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STUDY OBJECTIVES: The Veterans Health Administration cares for many veterans with sleep disorders who live in rural areas. The Veterans Health Administration's Office of Rural Health funded the TeleSleep Enterprise-Wide Initiative (EWI) to improve access to sleep care for rural veterans through creation of national telehealth networks. METHODS: The TeleSleep EWI consists of (1) virtual synchronous care, (2) home sleep apnea testing, and (3) REVAMP (Remote Veterans Apnea Management Platform), a patient- and provider-facing web application that enabled veterans to actively engage with their sleep care and sleep care team. The TeleSleep EWI was designed as a hub-and-spoke model, where larger sites with established sleep centers care for smaller, rural sites with a shortage of providers. Structured formative evaluation for the TeleSleep EWI is supported by the Veterans Health Administration's Quality Enhancement Research Initiative and was critical in assessing outcomes and effectiveness of the program. RESULTS: The TeleSleep EWI launched with 7 hubs and 34 spokes (2017) and rapidly expanded to 13 hubs and 63 spokes (2020). The TeleSleep EWI resulted in a significant increase in rural veterans accessing sleep care by utilizing home sleep apnea testing to establish a diagnosis of obstructive sleep apnea and virtual care for follow-up. Rates of virtual care utilization were greater in hubs and spokes participating in the TeleSleep EWI compared with non-EWI sleep programs. Additionally, veterans expressed satisfaction with their virtual care TeleSleep experiences. CONCLUSIONS: The TeleSleep EWI successfully increased sleep care access for rural veterans, promoted adoption of virtual care services, and resulted in high patient satisfaction. CITATION: Chun VS, Whooley MA, Williams K, et al. Veterans Health Administration TeleSleep Enterprise-Wide Initiative 2017-2020: bringing sleep care to our nation's veterans. J Clin Sleep Med. 2023;19(5):913-923.
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Síndromes da Apneia do Sono , Telemedicina , Veteranos , Humanos , Estados Unidos , Saúde dos Veteranos , Sono , Telemedicina/métodos , United States Department of Veterans AffairsRESUMO
PURPOSE: To describe and compare demographic characteristics and comorbidities of rural and urban Veterans diagnosed with sleep disorders, and to evaluate whether rurality is a disparity for sleep care among Veterans. METHODS: Numbers of Veterans with sleep disorders and comorbid conditions were determined using the Department of Veterans Affairs (VA's) Corporate Data Warehouse, a database that contains detailed clinical information for all Veterans who receive VA health care. Comparisons between urban and rural Veterans were conducted for fiscal years (FY) 2010-2021. FINDINGS: The prevalence of diagnosed sleep disorders was similar among rural and urban Veterans from FY2010 to 2021 and increased for both groups during this time period. The prevalence of chronic pulmonary disease, congestive heart failure, and diabetes mellitus was higher for rural Veterans with sleep disorders compared to their urban counterparts. From 2012 to 2021, the percentage of rural Veterans who received sleep care at VA facilities was lower than the percentage of urban Veterans who received VA sleep care during the same time span. CONCLUSIONS: Although rural Veterans exhibited a higher prevalence of 3 comorbid conditions associated with sleep disorders, the prevalence of sleep disorder diagnoses was similar between rural and urban Veterans. Therefore, it is possible that sleep disorders are underdiagnosed among rural Veterans. The fact that rural Veterans received VA sleep care at a lower rate compared to urban Veterans indicates that rurality is a disparity in access to care in this population. VA is addressing this disparity through a variety of programs, including telehealth initiatives.
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Transtornos do Sono-Vigília , Veteranos , Humanos , Estados Unidos/epidemiologia , Prevalência , População Urbana , Atenção à Saúde , Transtornos do Sono-Vigília/epidemiologia , População Rural , United States Department of Veterans AffairsRESUMO
BACKGROUND: Obstructive sleep apnea (OSA) is a very common and serious health condition which is highly prevalent among U.S. military Veterans. Because the demand for sleep medicine services often overwhelms the availability of such services, it is necessary to streamline diagnosis and treatment protocols. The goals of this study are to, (1) assess the efficacy of de-implementing the initial provider encounter for diagnosis and treatment of OSA; (2) determine the negative predictive value (NPV) of home sleep apnea testing (HSAT); (3) develop HSAT usage recommendations for various at-risk patient populations. METHODS: This is a large, pragmatic study that will take place in 3 VA sleep medicine programs: San Francisco, CA; Portland, OR; and Pittsburgh, PA. All Veterans referred for new sleep apnea evaluations at these sites will be included in this four-year study. Outcomes will include time from referral for OSA to sleep testing and treatment; positive airway pressure (PAP) treatment adherence measures; patient-reported clinical outcomes and measures of satisfaction; determination of the NPV of HSAT; HSAT usage recommendations for at-risk patient populations. DISCUSSION: The DREAM (Direct Referral for Apnea Monitoring) Project will inform sleep medicine providers and clinical organizations regarding strategies to streamline diagnosis and treatment protocols for OSA. Results of this study should have significant impact on clinical practices and professional guidelines. Trial registration The majority of this project is an observational study of clinical procedures. Therefore, clinical trial registration is not required.
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Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Humanos , Estudos Observacionais como Assunto , Polissonografia/métodos , Encaminhamento e Consulta , Sono , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/terapiaRESUMO
BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FUNDING: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411.
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COVID-19/complicações , COVID-19/patologia , COVID-19/diagnóstico , Humanos , SARS-CoV-2 , Síndrome de COVID-19 Pós-AgudaRESUMO
BACKGROUND: Computer-based documentation (CBD) is used commonly throughout the world to track patient care and clinical workloads. However, if capture of clinical services within the electronic health record (EHR) is not implemented properly, patient care services and workload credit will be inaccurate, which impacts business decisions related to demand for care and resources allocated to meet the demand. Understaffing of medical personnel can contribute to delays in treatment, missed treatments, and workforce turnover. OBJECTIVE: To illustrate the impact of CBD procedures on health care workload assessment and resource allocation, this article uses data from the US Department of Veterans Affairs Corporate Data Warehouse to provide examples from the Veterans Health Administration (VHA) sleep medicine programs. DISCUSSION: Inaccurate CBD led to underreporting of sleep medicine services provided at VHA facilities nationwide and contributed to insufficient allocation of resources and personnel. Recent modifications in CBD protocols (Stop Codes) improved the accuracy of data capture and reporting while providing VHA sleep programs with data they can use to advocate for workforce expansion to meet patient care needs. CONCLUSIONS: Inaccurate CBD of clinical workloads can result in inadequate allocation of health care personnel and resources to meet the needs of patients. Untreated sleep disorders are associated with increased risk of depression, anxiety, impaired neurocognitive functions, cardiovascular disease, motor vehicle accidents, and premature death. Educating health care providers and administrators on the importance of accurate designation of clinical services within the EHR is necessary to facilitate improvements in health care availability and delivery.
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The prevalence of diagnosed sleep disorders among Veterans treated at Veterans Affairs (VA) medical facilities increased significantly during fiscal years (FY) 2012 through 2018. Specifically, the prevalence of sleep-related breathing disorders (SRBD) increased from 5.5% in FY2012 to 22.2% in FY2018, and the prevalence of insomnia diagnoses increased from 7.4% in FY2012 to 11.8% in FY2018. Consequently, Veterans' demand for sleep medicine services also increased significantly between FY2012-2018, with steady increases in the annual number of VA sleep clinic appointments during this period (<250,000 in FY 2012; >720,000 in FY2018). Common co-morbid conditions among Veterans diagnosed with sleep disorders include obesity, diabetes, congestive heart failure, depression, post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). To address this healthcare crisis, the Veterans Health Administration (VHA) developed and/or implemented numerous innovations to improve the quality and accessibility of sleep care services for Veterans. These innovations include a TeleSleep Enterprise-Wide Initiative to improve rural Veterans' access to sleep care; telehealth applications such as the Remote Veteran Apnea Management Platform (REVAMP), Clinical Video Telehealth, and CBT-i Coach; increased use of home sleep apnea testing (HSAT); and programs for Veterans who experience sleep disorders associated with obesity, PTSD, TBI and other conditions.
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Acessibilidade aos Serviços de Saúde , Transtornos do Sono-Vigília/epidemiologia , Telemedicina , Veteranos/estatística & dados numéricos , Lesões Encefálicas Traumáticas , Comorbidade , Humanos , Obesidade , Prevalência , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/terapia , Transtornos do Sono-Vigília/terapia , Transtornos de Estresse Pós-Traumáticos , Estados Unidos/epidemiologia , United States Department of Veterans AffairsRESUMO
STUDY OBJECTIVES: (1) Review the prevalence and comorbidity of sleep disorders among United States military personnel and veterans. (2) Describe the status of sleep care services at Veterans Health Administration (VHA) facilities. (3) Characterize the demand for sleep care among veterans and the availability of sleep care across the VHA. (4) Describe the VA TeleSleep Program that was developed to address this demand. METHODS: PubMed and Medline databases (National Center for Biotechnology Information, United States National Library of Medicine) were searched for terms related to sleep disorders and sleep care in United States military and veteran populations. Information related to the status of sleep care services at VHA facilities was provided by clinical staff members at each location. Additional data were obtained from the VA Corporate Data Warehouse. RESULTS: Among United States military personnel, medical encounters for insomnia increased 372% between 2005-2014; encounters for obstructive sleep apnea (OSA) increased 517% during the same period. The age-adjusted prevalence of sleep disorder diagnoses among veterans increased nearly 6-fold between 2000-2010; the prevalence of OSA more than doubled in this population from 2005-2014. CONCLUSIONS: Most VA sleep programs are understaffed for their workload and have lengthy wait times for appointments. The VA Office of Rural Health determined that the dilemma of limited VHA sleep health care availability and accessibility might be solved, at least in part, by implementing a comprehensive telehealth program in VA medical facilities. The VA TeleSleep Program is an expansion of telemedicine services to address this need, especially for veterans in rural or remote regions. CITATION: Sarmiento KF, Folmer RL, Stepnowsky CJ, Whooley MA, Boudreau EA, Kuna ST, Atwood CW, Smith CJ, Yarbrough WC. National expansion of sleep telemedicine for veterans: the telesleep program. J Clin Sleep Med. 2019;15(9):1355-1364.
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Militares/estatística & dados numéricos , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/terapia , Telemedicina/métodos , Veteranos/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde , Humanos , Transtornos do Sono-Vigília/epidemiologia , Estados Unidos/epidemiologia , United States Department of Veterans AffairsRESUMO
PURPOSE OF REVIEW: Recent advances in our understanding of seizure generation have resulted in modified recommendations for when seizure treatment should be initiated, revisions to our definition of status epilepticus, and new pharmacological and neuromodulatory therapies. The goal of this review is to provide the anesthesiologist with an overview of the advancements they are most likely to encounter while providing clinical care. RECENT FINDINGS: There have been recent modifications to seizure definitions and treatment recommendations. These include the idea that treatment with antiepileptic therapy should be initiated after the first unprovoked seizure in individuals who are at high risk for another seizure, and that the idea that status epilepticus should be thought of as a two-phase process, related to an initial phase after which intervention should be started, and a second phase after which time risk of long-term sequelae is increased. Additionally, several new therapies have become available that have novel mechanisms of action, which are more efficacious and have fewer side-effects. SUMMARY: As knowledge about mechanisms of seizure generation has improved, there has been a concurrent evolution in our thinking about seizure-related definitions, and indications for initiation of treatment. Several next generation drug therapies with more specific targets have also become available. Taken together, there have been significant improvements in care options.
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Anticonvulsivantes/uso terapêutico , Terapia por Estimulação Elétrica/instrumentação , Epilepsia/terapia , Procedimentos Neurocirúrgicos/efeitos adversos , Assistência Perioperatória/métodos , Anestesiologistas , Terapia por Estimulação Elétrica/métodos , Epilepsia/classificação , Epilepsia/fisiopatologia , Humanos , Neuroestimuladores Implantáveis/efeitos adversos , Recidiva , Fatores de Risco , Fatores de TempoRESUMO
INTRODUCTION/BACKGROUND: Sleep disturbance may influence the development of cancer and responses to treatment. It is also closely tied to recovery and quality of life in cancer patients, survivors, and caregivers, and recent studies have begun to show beneficial effects of sleep-promoting interventions. Despite the importance of sleep to cancer and its treatment and the availability of numerous tools for measuring sleep quality and quantity, sleep measurements are underutilized in cancer studies. METHODS: This review, written for cancer researchers interested in incorporating sleep measures into their studies, is designed to raise awareness about the importance of sleep and suggests strategies for including sleep evaluation in cancer studies. CONCLUSIONS: Inclusion of readily available sleep measures may ultimately improve cancer care by facilitating studies that lead to a greater understanding of how sleep and sleep disturbance influence all aspects of cancer care and the patient experience.
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Neoplasias/epidemiologia , Qualidade de Vida , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/epidemiologia , Sobreviventes/estatística & dados numéricos , Humanos , Neoplasias/terapia , Garantia da Qualidade dos Cuidados de Saúde , Sono/fisiologiaRESUMO
Background. Fatigue is the most common symptom in people with multiple sclerosis (MS). Poor sleep also occurs in this population. Objective. The objective of this study was to determine the relationship between fatigue and sleep quality in people with MS and cognitive impairment. Method. This cross-sectional study assessed relationships among fatigue, assessed with the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS), sleep quality assessed with the Pittsburg Sleep Quality Index (PSQI), and demographics in 121 people with MS and cognitive impairment. Results. Fatigue was significantly correlated with poor sleep quality (MFIS: F = 15.60, P < 0.01; FSS: F = 12.09, P < 0.01). FSS scores were also significantly correlated with the PSQI subscore for daytime dysfunction and MFIS scores were significantly correlated with disability, age, and the PSQI subscores for sleep quality, sleep duration, and daytime dysfunction. Conclusions. This study demonstrates a relationship between fatigue and sleep quality in individuals with MS and cognitive impairment.
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OBJECTIVES: : The objectives of this study were to describe sleep quality and evaluate the association of sleep quality with delirium onset among patients enrolled in hospice. DESIGN: : The study utilized secondary data from a prospective, observational, longitudinal study. SETTING: : Veterans enrolled in hospice were recruited from the Portland Veterans Affairs Medical Center, Portland, Oregon. PARTICIPANTS: : The cohort consisted of 105 patients, of whom 73% had at least one sleep measurement. MEASUREMENTS: : Sleep quality was measured with the Pittsburgh Sleep Quality Index. Delirium was measured with the Confusion Assessment Method. Other important variables were recorded from the medical record and/or longitudinal interviews with patients and their caregivers. Cox regression was used to estimate hazard ratios (HRs) to measure the association between sleep quality and delirium onset. RESULTS: : Of the patients who could be assessed, 44% had poor average sleep quality and 58% reported at least one episode of poor sleep. Overall, sleep quality did not appear to worsen as patients neared death although an increasing number of patients were unable to report on sleep quality. Poor sleep quality was associated with an increased risk of developing delirium, with an HR of 2.37 (95% CI: 1.50-3.74), for every one point worsening in the sleep quality score on a 4-point scale. CONCLUSIONS: : Poor sleep quality was common among Veteran patients enrolled in hospice. These findings may help guide decision making between clinicians, patients, and families regarding the likely impact of sleep disturbance and may help identify patients at higher risk of developing delirium.
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Delírio/psicologia , Cuidados Paliativos na Terminalidade da Vida/estatística & dados numéricos , Distúrbios do Início e da Manutenção do Sono/psicologia , Veteranos/psicologia , Idoso , Estudos de Coortes , Delírio/complicações , Feminino , Humanos , Masculino , Oregon/epidemiologia , Prevalência , Fatores de Risco , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/epidemiologiaRESUMO
Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body's signal for nighttime darkness. Published reports of 24-hr melatonin secretion patterns in two independent SMS cohorts (US and France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion ( approximately 6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.2p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern.
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Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 17 , Melatonina/metabolismo , Distúrbios do Início e da Manutenção do Sono/genética , Anormalidades Múltiplas/metabolismo , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Anamnese , Estudos Retrospectivos , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Síndrome , Adulto JovemRESUMO
OBJECTIVE: To report a case of possible acute tiagabine toxicity secondary to administration of gemfibrozil. CASE SUMMARY: A 39-year-old male was taking tiagabine 16 mg orally 3 times per day and carbamazepine 500 mg orally twice per day for complex partial seizures secondary to mesial temporal sclerosis. He was found to have type IV hypertriglyceridemia and was prescribed gemfibrozil. Because he reported severe confusion and altered consciousness shortly after a single 600-mg dose of gemfibrozil, he was admitted for controlled challenge with that drug. A single 300-mg dose of gemfibrozil resulted in lightheadedness and led to a 59% and 75% increase in total tiagabine serum concentrations at 2 and 5 hours, respectively, without significant change in baseline carbamazepine concentrations. DISCUSSION: This is the first report of an interaction between the widely used antihyperlipidemic drug gemfibrozil and tiagabine. Since tiagabine, which was originally developed as an antiepileptic medication, is now being used widely for a variety of other indications such as anxiety and depression, there is an increased risk for clinically significant interactions with gemfibrozil. CONCLUSIONS: Increased total and unbound tiagabine concentrations following a single 300-mg dose of gemfibrozil and reproduction of clinical symptoms with gemfibrozil rechallenge suggests the toxicity our patient experienced was due to a pharmacokinetic drug interaction. Use of the Horn Drug Interaction Probability Scale showed a probable interaction between gemfibrozil and tiagabine.
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Anticonvulsivantes/farmacocinética , Genfibrozila/administração & dosagem , Hipolipemiantes/administração & dosagem , Ácidos Nipecóticos/sangue , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Interações Medicamentosas , Quimioterapia Combinada , Genfibrozila/efeitos adversos , Humanos , Hipolipemiantes/efeitos adversos , Masculino , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/efeitos adversos , TiagabinaRESUMO
The physiology of control and suppression of natural urges is not well understood. We used [(15)O]H(2)O positron-emission tomography imaging to identify neural circuits involved in suppression of spontaneous blinking as a model of normal urges. Suppression of blinking was associated with prominent activation of bilateral insular-claustrum regions, right more than left; activation was also found in bilateral anterior cingulate cortex (ACC), supplementary motor areas, and the face area of the primary motor cortex bilaterally. These results suggest a central role for the insula possibly together with ACC in suppression of blinking.
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Piscadela/fisiologia , Córtex Cerebral/fisiologia , Impulso (Psicologia) , Giro do Cíngulo/fisiologia , Inibição Psicológica , Motivação , Inibição Neural/fisiologia , Adulto , Retroalimentação/fisiologia , Feminino , Humanos , Intenção , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Mice are one of the most commonly used animal models of alcoholism, and extensive genetic and behavioral data related to alcohol consumption and its consequences in different strains are available. However, only recently have researchers begun to combine magnetic resonance imaging (MRI) technology with other experimental strategies to study the effects of alcohol in mice. This powerful combination enables structural and functional data of alcohol's effects on the brain of living animals to be obtained. This article reviews the challenges associated with the use of these technologies in mice and discusses the application of these advanced technologies to mouse models of alcoholism.
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Alcoolismo/diagnóstico , Encéfalo/patologia , Modelos Animais de Doenças , Imageamento por Ressonância Magnética/métodos , Alcoolismo/metabolismo , Animais , Encéfalo/metabolismo , Humanos , CamundongosRESUMO
West Nile virus (WNV) has re-emerged with a much wider geographic distribution and a higher incidence than ever. In spite of some recent reports on the neurological manifestations and EEG changes caused by WNV encephalitis, there are few data on the incidence of seizures, status epilepticus or post-encephalitic epilepsy. There is also no systematic review of EEG changes caused by WNV encephalitis that is based on a large series of patients. Here, we review the pertinent literature, and report the electroclinical evolution and therapeutic complexity of a patient with WNV encephalitis who developed refractory, non-convulsive status epilepticus.
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Epilepsias Parciais/etiologia , Estado Epiléptico/etiologia , Febre do Nilo Ocidental/complicações , Eletroencefalografia , Evolução Fatal , Humanos , Hospedeiro Imunocomprometido , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Hypothalamic hamartomas (HHs) have been associated with uncontrolled seizures, and aggressive therapy including surgery is often recommended. However, some patients, particularly those with other findings associated with Pallister-Hall syndrome (PHS), have a more benign course. METHODS: Thirty-seven of 40 PHS patients and 16 of 16 patients with isolated HH had a lesion confirmed on magnetic resonance imaging (MRI). Records for all patients were reviewed for the following information: presence of seizures, age at seizure onset, seizure type, seizure frequency, number of antiepileptic medications (AEDs) at the time of evaluation, past AEDs, MRI characteristics of the HH, presence of endocrine dysfunction, and presence of developmental and behavioral problems. RESULTS: All isolated HH patients had a history of seizures, compared with 13 of 40 PHS patients (all PHS patients with seizures had hamartomas). In isolated HH, seizures started earlier in life, occurred more frequently, and were harder to control than those in patients with PHS. Isolated HH patients were more likely to have behavioral and developmental problems than were PHS patients. The T2 signal of the hamartoma was isointense to gray matter in the majority of PHS patients, but showed a significant increase in all but one patient with isolated HH. CONCLUSIONS: Patients with isolated HH have a distinct clinical phenotype, showing more severe seizures and neurologic dysfunction, HH showing increased T2 signal, and are more likely to have precocious puberty. In contrast, PHS patients usually have well-controlled seizures and other endocrine disturbances than precocious puberty. Patients with HH with or without seizures should be evaluated carefully for other clinical manifestations of PHS, particularly before surgery is considered.
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Hamartoma/diagnóstico , Doenças Hipotalâmicas/diagnóstico , Convulsões/diagnóstico , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Diagnóstico Diferencial , Epilepsia/diagnóstico , Epilepsia/etiologia , Feminino , Hamartoma/complicações , Hamartoma/genética , Humanos , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/genética , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Puberdade Precoce/diagnóstico , Puberdade Precoce/genética , Convulsões/etiologiaRESUMO
The antibiotic drug, netropsin, was complexed with the DNA oligonucleotide duplex [d(GGTATACC)]2 to monitor drug 13C NMR chemical shifts changes. The binding mode of netropsin to the minor groove of DNA is well-known, and served as a good model for evaluating the relative sensitivity of 13C chemical shifts to hydrogen bonding. Large downfield shifts were observed for four resonances of carbons that neighbor sites which are known to form hydrogen bond interactions with the DNA minor groove. Many of the remaining resonances of netropsin exhibit shielding or relatively smaller deshielding changes. Based on the model system presented here, large deshielding NMR shift changes of a ligand upon macromolecule binding can likely be attributed to hydrogen bond formation at nearby sites.
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Antibacterianos/farmacologia , DNA/efeitos dos fármacos , Netropsina/metabolismo , Ressonância Magnética Nuclear Biomolecular/métodos , Sequência de Bases , Sítios de Ligação , Isótopos de Carbono , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Interações Medicamentosas , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Netropsina/química , Oligonucleotídeos/química , Oligonucleotídeos/metabolismoRESUMO
Pallister-Hall syndrome (PHS, MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 (c.3385_3386delTT) predicting a frameshift and premature stop at codon 1129 (p.F1129X) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report. Published 2003 Wiley-Liss, Inc.