Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
1.
Ann Neurol ; 94(5): 825-835, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37597255

RESUMO

OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.


Assuntos
Epilepsia do Lobo Temporal , Convulsões Febris , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/diagnóstico , Estudo de Associação Genômica Ampla , Convulsões Febris/genética , Imageamento por Ressonância Magnética , Eletroencefalografia , Síndrome , Hipocampo
2.
Sci Rep ; 13(1): 8435, 2023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-37225786

RESUMO

Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14-18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.


Assuntos
Adamantano , Glioblastoma , Antagonistas do Receptor Purinérgico P2X , Humanos , Adamantano/análogos & derivados , Adamantano/farmacologia , Aminoquinolinas/farmacologia , Glioblastoma/tratamento farmacológico , Receptores Purinérgicos P2X7 , Temozolomida/farmacologia , Microambiente Tumoral , Antagonistas do Receptor Purinérgico P2X/farmacologia
3.
Neurology ; 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192176

RESUMO

BACKGROUND AND OBJECTIVES: Mosaic pathogenic variants restricted to brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereo-electroencephalography (SEEG) electrodes. MATERIAL AND METHODS: We studied a patient with non-lesional multifocal epilepsy undergoing pre-surgical evaluation with SEEG. Following explantation, electrodes were divided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippocampus/temporal neocortex). Tissue from each pool was processed and DNA whole genome amplified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. Brain-specific GFAP protein assay enabled cell-of-origin analysis. RESULTS: We demonstrated a mosaic gradient for a novel pathogenic KCNT1 loss-of-function variant, c.530G>A, p.W177X, predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings as the highest mutant allele fraction was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. Elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. CONCLUSIONS: This study demonstrates proof-of-concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.

4.
Neurology ; 99(13): e1380-e1392, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-35705497

RESUMO

BACKGROUND AND OBJECTIVES: To examine the preferences and user experiences of people with epilepsy and caregivers regarding automated wearable seizure detection devices. METHODS: We performed a mixed-methods systematic review. We searched electronic databases for original peer-reviewed publications between January 1, 2000, and May 26, 2021. Key search terms included "epilepsy," "seizure," "wearable," and "non-invasive." We performed a descriptive and qualitative thematic analysis of the studies included according to the technology acceptance model. Full texts of the discussion sections were further analyzed to identify word frequency and word mapping. RESULTS: Twenty-two observational studies were identified. Collectively, they comprised responses from 3,299 participants including patients with epilepsy, caregivers, and healthcare workers. Sixteen studies examined user preferences, 5 examined user experiences, and 1 examined both experiences and preferences. Important preferences for wearables included improving care, cost, accuracy, and design. Patients desired real-time detection with a latency of ≤15 minutes from seizure occurrence, along with high sensitivity (≥90%) and low false alarm rates. Device-related costs were a major factor for device acceptance, where device costs of <$300 USD and a monthly subscription fee of <$20 USD were preferred. Despite being a major driver of wearable-based technologies, sudden unexpected death in epilepsy was rarely discussed. Among studies evaluating user experiences, there was a greater acceptance toward wristwatches. Thematic coding analysis showed that attitudes toward device use and perceived usefulness were reported consistently. Word mapping identified "specificity," "cost," and "battery" as key single terms and "battery life," "insurance coverage," "prediction/detection quality," and the effect of devices on "daily life" as key bigrams. DISCUSSION: User acceptance of wearable technology for seizure detection was strongly influenced by accuracy, design, comfort, and cost. Our findings emphasize the need for standardized and validated tools to comprehensively examine preferences and user experiences of wearable devices in this population using the themes identified in this study. Greater efforts to incorporate perspectives and user experiences in developing wearables for seizure detection, particularly in community-based settings, are needed. TRIAL REGISTRATION INFORMATION: PROSPERO Registration CRD42020193565.


Assuntos
Epilepsia , Dispositivos Eletrônicos Vestíveis , Cuidadores , Morte Súbita , Epilepsia/diagnóstico , Humanos , Convulsões/diagnóstico
5.
Neurology ; 98(19): e1923-e1932, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35387849

RESUMO

BACKGROUND AND OBJECTIVES: Epilepsy is associated with an increased risk of cardiovascular disease and premature mortality, including sudden unexpected death in epilepsy (SUDEP). Serious cardiac arrythmias might go undetected in routine epilepsy and cardiac investigations. METHODS: This prospective cohort study aimed to detect cardiac arrhythmias in patients with chronic drug-resistant epilepsy (≥5 years duration) using subcutaneous cardiac monitors for a minimum follow-up duration of 12 months. Participants with known cardiovascular disease or those with abnormal 12-lead ECGs were excluded. The device was programmed to automatically record episodes of tachycardia ≥140 beats per minute (bpm), bradycardia ≤40 bpm for ≥3 seconds, or asystole ≥3 seconds. FINDINGS: Thirty-one patients underwent subcutaneous cardiac monitoring for a median recording duration of 2.2 years (range 0.5-4.2). During this time, 28 patients (90.3%) had episodes of sustained (≥30 seconds) sinus tachycardia, 8/31 (25.8%) had sinus bradycardia, and 3 (9.7%) had asystole. Three patients (9.7%) had serious cardiac arrhythmias requiring additional cardiac interventions. Among them, 2 patients had prolonged sinus arrest and ventricular asystole (>6 seconds), leading to pacemaker insertion in one, and another patient with epileptic encephalopathy had multiple episodes of recurrent nonsustained polymorphic ventricular tachycardia and bundle branch conduction abnormalities. The time to first detection of a clinically significant cardiac arrhythmia ranged between 1.2 and 26.9 months following cardiac monitor insertion. DISCUSSION: Implantable cardiac monitors detected a high incidence of clinically significant cardiac arrhythmias in patients with chronic drug-resistant epilepsy, which may contribute to the incidence of premature mortality, including SUDEP.


Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Parada Cardíaca , Morte Súbita Inesperada na Epilepsia , Taquicardia Ventricular , Arritmias Cardíacas , Bradicardia , Epilepsia Resistente a Medicamentos/complicações , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Parada Cardíaca/complicações , Humanos , Estudos Prospectivos
6.
J Stroke Cerebrovasc Dis ; 29(8): 104901, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32439350

RESUMO

OBJECTIVE: Polymorphisms in the CYP2C9 gene may be associated with adverse vascular events following endovascular procedures independent of antiplatelet therapy. We aimed to investigate the impact of CYP2C9 loss-of-function polymorphisms on adverse vascular events following neurointervention. PATIENTS AND METHODS: Consecutive patients undergoing neurointervention were prospectively recruited between 2010 and 2016. Patients were genotyped for the CYP2C9*2 and *3 loss-of-function polymorphisms. On the basis of possible genetic influence on antiplatelet response, ex vivo clopidogrel response was measured using the VerifyNow® P2Y12 Assay. The primary endpoint was the 90-day incidence of adverse vascular events including ischemic stroke. RESULTS: A total of 229 patients were included. The median age was 57 years (IQR: 49-64), and 158 (69.00%) were female. Eighty-one (35.37%) patients carried at least one CYP2C9 loss-of-function (LOF) allele. After adjustment for stroke risk factors, the 90-day incidence of ischemic stroke was significantly lower in the LOF group compared to the wild type group (1.23% vs 10.14%; ORadj = 0.16, 95% CI: 0.03-0.91; p = 0.04). CONCLUSIONS: Our results suggest protection against ischemic stroke in carriers of CYP2C9*2 or *3 polymorphisms undergoing neurointervention. Our findings warrant further studies to investigate the mechanisms by which CYP2C9 may influence the risk of ischemic stroke.


Assuntos
Isquemia Encefálica/genética , Isquemia Encefálica/prevenção & controle , Transtornos Cerebrovasculares/terapia , Citocromo P-450 CYP2C9/genética , Procedimentos Endovasculares/efeitos adversos , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/prevenção & controle , Idoso , Isquemia Encefálica/diagnóstico , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C9/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores da Agregação Plaquetária/farmacocinética , Estudos Prospectivos , Fatores de Proteção , Queensland , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Fatores de Tempo , Resultado do Tratamento , Vitória
7.
Ann Neurol ; 87(6): 897-906, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32215971

RESUMO

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.


Assuntos
Anormalidades Induzidas por Medicamentos/genética , Anticonvulsivantes/efeitos adversos , Carga Genética , Variação Genética/genética , Teratogênicos , Anormalidades Induzidas por Medicamentos/epidemiologia , Adulto , DNA/genética , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Humanos , Recém-Nascido , Masculino , Idade Paterna , Polimorfismo de Nucleotídeo Único/genética , Gravidez
8.
Sensors (Basel) ; 19(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416185

RESUMO

Pre-treatment screening of individuals for human leukocyte antigens (HLA) HLA-B*57:01 is recommended for the prevention of life-threatening hypersensitivity reactions to abacavir, a drug widely prescribed for HIV treatment. However, the implementation of screening in clinical practice is hindered by the slow turnaround time and high cost of conventional HLA genotyping methods. We have developed a biosensor platform using interdigitated electrode (IDE) functionalized with a monoclonal antibody to detect cells expressing HLA-B*57:01. This platform was evaluated using cell lines and peripheral blood mononuclear cells expressing different HLA-B alleles. The functionalized IDE sensor was able to specifically capture HLA-B*57:01 cells, resulting in a significant change in the impedance magnitude in 20 min. This IDE platform has the potential to be further developed to enable point-of-care HLA-B*57:01 screening.


Assuntos
Técnicas Biossensoriais/métodos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/prevenção & controle , Antígenos HLA-B/análise , Leucócitos Mononucleares/metabolismo , Alelos , Anticorpos Imobilizados/química , Anticorpos Imobilizados/imunologia , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Didesoxinucleosídeos/uso terapêutico , Hipersensibilidade a Drogas/etiologia , Técnicas Eletroquímicas , Eletrodos , Infecções por HIV/tratamento farmacológico , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos
9.
Epilepsia ; 60(9): 1753-1767, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31353444

RESUMO

There is growing evidence that cardiac dysfunction in patients with chronic epilepsy could play a pathogenic role in sudden unexpected death in epilepsy (SUDEP). Recent animal studies have revealed that epilepsy secondarily alters the expression of cardiac ion channels alongside abnormal cardiac electrophysiology and remodeling. These molecular findings represent novel evidence for an acquired cardiac channelopathy in epilepsy, distinct from inherited ion channels mutations associated with cardiocerebral phenotypes. Specifically, seizure activity has been shown to alter the messenger RNA (mRNA) and protein expression of voltage-gated sodium channels (Nav 1.1, Nav 1.5), voltage-gated potassium channels (Kv 4.2, Kv 4.3), sodium-calcium exchangers (NCX1), and nonspecific cation-conducting channels (HCN2, HCN4). The pathophysiology may involve autonomic dysfunction and structural cardiac disease, as both are independently associated with epilepsy and ion channel dysregulation. Indeed, in vivo and in vitro studies of cardiac pathology reveal a complex network of signaling pathways and transcription factors regulating ion channel expression in the setting of sympathetic overactivity, cardiac failure, and hypertrophy. Other mechanisms such as circulating inflammatory mediators or exogenous effects of antiepileptic medications lack evidence. Moreover, an acquired cardiac channelopathy may underlie the electrophysiologic cardiac abnormalities seen in chronic epilepsy, potentially contributing to the increased risk of malignant arrhythmias and sudden death. Therefore, further investigation is necessary to establish whether cardiac ion channel dysregulation similarly occurs in patients with epilepsy, and to characterize any pathogenic relationship with SUDEP.


Assuntos
Arritmias Cardíacas/complicações , Canalopatias/complicações , Epilepsia/complicações , Coração/fisiopatologia , Morte Súbita Inesperada na Epilepsia/etiologia , Arritmias Cardíacas/fisiopatologia , Canalopatias/fisiopatologia , Epilepsia/fisiopatologia , Humanos
10.
Biosens Bioelectron ; 111: 174-183, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29673585

RESUMO

Prevention of life threatening hypersensitivity reactions to carbamazepine is possible through pre-treatment screening of the associated HLA-B*15:02 risk allele. However, clinical implementation of screening is hindered by the high cost and slow turnaround of conventional HLA typing methods. We have developed an interdigitated electrode (IDE) biosensor platform utilizing loop mediated isothermal amplification (LAMP) that can rapidly detect the HLA-B*15:02 allele. DNA amplification is followed by solid-phase hybridization of LAMP amplicons to a DNA probe immobilized on the IDE sensor surface, resulting in a change in sensor impedance. The testing platform does not require DNA extraction or post-amplification staining, achieving sample-to-answer in 1 h and 20 min. The platform was tested on 27 whole blood samples (14 HLA-B*15:02 positive and 13 negative) with sensitivity of 92.9% and specificity of 84.6% when applying a cutoff of impedance change. Based on these characters the LAMP-IDE platform has potential to be further developed into point-of-care use to help overcome barriers in HLA-B*15:02 screening.


Assuntos
Técnicas Biossensoriais/instrumentação , Hipersensibilidade a Drogas/genética , Técnicas de Genotipagem/instrumentação , Antígenos HLA-B/genética , Alelos , Sequência de Bases , Sondas de DNA/genética , Hipersensibilidade a Drogas/sangue , Eletricidade , Eletrodos , Desenho de Equipamento , Genótipo , Antígenos HLA-B/sangue , Humanos , Ácidos Nucleicos Imobilizados/genética , Técnicas de Amplificação de Ácido Nucleico/instrumentação , Sistemas Automatizados de Assistência Junto ao Leito
11.
Epilepsy Res ; 127: 19-29, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27544485

RESUMO

Alterations in cardiac electrophysiology are an established consequence of long-standing drug resistant epilepsy. Patients with chronic epilepsy display abnormalities in both sinoatrial node pacemaker current as well as ventricular repolarizing current that places them at a greater risk of developing life-threatening cardiac arrhythmias. The development of cardiac arrhythmias secondary to drug resistant epilepsy is believed to be a key mechanism underlying the phenomenon of Sudden Unexpected Death in EPilepsy (SUDEP). Though an increasing amount of studies examining both animal models and human patients have provided evidence that chronic epilepsy can detrimentally affect cardiac function, the underlying pathophysiology remains unclear. Recent work has shown the expression of several key cardiac ion channels to be altered in animal models of genetic and acquired epilepsies. This has led to the currently held paradigm that cardiac ion channel expression may be secondarily altered as a consequence of seizure activity-resulting in electrophysiological cardiac dysfunction. Furthermore, cortical autonomic dysfunction - resulting from seizure activity-has also been suggested to play a role, whereby seizure activity may indirectly influence cardiac function via altering centrally-mediated autonomic output to the heart. In this review, we discuss various cardiac dysrhythmias associated with seizure events-including tachycardia, bradycardia and QT prolongation, both ictally and inter-ictally, as well as the role of the autonomic nervous system. We further discuss key ion channels expressed in both the heart and the brain that have been shown to be altered in epilepsy and may be responsible for the development of cardiac dysrhythmias secondary to chronic epilepsy.


Assuntos
Epilepsia/fisiopatologia , Cardiopatias/fisiopatologia , Animais , Humanos
12.
Epilepsia ; 57(9): 1398-405, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27440235

RESUMO

OBJECTIVE: Fracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. We aimed to confirm the expression of voltage-gated sodium (NaV ) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels. METHODS: Immunocytochemistry was performed on primary calvarial osteoblasts extracted from neonatal C57BL/6J mice and additional RNA sequencing (RNASeq) was included to confirm expression of NaV . Whole-cell patch-clamp recordings were made to identify the native currents expressed and to assess the actions of carbamazepine (50 µm) or phenytoin (50 µm). RESULTS: NaV expression was demonstrated with immunocytochemistry, RNA sequencing, and functionally, with demonstration of robust tetrodotoxin-sensitive and voltage-activated inward currents. Application of carbamazepine or phenytoin resulted in significant inhibition of current amplitude for carbamazepine (31.6 ± 5.9%, n = 9; p < 0.001), and for phenytoin (35.5 ± 6.9%, n = 7; p < 0.001). SIGNIFICANCE: Mouse osteoblasts express NaV , and native NaV currents are blocked by carbamazepine and phenytoin, supporting our hypothesis that AEDs can directly influence osteoblast function and potentially affect bone strength.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Osteoblastos/efeitos dos fármacos , Fenitoína/farmacologia , Canais de Sódio/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Relação Dose-Resposta a Droga , Estimulação Elétrica , Regulação da Expressão Gênica/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo , Técnicas de Patch-Clamp , RNA Mensageiro , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia
13.
Calcif Tissue Int ; 98(6): 556-65, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26842957

RESUMO

Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had "failed" initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15 months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (-9.0 %; p < 0.001 in levetiracetam vs. -9.8 %; p < 0.001 in older AED group), FA (-1.46 %; p < 0.001 vs. -0.96 %; p < 0.001, respectively) and radial trabecular BMD (-1.46 %; p = 0.048 and -2.31 %; p = 0.013, respectively). C-terminal telopeptides of type I collagen (ßCTX; bone resorption marker) decreased in both groups (-16.1 %; p = 0.021 vs. -15.2 %; p = 0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP; bone formation marker) decreased in older AED group (-27.3 %; p = 0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites and a reduction in bone turnover.


Assuntos
Anticonvulsivantes/efeitos adversos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Piracetam/análogos & derivados , Absorciometria de Fóton , Adulto , Idoso , Densidade Óssea/efeitos dos fármacos , Carbamazepina/efeitos adversos , Feminino , Humanos , Levetiracetam , Masculino , Pessoa de Meia-Idade , Piracetam/efeitos adversos , Tomografia Computadorizada por Raios X , Ácido Valproico/efeitos adversos
14.
Pharmacogenomics ; 16(12): 1399-409, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26229012

RESUMO

Point-of-care molecular diagnostic devices are a rapidly expanding market. A variety of technologies are being developed for DNA detection and amplification, mostly aiming to detect pathogens. Of the two devices for detection of human genetic variations, both focus on CYP2C19 and have obtained regulatory approval. Most other devices have not obtained US FDA approval and are still undergoing clinical trials. Most, if not all, devices in development require equipment to which disposable test cartridges are placed. Thus, they may not fulfill FDA's definition of being 'simple'. There is a clear need to develop completely disposable devices that do not require equipment maintenance, and to detect other genetic variants predictive of disease susceptibility and drug response.


Assuntos
Técnicas de Diagnóstico Molecular/instrumentação , Citocromo P-450 CYP2C19/genética , DNA/genética , Variação Genética/genética , Humanos , Técnicas de Diagnóstico Molecular/métodos , Patologia Molecular/instrumentação , Sistemas Automatizados de Assistência Junto ao Leito , Estados Unidos , United States Food and Drug Administration
15.
Hum Mol Genet ; 23(1): 247-58, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23962720

RESUMO

We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a minimum of 12 months in accordance with the consensus statement from the International League Against Epilepsy (ILAE). Genetic effects on remission of seizures after starting treatment were analysed with and without adjustment for significant clinical prognostic factors, and the results from each cohort were combined using a fixed-effects meta-analysis. After quality control (QC), we analysed 889 newly treated epilepsy patients using 472 450 genotyped and 6.9 × 10(6) imputed single-nucleotide polymorphisms. Suggestive evidence for association (defined as Pmeta < 5.0 × 10(-7)) with remission of seizures after starting treatment was observed at three loci: 6p12.2 (rs492146, Pmeta = 2.1 × 10(-7), OR[G] = 0.57), 9p23 (rs72700966, Pmeta = 3.1 × 10(-7), OR[C] = 2.70) and 15q13.2 (rs143536437, Pmeta = 3.2 × 10(-7), OR[C] = 1.92). Genes of biological interest at these loci include PTPRD and ARHGAP11B (encoding functions implicated in neuronal development) and GSTA4 (a phase II biotransformation enzyme). Pathway analysis using two independent methods implicated a number of pathways in the prognosis of epilepsy, including KEGG categories 'calcium signaling pathway' and 'phosphatidylinositol signaling pathway'. Through a series of power curves, we conclude that it is unlikely any single common variant explains >4.4% of the variation in the outcome of newly treated epilepsy.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Estudo de Associação Genômica Ampla , Adulto , Anticonvulsivantes/uso terapêutico , Sinalização do Cálcio/genética , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9 , Epilepsia/tratamento farmacológico , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilinositóis/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
16.
Neurology ; 81(10): 920-7, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-23925763

RESUMO

OBJECTIVE: To determine the frequency and nature of potentially epileptogenic lesions on MRI in adults with new-onset seizures. METHODS: We prospectively studied a consecutive series of 993 patients (597 males [61%]; mean [SD] age: 42.2 [18.8] years, range 14.3-94.3 years) who presented to an adult First Seizure Clinic over a 10-year period. The MRI scans, performed clinically on 3- and 1.5-tesla scanners, were reviewed for their diagnostic yield, nature of abnormalities, and their association with abnormal electrical activity on EEG. RESULTS: MRI scans were acquired in 764 patients (77%); potentially epileptogenic lesions were detected in 177 (23%). The frequency of potentially epileptogenic lesions was higher in patients who were diagnosed as having an epileptic seizure (28%) than in those with a nonepileptic event (8%) (p < 0.001), and highest in those who had focal-onset seizures (53%) (p < 0.001). The most common lesion type in patients with focal seizures was gliosis or encephalomalacia (49%). Other common lesion types were tumors (15%), cavernomas (9%), and mesial temporal sclerosis (9%). Abnormal MRI and EEG were concordant in 18% of patients, with EEG being normal in 55% of patients with epileptogenic lesions. CONCLUSIONS: MRI reveals potentially epileptogenic lesions in a minority of patients with a newly diagnosed seizure disorder. Lesions are most common in patients who have experienced focal seizures. The presence of a potentially epileptogenic MRI lesion did not influence the chance of having an abnormal EEG.


Assuntos
Imageamento por Ressonância Magnética/métodos , Convulsões/diagnóstico , Convulsões/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Convulsões/patologia , Adulto Jovem
18.
Arch Neurol ; 69(12): 1563-71, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22945760

RESUMO

OBJECTIVE To determine whether patients who fail their first antiepileptic drug (AED) have better neuropsychiatric and quality-of-life (QOL) outcomes if substituted to levetiracetam monotherapy compared with a second older AED. DESIGN Randomized comparative trial. Participants with partial epilepsy who had failed monotherapy with phenytoin sodium, carbamazepine, or valproate sodium were randomized to substitution monotherapy with levetiracetam or a different older AED. Assessments were performed at baseline, 3 months, and 12 months using questionnaires measuring neuropsychiatric, QOL, seizure control, AED adverse effects, and neurocognitive outcomes. SETTING Epilepsy service of a teaching hospital. PATIENTS Fifty-one patients were randomized to levetiracetam and 48 were randomized to a second older AED (25 to valproate and 23 to carbamazepine). MAIN OUTCOME MEASURES Proportions showing improvements in depression (on the Hospital Anxiety and Depression Scale) and QOL scores (on the 89-item Quality of Life in Epilepsy Inventory) at 3 months. RESULTS There were no differences between the groups in depression scores at 3 months (improvement in 17 of 43 patients [39.5%] in the levetiracetam group and 15 of 44 patients [34.1%] in the older AED group; P = .60), but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory compared with the levetiracetam group (27 of 38 patients [71.1%] vs 21 of 43 patients [48.8%], respectively; P = .04). The QOL, anxiety, and AED adverse effects scores were improved in both groups at 3 and 12 months after randomization. CONCLUSIONS Substitution monotherapy in a patient experiencing ongoing seizures or tolerability issues is associated with sustained improvements in measures of QOL, psychiatric, and adverse events outcomes. Patients switched to levetiracetam do not have better outcomes than those switched to a second older AED. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12606000102572.

19.
Hum Mutat ; 28(8): 816-23, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17394239

RESUMO

Targeted corrective gene conversion (TCGC) holds much promise as a future therapy for many hereditary diseases in humans. Mutation correction frequencies varying between 0.0001% and 40% have been reported using chimeraplasty, oligoplasty, triplex-forming oligonucleotides, and small corrective PCR amplicons (CPA). However, PCR technologies used to detect correction events risk either falsely indicating or greatly exaggerating the presence of corrected loci. This is a problem that is considerably exacerbated by attempted improvement of the TCGC system using high corrective nucleic acid (CNA) to nuclear ratios. Small fragment homologous replacement (SFHR)-mediated correction of the exon 23 dystrophin (DMD) gene mutation in the mdx mouse model of DMD has been used in this study to evaluate the effect of increasing CPA amounts. In these experiments, we detected extremely high levels of apparently corrected loci and determined that at higher CNA to nuclear ratios the extent of locus correction was highly exaggerated by residual CNA species in the nucleic acids extracted from the treated cells. This study describes a generic locus-specific detection protocol designed to eradicate residual CNA species and avoid the artifactual or exaggerated detection of gene correction.


Assuntos
Distrofina/genética , Mioblastos/citologia , Mioblastos/metabolismo , Análise de Sequência de DNA/métodos , Células-Tronco/metabolismo , Animais , Células Cultivadas , Reações Falso-Positivas , Masculino , Camundongos , Camundongos Endogâmicos mdx , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Transfecção
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...