biossíntese , Receptores de GABA-B , Convulsões/metabolismo , Espasmos Infantis/metabolismo , Animais , Feminino , Humanos , Recém-Nascido , Masculino , Camundongos , Camundongos Transgênicos , Convulsões/induzido quimicamente , Espasmos Infantis/induzido quimicamente
4.
J Nat Prod ; 76(4): 702-9, 2013 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-23586920

RESUMO

Five new xanthoquinodins, A4-A6 (1-3), B4 (4), and B5 (5), were isolated from the crude extract of the endolichenic fungal strain Chaetomium elatum (No. 63-10-3-1), along with three known xanthoquinodins, A1-A3 (6-8). Their structures were determined by detailed spectroscopic analysis and comparison of the NMR data with those of the closely related compounds previously reported. The absolute configuration of 1 was established by X-ray crystallographic analysis and ECD calculation. The cytotoxic activity of all compounds was tested against HL-60, SMMC-7721, A-549, MCF-7, and SW480 human cancer cell lines.


Assuntos
Antineoplásicos/isolamento & purificação , Chaetomium/química , Cromonas/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/farmacologia , Cromonas/química , Cromonas/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HL-60 , Humanos , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
5.
Pharmacol Biochem Behav ; 94(1): 124-30, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19666047

RESUMO

The objective of the current study was to determine the origin of the slow spike and wave discharges (SSWD) in the transgenic mouse with postnatal over-expression of the GABA(B) receptor subunit R1a (GABA(B)R1a(tg)), a mutant animal with a characteristic phenotype consisting of atypical absence seizures and cognitive dysfunction. Using simultaneous electrocorticographic (ECoG) recordings from cortical and depth electrodes in freely moving GABA(B)R1a(tg) mice, we showed that the SSWD in this model of atypical absence seizures arise exclusively from midline thalamus (MT), reticular nucleus of the thalamus (nRT), and the CA1 region of the hippocampus. Lesioning of the MT and nRT with ibotenic acid abolished SSWD. Microinjection of the GABA(B) receptor agonist, (-) baclofen, into MT and nRT exacerbated, and the GABA(B)R antagonist, CGP 35348 abolished, SSWD in the GABA(B)R1a(tg) mice. These data suggest that the nRT and MT are necessary for the generation of SSWD in the GABA(B)R1a(tg) model of atypical absence seizures, and indicate that GABA(B)R-mediated mechanisms within thalamus are necessary for the genesis of SSWD in atypical absence seizures. A putative cortico-thalamo-hippocampal circuit is proposed to explain the unique electrographic findings, ictal behavior, pharmacology, and impairment of cognition that characterize atypical absence seizures.


Assuntos
Epilepsia Tipo Ausência/fisiopatologia , Hipocampo/fisiopatologia , Neurônios/fisiologia , Receptores de GABA-B/fisiologia , Tálamo/fisiopatologia , Potenciais de Ação , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Mapeamento Encefálico/métodos , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Tipo Ausência/genética , Agonistas de Aminoácidos Excitatórios/toxicidade , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Antagonistas de Receptores de GABA-B , Ácido Ibotênico/toxicidade , Injeções Intraventriculares , Camundongos , Camundongos Transgênicos , Microinjeções , Isoformas de Proteínas , Receptores de GABA-B/genética
6.
Pediatr Res ; 65(5): 499-503, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19190545

RESUMO

Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. Children with Down syndrome are highly susceptible to infantile spasms. The Ts65Dn mouse is a valid model for Down syndrome; therefore, we tested the hypothesis that the Ts65Dn mouse represents a substrate for an animal model of infantile spasms. The baseline of naïve Ts65Dn mice showed spontaneous spike-and-wave discharges, a pattern that worsened with baclofen and gamma-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABABR-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABABR protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABABR agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABABR-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms.


Assuntos
4-Butirolactona , Baclofeno , Encéfalo/metabolismo , Síndrome de Down/complicações , Agonistas GABAérgicos , Receptores de GABA-B/metabolismo , Espasmos Infantis/induzido quimicamente , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Síndrome de Down/fisiopatologia , Eletroencefalografia , Etossuximida/farmacologia , Genótipo , Humanos , Lactente , Camundongos , Camundongos Mutantes , Compostos Organofosforados/farmacologia , Fenótipo , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA-B/efeitos dos fármacos , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Espasmos Infantis/prevenção & controle , Fatores de Tempo , Ácido Valproico/farmacologia , Vigabatrina/farmacologia
7.
Neurobiol Dis ; 26(2): 439-51, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17363260

RESUMO

In this study, we tested whether over-expressing the GABA(B) receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3-6 Hz slow spike and wave discharges between 2 and 4 months of age. These discharges are blocked by ethosuximide and exacerbated by baclofen confirming their absence nature. The discharges occur coincident with absence-like behaviors such as staring, facial myoclonus, and whisker twitching. However, in contrast to typical absence epilepsy models, these mice move during the ictal event, display spike and wave discharges in both thalamocortical and limbic circuitry, exhibit impaired hippocampal synaptic plasticity, and display significantly impaired learning ability. Collectively, these features are more characteristic of the less common but more debilitating atypical form of absence epilepsy. Thus, these data support a role for the GABA(B)R1a receptor subtype in the etiology of atypical absence epilepsy.


Assuntos
Química Encefálica/genética , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Epilepsia Tipo Ausência/metabolismo , Receptores de GABA-B/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Comportamento Animal/fisiologia , Encéfalo/anatomia & histologia , Modelos Animais de Doenças , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/fisiopatologia , Expressão Gênica/fisiologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Camundongos , Camundongos Transgênicos , Inibição Neural/fisiologia , Vias Neurais/anatomia & histologia , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Plasticidade Neuronal/fisiologia , Fenótipo , Receptores de GABA-B/biossíntese , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
8.
Ann Neurol ; 59(1): 42-52, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16240371

RESUMO

The epilepsy that occurs in SSADH deficiency has a seizure phenotype similar to that occurring in the SSADH(-/-) mouse. We examined the expression and function of the GABA(A) receptor (GABA(A)R) in SSADH-deficient mice. A selective decrease in binding of [(35)S]tert-butylbicyclophosphorothionate was observed in SSADH(-/-) mice at postnatal day 7 that was progressive until the third postnatal week of life when, at the nadir of the decreased [(35)S]tert-butylbicyclophosphorothionate binding, generalized convulsive seizures emerged that rapidly evolved into status epilepticus. We also observed a substantial downregulation of the beta(2) subunit of GABA(A)R, a reduction in GABA(A)-mediated inhibitory postsynaptic potentials, and augmented postsynaptic population spikes recorded from hippocampal slices. The SSADH(-/-) mouse model represents a powerful investigative tool for understanding the pathophysiology of the seizures associated with human SSADH deficiency. These data raise the possibility that progressive dysfunction of the GABA(A)R may be involved in the development of seizures in SSDAH-deficient mice. Elucidation of the precise fundamental mechanisms of the perturbation of the GABA(A)R-mediated function in SSADH(-/-) mice could lead to the development of novel treatment modalities designed to reduce the neurological morbidity in children with SSADH deficiency.


Assuntos
Receptores de GABA-A/metabolismo , Estado Epiléptico/enzimologia , Succinato-Semialdeído Desidrogenase/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Convulsivantes/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Camundongos Knockout , Neurônios/citologia , Neurônios/metabolismo , Compostos Organofosforados/metabolismo , Técnicas de Patch-Clamp , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Ensaio Radioligante , Receptores de GABA-A/genética , Estado Epiléptico/genética , Succinato-Semialdeído Desidrogenase/genética , Radioisótopos de Enxofre/metabolismo
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