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BACKGROUND: Williams syndrome (WS) is a neurodevelopmental disorder that has been attributed to heterozygous deletions in chromosome 7q11.23 and exhibits a variety of physical, cognitive, and behavioral features. However, the genetic basis of this phenotypic variability is unclear. In this study, we identified genetic clues underlying these complex phenotypes. METHODS: Neurobehavioral function was assessed in WS patients and healthy controls. Total RNA was extracted from peripheral blood and subjected to microarray analysis, RNA-sequencing, and qRT-PCR. Weighted gene co-expression network analysis was performed to identify specific alterations related to intermediate disease phenotypes. To functionally interpret each WS-related module, gene ontology and disease-related gene enrichment were examined. We also investigated the micro (mi)RNA expression profiles and miRNA co-expression networks to better explain the regulation of the transcriptome in WS. RESULTS: Our analysis identified four significant co-expression modules related to intermediate WS phenotypes. Notably, the three upregulated WS-related modules were composed exclusively of genes located outside the 7q11.23 region. They were significantly enriched in genes related to B-cell activation, RNA processing, and RNA transport. BCL11A, which is known for its association with speech disorders and intellectual disabilities, was identified as one of the hub genes in the top WS-related module. Finally, these key upregulated mRNA co-expression modules appear to be inversely correlated with a specific downregulated WS-related miRNA co-expression module. CONCLUSIONS: Dysregulation of the mRNA/miRNA network involving genes outside of the 7q11.23 region is likely related to the complex phenotypes observed in WS patients.
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Transtorno do Espectro Autista/genética , Perfilação da Expressão Gênica , Expressão Gênica/genética , Síndrome de Williams/genética , Criança , Cromossomos Humanos Par 7/genética , Humanos , MicroRNAs/genética , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Numerous reports indicate that multifaceted pain management programs based on cognitive-behavioral principles are associated with clinically meaningful long-term improvements in chronic pain. However, this has not yet been investigated in Japan. This study investigated the effects of a multifaceted pain management program in Japanese patients with chronic pain, both immediately after the program and 6 months thereafter. METHODS: A total of 96 patients, 37 male and 59 female (mean age 63.8 years) experiencing treatment difficulties and suffering from intractable pain for more than 6 months were enrolled in the study. The programs were conducted with groups of 5-7 patients who met weekly for 9 weeks. Weekly sessions of approximately 2 h in duration incorporating a combination of lectures and exercise were conducted. Several measures related to pain and physical function were assessed at the start of the program, the end of the program, and 6 months after completion of the program. The resulting data were analyzed via Wilcoxon signed-rank test, and 'r' estimated by effect size was also assessed. RESULTS: Of the 96 initial participants, 11 dropped out during the program and 85 completed it. Thereafter, we evaluated 62 subjects at 6 months after the program, while 23 could not be evaluated at that time-point. Pain intensity upon moving, catastrophizing scores, and pain disability scores showed good improvements at the 6-month follow-up, with large efficacy (r > 0.5). Moving capacity and 6-min walking distance also showed good improvements with large efficacy, both at the end of the program and at the 6-month follow-up (r > 0.5). CONCLUSIONS: A multifaceted pain-management program based on cognitive-behavioral principles was effective in Japanese patients with chronic pain, resulting in improved long-term clinical outcomes.
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Cases of sudden death due to pulmonary thromboembolism (PTE) following laparoscopic surgery are very rare. The risk factors for PTE include sex, operation duration, age, obesity, and underlying diseases. The development of thromboprophylaxis according to specific risk factors has contributed to the decrease in postoperative mortality. Here, we describe the case of a 50-year-old patient with sudden death due to PTE at 24 hours after laparoscopic cholecystectomy. The origin of the thrombi were bilateral deep vein thromboses in both the lower extremities. No severe risk factors for PTE were detected in the patient, and pneumatic compression devices were used during the surgery for thromboprophylaxis. We believe that the accumulation of minor risk factors may have contributed to the onset of PTE. Hence, a more cautious assessment of the risk factors for PTE prior to surgery is required in such cases.
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Colecistectomia Laparoscópica/efeitos adversos , Morte Súbita/etiologia , Embolia Pulmonar/etiologia , Feminino , Humanos , Dispositivos de Compressão Pneumática Intermitente , Cuidados Intraoperatórios , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Trombose Venosa/complicaçõesRESUMO
BACKGROUND: Reports of locomotive syndrome (LS) have recently been increasing. Although physical performance measures for LS have been well investigated to date, studies including psychiatric assessment are still scarce. Hence, the aim of this study was to investigate both physical and mental parameters in relation to presence and severity of LS using a 25-question geriatric locomotive function scale (GLFS-25) questionnaire. METHODS: 150 elderly people aged over 60 years who were members of our physical-fitness center and displayed well-being were enrolled in this study. Firstly, using the previously determined GLFS-25 cutoff value (=16 points), subjects were divided into two groups accordingly: an LS and non-LS group in order to compare each parameter (age, grip strength, timed-up-and-go test (TUG), one-leg standing with eye open, back muscle and leg muscle strength, degree of depression and cognitive impairment) between the groups using the Mann-Whitney U-test followed by multiple logistic regression analysis. Secondly, a multiple linear regression was conducted to determine which variables showed the strongest correlation with severity of LS. RESULTS: We confirmed 110 people for non-LS (73%) and 40 people for LS using the GLFS-25 cutoff value. Comparative analysis between LS and non-LS revealed significant differences in parameters in age, grip strength, TUG, one-leg standing, back muscle strength and degree of depression (p < 0.006, after Bonferroni correction). Multiple logistic regression revealed that functional decline in grip strength, TUG and one-leg standing and degree of depression were significantly associated with LS. On the other hand, we observed that the significant contributors towards the GLFS-25 score were TUG and degree of depression in multiple linear regression analysis. CONCLUSIONS: The results indicate that LS is associated with not only the capacity of physical performance but also the degree of depression although most participants fell under the criteria of LS.
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Transtorno Depressivo/diagnóstico , Tolerância ao Exercício/fisiologia , Limitação da Mobilidade , Força Muscular/fisiologia , Inquéritos e Questionários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Transtorno Depressivo/epidemiologia , Feminino , Avaliação Geriátrica , Humanos , Locomoção/fisiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Aptidão Física/fisiologia , Equilíbrio Postural/fisiologia , Qualidade de Vida , Estatísticas não Paramétricas , SíndromeRESUMO
The positive identification of decomposed corpses is often difficult. We describe two autopsy cases in which medical materials, which had been implanted during previous surgical treatments, facilitated positive identification. The discovery of decomposed corpses is increasingly common in Japan, due to the increasing number of lonely deaths. Implanted medical materials and devices may be a useful tool for personal identification in the near future.
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Autopsia , Restos Mortais , Patologia Legal , Aneurisma Aórtico/cirurgia , Fraturas do Fêmur/cirurgia , Humanos , Japão , Mudanças Depois da MorteRESUMO
OBJECTIVE: Topiramate (TPM), lamotrigine (LTG), and levetiracetam (LEV) are three new-generation antiepileptic drugs (AEDs) which have recently come into use in add-on therapy for refractory childhood epilepsy in Japan. The aim of this study was to evaluate their efficacy and tolerability, and to clarify the role of these three AEDs in childhood epilepsy therapy. METHODS: Three separate audits were conducted between July 2007 and July 2012. All patients studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure-free or achieved > 50% reduction (50% responder rate: 50% RR) in seizure frequency for 12 months after starting add-on therapy. RESULTS: A total of 55 children received TPM, 44 LTG, and 38 LEV. The 50% RR of partial epilepsy was 31.8% for LTG, 41.8% for TPM, and 52.6% for LEV. The 50% RR of generalized epilepsy was 28.6% for LTG, 26.7% for TPM, and 44.4% for LEV. The incidence of adverse events was 9.1% for LTG, 43.6% for TPM, and 15.8% for LEV. CONCLUSION: LEV was the most effective of the three add-on therapies in refractory childhood epilepsy with partial and generalized onset. Regarding seizure-free, TPM was more effective than the other therapies, but it had many side effects. LTG tended to be more effective for generalized epilepsy, particularly idiopathic epilepsy, than partial epilepsy. We conclude that it is necessary to develop a treatment plan for pediatric epilepsies after considering the advantages and disadvantage of these new AEDs.
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Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Frutose/análogos & derivados , Piracetam/análogos & derivados , Triazinas/uso terapêutico , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Feminino , Frutose/efeitos adversos , Frutose/uso terapêutico , Humanos , Lamotrigina , Levetiracetam , Masculino , Piracetam/efeitos adversos , Piracetam/uso terapêutico , Estudos Retrospectivos , Topiramato , Triazinas/efeitos adversosRESUMO
BACKGROUND: Pasteurella multocida-related sepsis can cause purpura fulminans (PF), a rare thrombotic disorder that often presents acutely and is potentially fatal. As a consequence of disseminated intravascular coagulation, this hematological emergency originates from micro-thrombotic occlusion of peripheral blood vessels and resulting circulatory failure. Thus far, no studies have reported the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for saving lives in patients with worsening respiratory and circulatory failure. Moreover, the development of non-occlusive mesenteric ischemia after VA-ECMO has not yet been documented. Here, we describe the case of a 52-year-old female patient with PF and non-occlusive mesenteric ischemia due to Pasteurella multocida-related sepsis who received VA-ECMO. CASE PRESENTATION: A 52-year-old-female patient presented to the hospital with a week-long fever and worsening cough. Chest radiography findings revealed ground-glass opacity. We made a diagnosis of acute respiratory distress syndrome due to sepsis and initiated ventilatory management. Because respiratory and circulatory parameters were not maintained, VA-ECMO was introduced. After admission, ischemic findings were observed in the periphery of the extremities, and a diagnosis of PF was made. Pasteurella multocida was detected in blood cultures. On day 9, the sepsis was cured with antimicrobial treatment. The patient's respiratory and circulatory status improved, and she was weaned off VA-ECMO. However, on day 16, her stable circulatory system collapsed again, and her abdominal pain worsened. We performed exploratory laparotomy and noted necrosis and perforation of the small intestine. As a result, partial resection of the small intestine was performed. CONCLUSION: In this case, VA-ECMO was used to maintain circulatory dynamics during septic shock in a patient with Pasteurella multocida infection who developed PF. Surgery was also performed for complicated ischemic necrosis of the intestinal tract, helping save the patient's life. This development illustrated the importance of paying attention to intestinal ischemia during intensive care.
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This case highlights the necessity to inform patients with vein ligation about the possibility of varicose vein formation in the periphery and brings awareness to emergency staff that bleeding could be caused by a ruptured peripheral varicose vein.
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Aim: This study aimed to compare open abdominal management (OAM) between visible negative pressure wound therapy (NPWT) and commercial NPWT to determine whether NPWT can detect intestinal ischemia in its early stages without causing complications or worsening prognosis, and to determine whether the actual visualization results in early detection. Methods: Patients were divided into two groups: those who underwent OAM with visible NPWT (A: 32 patients) and those who underwent OAM with commercial NPWT (B: 12 patients). We compared background factors, disease severity, vital signs, blood test values, and 28-day outcomes between the two groups. We also checked the records to determine how many visualized cases were detected early and operated on. We then examined the weaknesses of this method. Results: No differences were observed in the background factors or disease severity between the two groups. The duration of the open abdomen and intensive care unit stay were significantly shorter for group A than for group B. The groups showed no significant differences in lactate levels, 28-day outcomes, complications during OAM, or other factors. After a review of the medical records, ischemic progression was detected early, and surgery could be performed in seven cases in the visible NPWT group. The progression of ischemia was confirmed at the time of the second-look operation in two cases in the ascending colon. Conclusion: The visualization device allowed us to gain insights into the intra-abdominal cavity and determine the appropriate time for closing the abdomen without worsening the prognosis.
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Attention deficit-hyperactivity disorder (ADHD) is a prevalent neuropsychiatric disorder found in children. It is characterized by inattention, hyperactivity, and impulsivity. Methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed for the treatment of ADHD. In the present study, we examined the behavioral and brain transcriptome changes in MPH-treated and ATX-treated zebrafish. In behavioral analysis, zebrafish showed opposite response to each treatment. MPH-treated fish showed higher anxiety-like behavior while ATX-treated fish showed lower anxiety-like behavior. Further, we performed RNA sequencing analysis of zebrafish brain to elucidate the underlying biological pathways associated with MPH and ATX treatment. Interestingly, we found that shared differentially expressed genes in MPH-treated and ATX-treated fish were instrumental in cholesterol biosynthesis pathway and were regulated in opposite manner. Our findings highlight the contrast between MTH and ATX, and may suggest the alterations in clinical practice for these medications and drug development for ADHD.
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Cloridrato de Atomoxetina/administração & dosagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Metilfenidato/administração & dosagem , Transcriptoma/efeitos dos fármacos , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Escala de Avaliação Comportamental , Encéfalo/metabolismo , Ontologia Genética , Metabolismo dos Lipídeos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcriptoma/genética , Peixe-ZebraRESUMO
Williams syndrome (WS) is caused by a microdeletion of chromosome 7q11.23, and is characterized by various physical and cognitive symptoms. In particular, WS is characterized by hypersocial (overfriendly) behavior; WS has gained attention as aspects of the WS phenotype contrast with those of autism spectrum disorder (ASD). The oxytocin receptor gene (OXTR) contributes to social phenotypes in relation to regulation of oxytocin (OXT) secretion. Additionally, mounting evidence has recently shown that DNA methylation of OXTR is associated with human social behavior. However, the role of OXTR in WS remains unclear. This study investigated the regulation of OXTR in WS. We examined the gene expression levels in blood from WS patients and controls, and then analyzed the methylation levels in two independent cohorts. We showed that OXTR was down-regulated and hypermethylated in WS patients compared to controls. Our findings may provide an insight into OXTR in mediating complex social phenotypes in WS.
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Metilação de DNA/genética , Expressão Gênica/genética , Receptores de Ocitocina/genética , Síndrome de Williams/genética , Conjuntos de Dados como Assunto , Regulação para Baixo , Feminino , Humanos , Masculino , Comportamento SocialRESUMO
Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.
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Transtorno do Espectro Autista , Síndrome de Williams , Transtorno do Espectro Autista/genética , Metilação de DNA , Epigênese Genética , Humanos , Fenótipo , Síndrome de Williams/genéticaRESUMO
Increasing evidence suggests that epigenetic mechanisms play a role in the etiology of autism spectrum disorder (ASD). To date, several studies have attempted to identify epigenetic biomarkers for ASD. However, reliable markers remain to be established and most of these studies have focused on pediatric patients with ASD. In this study, we sought to find an epigenetic DNA methylation biomarker from peripheral blood for adult patients with high-functioning ASD. DNA methylation profiles were analyzed using the Illumina 450 K methylation array. To identify robust candidate markers, we employed two types of machine-learning algorithms for marker selection. We identified a potential marker (cg20793532) for which is the AUC value was 0.79. Notably, cg20793532 was annotated to the PPP2R2C gene, which was hypermethylated and down-regulated in blood from ASD patients compared to that in the controls. Although requiring careful interpretation, this pilot study seems to provide a potential blood biomarker for identifying individuals with high-functioning ASD.
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Transtorno do Espectro Autista/genética , Metilação de DNA , Regulação para Baixo , Proteína Fosfatase 2/genética , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Transtorno do Espectro Autista/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Epigênese Genética , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Projetos Piloto , Proteína Fosfatase 2/sangueRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and repetitive behaviors. Owing to the difficulty of clinical diagnosis, ASD without intellectual disability (i.e., high-functioning ASD) is often overlooked. MicroRNAs (miRNAs) have been recently recognized as potential biomarkers of ASD as they are dysregulated in various tissues of individuals with ASD. However, it remains unclear whether miRNA expression is altered in individuals with high-functioning ASD. Here, we investigated the miRNA expression profile in peripheral blood from adults with high-functioning ASD, and age and gender-matched healthy controls. We identified miR-6126 as being robustly down-regulated in ASD and correlated with the severity of social deficits. Enrichment analysis of predicted target genes revealed potential association with neurons, synapses, and oxytocin signaling pathways. Our findings may provide insights regarding the molecular clues for recognizing high-functioning ASD.
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Transtorno do Espectro Autista/genética , Perfilação da Expressão Gênica , MicroRNAs/genética , Adulto , Transtorno do Espectro Autista/sangue , Estudos de Casos e Controles , Regulação da Expressão Gênica , Humanos , MicroRNAs/sangue , MicroRNAs/metabolismoRESUMO
Williams-Beuren syndrome (WBS) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion on chromosome 7q11.23. Though at present there is a limited number of reports on WBS patients with tumors, most cases are related to blood cancer in children with WBS. We describe a case of Burkitt lymphoma in a 21-year-old man with WBS. In addition to providing a summary of published reports describing tumors observed in patients with WBS, we present a hypothesis about a possible mechanism of oncogenesis. In particular, we identified some significantly dysregulated cancer-related genes using blood samples from this patient at the age of 19 years (who have not yet developed Burkitt lymphoma). Our findings may provide a new perspective on the relation between WBS and Burkitt lymphoma.
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Proteínas Motores Moleculares/genética , Mutação/genética , Cadeias Pesadas de Miosina/genética , Qualidade de Vida , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Primers do DNA/química , Primers do DNA/genética , Diagnóstico Precoce , Humanos , Lactente , Masculino , Trombocitopenia/sangueRESUMO
The fluidity of cadaveric blood is an important characteristic in the post-mortem examination of cases of asphyxial death. Although it is empirically known that soft blood clots are present in cadaveric blood containing alcohol, the relationship between such clots and blood alcohol is unclear. We addressed this issue through in vitro studies using blood collected from healthy volunteers. Assessment of global hemostasis by rotational thromboelastometry revealed that ethanol treatment enhanced the procoagulant activity of whole blood. However, ethanol inhibited epinephrine-induced platelet aggregation, whereas plasma levels of von Willebrand factor and the activity of coagulation factors VIII and IX were unaffected. In contrast, tissue factor (TF) activity was higher in plasma obtained from ethanol-treated whole blood than that in plasma from untreated blood. Ethanol induced hemolysis of red blood cells, and the consequent hemoglobin (Hb) release promoted de novo synthesis of TF in isolated monocytes, as determined by real-time reverse transcription PCR, western blotting, and flow cytometry. However, ethanol itself did not induce TF expression in monocytes. Given that TF activates the extrinsic coagulation pathway and amplifies hemostatic reactions, Hb-induced TF expression in monocytes might contribute to soft blood clot formation.
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Coagulação Sanguínea/efeitos dos fármacos , Etanol/sangue , Hemólise , Monócitos/efeitos dos fármacos , Tromboplastina/efeitos dos fármacos , Autopsia , Cadáver , Citometria de Fluxo , Medicina Legal , HumanosRESUMO
A car containing a male corpse with complete adipocere formation was found at the bottom of a lake. The deceased had presumably driven into the lake 7 years earlier. The surface of the deceased was unusually hard and firm like a gypsum board, and the entire internal viscera had turned into adipocere. Since the time required for adipocerous changes depends largely on environmental conditions, we considered the key conditions, namely, water temperature, pH, and oxygen content. In our case, cold, acidic water may have delayed adipocere formation, thus necessitating a long period of time for completeness. On the other hand, anoxic conditions and the peculiar environment of a lake bottom presumably contributed to complete adipocere formation.
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Meio Ambiente , Patologia Legal/métodos , Mudanças Depois da Morte , Animais , Autopsia , Água Doce/química , Humanos , Masculino , Temperatura , Fatores de TempoRESUMO
BACKGROUND: In Japan, adrenocorticotropic hormone (ACTH) therapy has been the mainstay of treatment of West syndrome. Conventional ACTH therapy is administered short-term with efficacy, yet the relapse rate is high. Relapse after initial ACTH therapy is a poor prognostic factor for long-term seizure control and outcome of cognitive function. Here, we report successful long-term weekly ACTH therapy for relapsed WS in a tuberous sclerosis complex (TSC) child after conventional ACTH therapy. PATIENT: The patient had a series of epileptic spasms (ES) and hypsarrhythmia at age 3 months. She was diagnosed with WS associated with TSC, and was treated with conventional ACTH therapy at age 4 months, and a second course of ACTH therapy at age 8 months. Both courses of therapy were transiently effective. A third course of ACTH therapy was started at age 1 year and 2 months, and long-term weekly ACTH therapy was continued thereafter. During this therapy, both ES and hypsarrhythmia remained completely resolved. Therapy was continued, and dose reduction was started when the patient was 2 years and 10 months old. No serious adverse events had occurred during this therapy. CONCLUSION: This case demonstrated that long-term weekly ACTH may be safe and effective. Although at present, this therapy may only be considered for relapsed symptomatic WS patients, it may be a good alternative therapy when frequent relapses occur after favorable response to conventional ACTH therapy.
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Hormônio Adrenocorticotrópico/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Esclerose Tuberosa/complicações , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Japão , Recidiva , Espasmos Infantis/complicações , Resultado do TratamentoRESUMO
BACKGROUND: Rufinamide, a triazole derivative, is a novel antiepileptic drug (AED) chemically unrelated to other current AEDs. Previous studies on pediatric epilepsy treatment with rufinamide have demonstrated a frequency of leukopenia as an adverse event of 0.5%, and there has been no report of the development of agranulocytosis. Here, we report a patient with Lennox-Gastaut syndrome (LGS) who developed agranulocytosis associated with fever and skin rash with rufinamide. To the best of our knowledge, this is the first reported case of agranulocytosis induced by rufinamide. PATIENT: A 10-year-old boy with a history of herpes encephalitis at the age of 1 year developed LGS, and was administered rufinamide as add-on therapy to valproate, lamotrigine, and clonazepam because of difficulties in controlling tonic seizures. Eighteen days after initiation of rufinamide, agranulocytosis developed associated with high fever and skin rash, all of which resolved after withdrawal of rufinamide. Bone marrow aspiration demonstrated normocellular marrow with selective decrease of mature myeloid series, and suggested that agranulocytosis was not related to malignancy or serious infection. CONCLUSION: This case suggests that rufinamide may induce the potentially serious adverse effect of agranulocytosis. Patients should be monitored for clinical signs of agranulocytosis and consideration should be given to routine blood count determination for early detection of this.