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BACKGROUND: Patients with epilepsy have a higher mortality rate than the general population. Up-to-date estimates of epilepsy incidence, prevalence, and medication use are critical to assist policymaking. METHODS: Using the National Taiwan Insurance Research Database, the standardized incidence and prevalence of epilepsy were estimated in each calendar year from 2007 to 2015. We used the incident cases of epilepsy to analyze the change in prescribing patterns from 2007 to 2015. Joinpoint regression was used to estimate secular trends. RESULTS: From 2007 to 2015, the age- and sex-standardized incidence decreased from 0.72 (95% confidence interval [CI] 0.70-0.73) to 0.54 (95% CI 0.53-0.55) per 1,000 person-years, giving an annual percentage change (APC) of -2.73 (p < 0.05). Among patients younger than 20 years, the incidence did not change significantly. The age- and sex-standardized prevalence decreased from 6.94 (95% CI 6.90-6.98) to 6.86 (95% CI, 6.82-6.89) per 1,000 people, giving an APC of -0.31 (p < 0.05). However, the prevalence increased in the 35- to 49- and 50- to 64-year age-groups. The most common first-line anticonvulsant was phenytoin in 2007 and valproate in 2015. The use of levetiracetam, clobazam, and valproate increased during the study period, with APCs of 25.48% (95% CI 19.97-31.24), 6.41 (3.09-9.85), and 2.83 (1.51-4.16), respectively. The use of carbamazepine, phenytoin, and topiramate decreased; the APCs were -23.86% (95% CI -25.25 to -22.44), -6.61 (-8.40 to -4.79), and -4.29% (-7.87 to -0.57), respectively. CONCLUSIONS: The overall prevalence and incidence of epilepsy decreased slightly from 2007 to 2015. The prescribed first-line anticonvulsant also changed over time.
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Epilepsia , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Humanos , Incidencia , Levetiracetam/uso terapéutico , Prevalencia , Taiwán/epidemiologíaRESUMEN
In Schizosaccharomyces pombe, the expression of the zrt1 zinc uptake gene is tightly regulated by zinc status. When intracellular zinc levels are low, zrt1 is highly expressed. However, when zinc levels are high, transcription of zrt1 is blocked in a manner that is dependent upon the transcription factor Loz1. To gain additional insight into the mechanism by which Loz1 inhibits gene expression in high zinc, we used RNA-seq to identify Loz1-regulated genes, and ChIP-seq to analyze the recruitment of Loz1 to target gene promoters. We find that Loz1 is recruited to the promoters of 27 genes that are also repressed in high zinc in a Loz1-dependent manner. We also find that the recruitment of Loz1 to the majority of target gene promoters is dependent upon zinc and the motif 5'-CGN(A/C)GATCNTY-3', which we have named the Loz1 response element (LRE). Using reporter assays, we show that LREs are both required and sufficient for Loz1-mediated gene repression, and that the level of gene repression is dependent upon the number and sequence of LREs. Our results elucidate the Loz1 regulon in fission yeast and provide new insight into how eukaryotic cells are able to respond to changes in zinc availability in the environment.
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Elementos de Respuesta/fisiología , Proteínas de Schizosaccharomyces pombe/metabolismo , Factores de Transcripción/metabolismo , Zinc/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Expresión Génica/genética , Regulación Fúngica de la Expresión Génica/genética , Homeostasis , Regiones Promotoras Genéticas/genética , Elementos de Respuesta/genética , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Factores de Transcripción/genética , Dedos de Zinc/genéticaRESUMEN
In Schizosaccharomyces pombe, alcohol dehydrogenase 1 (Adh1) is an abundant zinc-requiring enzyme that catalyses the conversion of acetaldehyde to ethanol during fermentation. In a zinc-replete cell, adh1 is highly expressed. However, in zinc-limited cells, adh1 gene expression is repressed, and cells induce the expression of an alternative alcohol dehydrogenase encoded by the adh4 gene. In our studies examining this zinc-dependent switch in alcohol dehydrogenase gene expression, we isolated an adh1Δ strain containing a partial loss of function mutation that resulted in higher levels of adh4 transcripts in zinc-replete cells. This mutation also led to the aberrant expression of other genes that are typically regulated by zinc. Using linkage analysis, we have mapped the position of this mutation to a single gene called Loss Of Zinc sensing 1 (loz1). Loz1 is a 55-kDa protein that contains a double C2H2-type zinc finger domain. The mapped mutation that disrupts Loz1 function leads to an arginine to glycine substitution in the second zinc finger domain, suggesting that the double zinc finger domain is important for Loz1 function. We show that loz1Δ cells hyperaccumulate zinc and that Loz1 is required for gene repression in zinc-replete cells. We also have found that Loz1 negatively autoregulates its own expression. We propose that Loz1 is a unique metalloregulatory factor that plays a central role in zinc homeostasis in S. pombe.
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Regulación Fúngica de la Expresión Génica/genética , Homeostasis/fisiología , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/fisiología , Factores de Transcripción/genética , Dedos de Zinc/genética , Zinc/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Immunoblotting , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Factores de Transcripción/metabolismo , beta-GalactosidasaRESUMEN
BACKGROUND: The decline of inhibitory in cognitive aging is linked to reduced cognitive and mental capacities in older adults. However, this decline often shows inconsistent clinical presentations, suggesting varied impacts on different inhibition-related tasks. Inhibitory control, a multifaceted construct, involves various types of inhibition. Understanding these components is crucial for comprehending how aging affects inhibitory functions. Our research investigates the influences of aging on large-scale and focal-scale inhibitory and examines the relationship with brain markers. METHODS: We examined the impact of aging on inhibitory in 18 younger (20-35 years) and 17 older adults (65-85 years) using focal and large-scale inhibition tasks. The Gabor task assessed focal-scale inhibition, while the Stop Signal Task (SST) evaluated large-scale inhibition. Participants underwent neuropsychological assessments and MRI scans, including magnetic resonance spectroscopy (MRS) and structural and resting fMRI. RESULTS: Older adults exhibited a marked decline in inhibitory function, with slower SST responses indicating compromised large-scale inhibition. Conversely, the Gabor task showed no significant age-related changes. MRS findings revealed decreased levels of GABA, glutamate, glutamine, and NAA in the pre-SMA, correlating with observed large-scale inhibition in older adults. Additionally, pre-SMA seed-based functional connectivity analysis showed reduced brain network connections in older adults, potentially contributing to inhibitory control deficits. CONCLUSIONS: Our study elucidates the differential effects of aging on inhibitory functions. While large-scale inhibition is more vulnerable to aging, focal-scale inhibition is relatively preserved. These findings highlight the importance of targeted cognitive interventions and underscore the necessity of a multifaceted approach in aging research.
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INTRODUCTION: Limited studies have evaluated the association between Clostridium difficile infection (CDI) and the duration of proton pump inhibitor (PPI) or histamine H2-receptor blocker (H2RA) use and provided a cutoff duration for PPI or H2RA use to mitigate a substantially increased risk of CDI. We aimed to evaluate these associations in hospitalized patients using a nationwide insurance claims database. METHODS: We conducted a nested case-control study to identify cases with a first ever record of CDI in a study cohort undergoing PPI or H2RA therapy from the National Health Insurance Database from 2012 to 2018. Each case was matched with one control by age, sex, and calendar year. We used conditional logistic regression to estimate the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC ROC). Youden's J statistic was used to identify the optimal cutoff duration in days for PPI or H2RA use. RESULTS: In the main analysis, the AUC ROC was 0.64 (95% CI 0.63-0.66) and optimal cutoff duration was 15 days for PPI users. The AUC ROC was 0.63 (95% CI 0.62-0.64) and optimal cutoff duration was 16 days for H2RA users. In the sensitivity analyses, the results were similar to those of the main analysis, and the optimal cutoff duration was in the range of 14-15 days. CONCLUSIONS: The optimal cutoff duration for PPI and H2RA use was about 2 weeks. It is necessary to be cautious regarding the risk of CDI in patients taking PPIs or H2RAs for longer than 2 weeks.
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Introduction: Chimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) is a treatment option for patients with relapsed or refractory multiple myeloma that has led to unprecedented treatment outcomes. Among CAR T therapies available, ciltacabtagene autoleucel (cilta-cel) is a good candidate for outpatient administration due to its generally predictable safety profile. There are multiple advantages of outpatient administration of cilta-cel, including reduced healthcare burden, expanded access, and patient autonomy. This mixed methods qualitative study aimed to identify key factors for outpatient administration of CAR T and best practice recommendations by combining a targeted literature review with expert interviews and panels. Methods: The targeted review (Phase 1) aimed to identify factors for outpatient CAR T administration in the US and determine key topics for the exploratory interviews (Phase 2) and expert panels (Phase 3), which aimed to inform on best practices and challenges of outpatient CAR T administration (focusing on cilta-cel). Participants in clinical and administrative positions based in treatment centers that had experience with real-world outpatient administration of cilta-cel were recruited. Results: Seventeen studies were identified in Phase 1. Key factors for outpatient administration included the development of protocols for CAR T complications, education for caregivers, outpatient specialists, hospital staff, and emergency services staff for identification and referral after possible adverse events, the creation of multidisciplinary teams for effective communication and management, straightforward patient intake processes encompassing financial eligibility review and provision of patient education materials, and close patient monitoring throughout the treatment journey. In Phase 2, 5 participants from 2 centers were interviewed. In Phase 3, 14 participants across 6 treatment centers were interviewed. Two 90-minute virtual panel discussions took place. All participants agreed that cilta-cel can be safely and effectively administered in an outpatient setting. Key recommendations included the creation of educational resources for patients and caregivers, the development of standard operating procedures, dedicated outpatient infrastructure and establishment of interdisciplinary teams, outpatient monitoring for toxicity management, and monitoring of the reimbursement landscape. Discussion: This study offers a comprehensive understanding of the feasibility of outpatient cilta-cel administration in participating CAR T centers and provides actionable recommendations while acknowledging existing challenges.
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Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Pacientes Ambulatorios , Productos Biológicos/uso terapéutico , Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Atención Ambulatoria , Receptores Quiméricos de Antígenos/inmunología , MasculinoRESUMEN
A qualitative study of the experiences of patients who received autologous stem cell transplant (ASCT) for the treatment of multiple myeloma (MM) was conducted to better understand their MM disease journey, including first symptoms, diagnosis, ASCT, and recovery. Sixteen participants, including 12 patients with MM and 4 caregivers of patients with MM, were interviewed in focus group meetings. Pain, weakness, and bone pain were common first symptoms among patients. The MM diagnosis was often made by a hematologist or oncologist. Patients were referred to a specialized oncologist after diagnosis, who was the primary driver in making ASCT treatment decisions. Eight patients received their ASCT in the inpatient setting, with some having lengthy hospital stays; 4 received their ASCT in an outpatient setting with 3 eventually being hospitalized. The focus groups identified that patients and caregivers perceived various unmet needs and impacts on quality of life throughout their transplant journey. Educational resources and innovative therapies are needed to reduce the disease burden of MM and enhance the quality of life for both patients and their caregivers.
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Although chimeric antigen receptor (CAR)-T cell therapies are typically administered in the inpatient setting, outpatient administration is rapidly expanding. However, there is limited summarized evidence comparing outcomes between outpatient and inpatient administration. This systematic literature review aims to compare the safety, efficacy, quality of life (QoL), costs, and healthcare resource utilization (HCRU) outcomes in patients with hematological cancer who are administered CAR-T therapy in an outpatient versus an inpatient setting. Publications (2016 or later) that reported the outcomes of interest in patients treated with a CAR-T therapy in both outpatient and inpatient settings, or only the outpatient setting, were reviewed. In total, 38 publications based on 21 studies were included. Safety findings suggested the comparable frequency of adverse events in the two settings. Eleven studies that reported data in both settings showed comparable response rates (80-82% in outpatient and 72-80% in inpatient). Improvements in the QoL were observed in both settings while costs associated with CAR-T therapy were lower in the outpatient setting. Although unplanned hospitalizations were higher in the outpatient cohort, overall HCRU was lower. Outpatient administration of CAR-T therapy appears to have comparable outcomes in safety, efficacy, and QoL to inpatient administration while reducing the economic burden.
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This study aims to depict and compare clinical characteristics and risk behavior among groups of individuals using ketamine, polydrugs or smoking cigarette. A total of 185 drug-using participants and 49 smokers participated in this study. A cross-sectional interview was used to collect information on demographics, drug- and sex-related behaviors, HIV serostatus, lower urinary tract symptoms (LUTS), behavioral dispositions. N-back memory test was used to measure short-term memory. Result shows that 10 participants (5.41%) were HIV positive and 14 (7.57%) having LUTS. Individuals with ketamine and polydrugs use have significantly worse drug-related problem than cigarette smokers. Compared to cigarette smokers and ketamine users, individuals with polydrug users scored significantly higher on impulsivity measures. Cigarette smokers performed significantly better than the other two groups on the memory tests. A few patients had been infected with HIV and diagnosed with LUTS. Findings support that memory on short term recalls of patients with ketamine use might be impaired. Study findings warrants the necessarily of further study on influences of using ketamine.
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Conducta Impulsiva , Ketamina/efectos adversos , Memoria a Corto Plazo , Asunción de Riesgos , Conducta Sexual , Trastornos Relacionados con Sustancias/etiología , Trastornos Relacionados con Sustancias/psicología , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Síntomas del Sistema Urinario Inferior/inducido químicamente , Masculino , Fumar/efectos adversos , Adulto JovenRESUMEN
Anti-glutamic acid decarboxylase (anti-GAD) antibodies are associated with different types of syndromes. However, few studies have investigated the correlation between anti-GAD antibody titers with clinical severity and outcomes in children with encephalitis/encephalopathy. In this single-center retrospective cohort study, we consecutively enrolled hospitalized children who had encephalitis and/or encephalopathy with positive anti-GAD antibodies in serum and/or cerebrospinal fluid (CSF) from February 2010 to October 2021. Thirty-seven patients were included and divided into high-titer and low-titer groups. The patients with high anti-GAD antibody titers were associated with initial symptoms of language difficulty and ataxia. The level of titers was not associated with severity or outcomes. Anti-GAD antibody titers decreased after immunotherapy, however, the clinical response to immunotherapy was variable. A transient elevation in anti-GAD antibody titers during immunotherapy was noted. Further studies are warranted to investigate the role of anti-GAD antibodies in the pathogenesis and immune mechanisms of encephalitis/encephalopathy.
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BACKGROUND: Several dietary components have been shown to be neuroprotective against risk of neurodegeneration. However, limited observational studies have examined the role of overall diet quality on risk of Parkinson's disease. OBJECTIVES: We examined the associations between diet quality and risk of Parkinson's disease in a prospective cohort study and meta-analysis. METHODS: Included in the cohort study were 3,653 participants (1,519 men and 2,134 women; mean age: 81.5 years) in the Geisinger Rural Aging Study longitudinal cohort in Pennsylvania. Diet quality was assessed using a validated dietary screening tool containing 25 food- and behavior-specific questions in 2009. Potential Parkinson's cases were identified using electronic health records based on ICD9 (332.*), ICD10 (G20), and Parkinson-related treatments. Hazard ratios (HRs) and 95% confidence intervals (CIs) across diet quality tertiles were calculated using Cox proportional hazards models after adjusting for potential confounders. We further performed a meta-analysis by pooling our study with four published papers on this topic. Random-effects model was utilized to calculate the pooled risk ratios and 95% CIs. RESULTS: During a mean of 6.94 years of follow-up, 47 incident Parkinson's cases were documented. Having high diet quality at baseline was associated with lower Parkinson's disease risk (adjusted HR for the highest vs the lowest diet quality tertileâ=â0.39; 95% CI: 0.17, 0.89; p-trendâ=â0.02). The meta-analysis including 140,617 individuals also showed that adherence to high diet quality or a healthy dietary pattern was associated with lower risk of Parkinson's disease (pooled risk ratioâ=â0.64; 95% CI: 0.49, 0.83). CONCLUSION: Having high diet quality or a healthy dietary pattern was associated with lower future risk of Parkinson's disease.
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Dieta/estadística & datos numéricos , Enfermedad de Parkinson/epidemiología , Anciano , Anciano de 80 o más Años , Dieta Saludable/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pennsylvania/epidemiología , Modelos de Riesgos Proporcionales , Estudios Prospectivos , RiesgoRESUMEN
More perceived physical fatigability and poor diet quality are associated with impairments in physical function in older adults. However, the degree to which more perceived fatigability explains the association between poor diet quality and low physical function is unknown. We examined this relationship in 122 (66F, 56M) of the oldest-old participants from the Geisinger Rural Aging Study (GRAS). We used 24-h dietary recalls to assess the Healthy Eating Index (HEI), the Pittsburgh Fatigability Scale (PFS, 0-50) to assess perceived physical fatigability, and the PROMIS Physical Function 20a* to assess physical function. We grouped participants into three age categories: 80-84 (n = 51), 85-89 (n = 51), and 90+ (n = 20) years. Multiple linear regression revealed that a lower HEI was associated with higher PFS Physical score after adjusting for age group, sex, body mass index, and the number of medical conditions (p = 0.001). Several macro- and micro-nutrient intakes were also lower in those reporting more (≥15) compared to less (<15) perceived physical fatigability. Mediation analysis revealed that PFS Physical scores explained ~65% (p = 0.001) of the association between HEI total score and PROMIS19 Physical Function score. Poor diet quality may contribute to more perceived physical fatigability, which could exacerbate impairments in the oldest-old's physical function.
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BACKGROUND: Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy and SCN1A gene mutations. In some cases, non-SCN1A gene mutations can present with a phenotype very similar to that of Dravet syndrome. The aim of this study was to compare phenotypes of patients with SCN1A and non-SCN1A gene mutation-related Dravet syndrome. METHODS: Thirty-six patients with Dravet syndrome-like phenotypes were followed from July 2017 to December 2019. We retrospectively analyzed their clinical profiles and genetic surveys. RESULTS: Of the 36 enrolled patients, 15 (41.7%) had SCN1A mutations, one (2.8%) had an SCN8A mutation, one (2.8%) had an STX1B mutation, and five females (13.9%) had PCDH 19 mutations. The median age at first seizure onset was 7 months in those with SCN1A mutations, 1.3 years in those with PCDH19 mutations, and 10 months for the remaining patients. The majority of the patients with SCN1A mutations had status epilepticus (80% vs. 20%) and fever-sensitive seizures (76% vs. 31%) compared to those with PCDH19 mutations. The patients with SCN1A-related seizures had a higher rate of focal seizures as first seizure type than those without SCN1A mutations. Three of five (60%) patients with PCDH19 mutations had brain magnetic resonance imaging abnormalities. The three most commonly used antiseizure medications were sodium valproate, levetiracetam, and clobazam. Seven of the 15 patients with SCN1A mutations used stiripentol. The median time from seizure onset to genetic diagnosis was 6.6 years (range 4 months-22.3 years). CONCLUSION: The patients with SCN1A mutations in this study had high rates of fever-sensitive seizures, status epilepticus, seizure onset with focal seizure type, and relatively young age at seizure onset. The patients with PCDH19 mutations had a relatively high rate of abnormal brain magnetic resonance imaging findings.
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Epilepsias Mioclónicas , Canal de Sodio Activado por Voltaje NAV1.1 , Cadherinas/genética , Epilepsias Mioclónicas/diagnóstico , Epilepsias Mioclónicas/genética , Femenino , Humanos , Mutación , Canal de Sodio Activado por Voltaje NAV1.1/genética , Fenotipo , Protocadherinas , Estudios Retrospectivos , TaiwánRESUMEN
BACKGROUND: Diet is an important lifestyle factor that may prevent or slow the onset and progression of neurodegeneration. Some, but not all, recent studies have suggested that adherence to a healthy dietary pattern may be associated with reduced risk of dementia. OBJECTIVE: In this meta-analysis, we systematically examined the associations between overall dietary patterns, assessed a priori and a posteriori, and risk of dementia. METHODS: We systematically searched PubMed, Web of Science, and the Cumulative Index for Nursing and Allied Health databases from January 1, 1981 to September 11, 2019. Prospective studies published in English were included. Random-effects model was used to calculate the pooled risk ratios and 95% confidence intervals (CIs). RESULTS: Sixteen research articles were identified in the systematic review and 12 research articles including 66,930 participants were further included for the meta-analysis. Adherence to high diet quality or a healthy dietary pattern was significantly associated with lower risk of overall dementia (pooled risk ratioâ=â0.82; 95% CI: 0.70, 0.95; nâ=â12) and Alzheimer's disease (pooled risk ratioâ=â0.61; 95% CI: 0.47, 0.79; nâ=â6) relative to those with low diet quality or an unhealthy dietary pattern. Subgroup analyses stratified by age, sex, follow-up duration, diet quality assessment approach, study location, and study quality generated similar results. CONCLUSION: Adherence to a healthy dietary pattern was associated with lower risk of overall dementia. Further randomized controlled trials are needed to provide additional evidence about the role of a healthy diet on the development and progression of dementia.
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Demencia/epidemiología , Dieta Saludable , Conducta Alimentaria , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Estudios de Cohortes , Dieta , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Objective: Valproic acid is the most high-risk teratogenic antiepileptic drug, and it may lead to fetal major congenital malformations. However, it is still used in women of childbearing age with epilepsy. The aim of this study was to report our experience of discontinuing or lowering valproic acid by adding levetiracetam, a low-risk teratogenic antiepileptic drug. Methods: We reviewed the medical records of childbearing age female patients with epilepsy who were treated with valproic acid initially and then switched to levetiracetam. The clinical profiles were recorded. The primary outcome was successful switching, which was defined as a decrease in the daily valproic acid dosage, after levetiracetam had been added. Results: Twenty-four female patients were enrolled (median age 22 years). The successful switching rate was 83.3% (20/24), and 55% (11/20) discontinued valproic acid after levetiracetam had been added. There were no significant differences between the successful and unsuccessful groups in etiology, electroencephalogram, and magnetic resonance imaging findings. Pharmacoresistant to levetiracetam was much higher in the unsuccessful group (45 vs. 100%). The median switching duration was 19.5 months in the successful group. There were improvements in metrorrhagia and alopecia in all of the patients in the successful group after valproic acid had been tapered. Conclusions: Our experience supports switching valproic acid to levetiracetam in childbearing age women with epilepsy as an effective strategy to lower the teratogenic rate and adverse effects. A long switching period was noted in this study. We suggest starting early in childbearing age women with epilepsy.
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Ketamine has been used for medical purposes, most typically as an anesthetic, and recent studies support its use in the treatment of depression. However, ketamine tends to be abused by adolescents and young adults. In the current study, we examined the effects of early ketamine exposure on brain structure and function. We employed MRI to assess the effects of ketamine abuse on cerebral gray matter volume (GMV) and functional connectivity (FC) in 34 users and 19 non-users, employing covariates. Ketamine users were categorized as adolescent-onset and adult-onset based on when they were first exposed to ketamine. Imaging data were processed by published routines in SPM and AFNI. The results revealed lower GMV in the left precuneus in ketamine users, with a larger decrease in the adolescent-onset group. The results from a seed-based correlation analysis show that both ketamine groups had higher functional connectivity between left precuneus (seed) and right precuneus than the control group. Compared to controls, ketamine users showed decreased GMV in the right insula, left inferior parietal lobule, left dorsolateral prefrontal cortex/superior frontal gyrus, and left medial orbitofrontal cortex. These preliminary results characterize the effects of ketamine misuse on brain structure and function and highlight the influence of earlier exposure to ketamine on the development of the brain. The precuneus, a structure of central importance to cerebral functional organization, may be particularly vulnerable to the influences of early ketamine exposure. How these structural and functional brain changes may relate to the cognitive and affective deficits remains to be determined with a large cohort of participants.
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Sustancia Gris/efectos de los fármacos , Ketamina/efectos adversos , Trastornos Relacionados con Sustancias/patología , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Neuroimagen , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Trastornos Relacionados con Sustancias/fisiopatología , Adulto JovenRESUMEN
C-terminal truncation mutagenesis was used to explore the functional and structural significance of the C-terminal region of Aeromonas caviae D1 chitinase (AcD1ChiA). Comparative studies between the engineered full-length AcD1ChiA and the truncated mutant (AcD1ChiAK606) included initial rate kinetics, fluorescence and circular dichroism (CD) spectrometric properties, and substrate binding and hydrolysis abilities. The overall catalytic efficiency, k(cat)/K(M), of AcD1ChiAK606 with the 4MU-(GlcNAc)(2) and the 4MU-(GlcNAc)(3) chitin substrates was 15-26% decreased. When compared with AcD1ChiA, the truncated mutant AcD1ChiAK606 maintained 80% relative substrate-binding ability and about 76% of the hydrolyzing efficiency against the insoluble alpha-chitin substrate. Both fluorescence and CD spectroscopy indicated that AcD1ChiAK606 retained the same conformation as AcD1ChiA. These results indicated that removal of the C-terminal 259 amino acid residues, including the putative chitin-binding motif and the A region (a motif of unknown function) of AcD1ChiA, did not seriously affect the enzyme structure integrity as well as activity. The present study provided evidences illustrating that the binding and hydrolyzing of insoluble chitin substrates by AcD1ChiA were not absolutely dependent on the putative C-terminal chitin-binding domain and the function-unknown A region.
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Aeromonas/enzimología , Proteínas Bacterianas/metabolismo , Quitinasas/metabolismo , Aeromonas/genética , Proteínas Bacterianas/genética , Sitios de Unión , Quitina/metabolismo , Quitinasas/genética , Dicroismo Circular , Cinética , Mutagénesis , Unión Proteica , Pliegue de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The oldest old (aged ≥80 years) are often the population subgroup at high nutritional risk due to age-related metabolic changes. We performed a validation analysis of a dietary screening tool (DST) which was developed for older adults among the oldest old. We examined dietary intakes using three 24-hour dietary recalls and the DST among 122 participants (aged 82-97) of the Geisinger Rural Aging Study. DST scores were compared with the Health Eating Index (HEI)-2015 scores, which were calculated based on three-day dietary recalls. Pearson correlations were used to characterize concurrent validity and Bland-Altman plots were used to identify potential bias. DST scores were significantly correlated with HEI scores (adjusted r = 0.68; p < 0.001) in an age- and sex-adjusted model. Those within the not-at-risk DST group had significantly higher HEI scores (adjusted means = 79.6 ± 3.68) compared with those who were in the at-risk (adjusted means = 51.2 ± 1.56) and the possibly-at-risk (adjusted means = 66.3 ± 1.79) groups (p-trend < 0.001). The DST appears to be a valid measure of diet quality in the oldest old when compared with the HEI and may be a potential tool to assess overall diet quality in this population.
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Dieta/estadística & datos numéricos , Desnutrición/epidemiología , Tamizaje Masivo/métodos , Encuestas Nutricionales/métodos , Estado Nutricional , Anciano de 80 o más Años , Estudios de Cohortes , Estudios Transversales , Dieta Saludable , Femenino , Evaluación Geriátrica/métodos , Humanos , Masculino , Pennsylvania , Población RuralRESUMEN
OBJECTIVES: Diet quality has been associated with health outcomes and quality of life. However, the association between diet quality and mortality in older people, those aged 80 years and older, is understudied. Therefore, we conducted a prospective study to examine whether better diet quality, assessed by a validated dietary screening tool (DST), was associated with lower mortality in those aged 80 years and older. METHODS: Our study included 1990 participants (812 men and 1178 women), with a mean age of 84.1 years at baseline (ranging from 80 to 102 years old), from the Geisinger Rural Aging Study longitudinal cohort in Pennsylvania. Baseline descriptive information was obtained in 2009, and the DST was administered via mailed survey. The DST is composed of 25 food- and behavior-specific questions associated with dietary intake that generate a diet quality score ranging from 0 (lowest) to 100 (highest). Death was identified using electronic medical record and the Social Security Death Index data. Hazard ratios (HRs) and 95% confidence intervals (CIs) across three diet quality categories were calculated by using Cox proportional hazards models after adjusting for potential confounders. RESULTS: Over 8 years of follow-up (October 2009-February 2018), 931 deaths were documented. Higher diet quality was associated with lower mortality risk (P-trend = .04). Participants with high diet quality (defined as DST scores >75) had significantly lower risk of mortality compared with those with low diet quality (defined as DST scores <60) after adjusting for potential risk factors (adjusted HR = 0.76; 95% CI = 0.59-0.97). CONCLUSION: Diet quality, assessed by DST, is significantly associated with risk of mortality in older adults aged 80 years and older in our prospective cohort. Our results indicate that nutrition may have an important role in healthy aging, and more studies are needed to develop appropriate dietary recommendations for older persons. J Am Geriatr Soc 67:2180-2185, 2019.