RESUMO
Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.
Assuntos
Testes Genéticos , Canal de Sódio Disparado por Voltagem NAV1.7 , Canal de Sódio Disparado por Voltagem NAV1.8 , Canal de Sódio Disparado por Voltagem NAV1.9 , Humanos , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Japão/epidemiologia , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Masculino , Feminino , Testes Genéticos/métodos , Adulto , Adolescente , Criança , Predisposição Genética para Doença , Adulto Jovem , Pré-Escolar , Mutação , Dor , Reto/anormalidadesRESUMO
BACKGROUND: Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis in children. The mortality and morbidity of JXG with extracutaneous lesions remain unclear. METHODS: Data of patients aged < 18 years who were diagnosed with JXG between 2001 and 2010 were retrospectively collected through a nationwide survey. RESULTS: Twenty patients (11 male and nine female) had extracutaneous lesions. The median observation time was 10 years (range, 0-17). Six patients presented with symptoms at birth. The median age at diagnosis was 8.5 months (range, 0 month-13 years). Fifteen patients underwent treatment for JXG, including chemotherapy (n = 11), and five did not receive treatment. All patients except one survived; 17 were disease-free and two survived with disease. One newborn-onset patient with liver, spleen, and bone marrow involvement died of the disease. Permanent sequelae included central diabetes insipidus, growth hormone deficiency, and panhypopituitarism detected at diagnosis in three, one, and two patients, respectively. Four patients had visual impairment (optic nerve compression and intraocular invasion in two each), three had epilepsy, one had mental retardation, and one had a skin scar. Eight patients who had intracranial lesions were older at diagnosis, and had a higher frequency of disease-related comorbidities and permanent sequelae than those without intracranial involvement. CONCLUSIONS: Patients with extracutaneous JXG had good outcomes, although those with intracranial lesions had serious permanent sequelae. Effective and safe treatment regimens for patients with intracranial JXG need to be developed.
Assuntos
Xantogranuloma Juvenil/complicações , Xantogranuloma Juvenil/patologia , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Diabetes Insípido Neurogênico/complicações , Feminino , Histiocitose de Células não Langerhans/patologia , Humanos , Hipopituitarismo/complicações , Lactente , Recém-Nascido , Japão , Masculino , Estudos Retrospectivos , Pele/patologia , Inquéritos e Questionários , Taxa de Sobrevida , Resultado do Tratamento , Xantogranuloma Juvenil/mortalidade , Xantogranuloma Juvenil/terapiaRESUMO
PURPOSE: Spinal angiography is the gold standard for evaluation or diagnosis of spinal arteriovenous malformations (AVMs). However, some feeding arteries might be overlooked when multiple feeders exist. This study aimed to retrospectively review cases of spinal intra-dural AVMs, which were identified by three-dimensional digital subtraction angiography (3D-DSA), and attempted to estimate the number of feeding arteries. METHODS: We retrospectively reviewed patients with spinal intra-dural AVMs who underwent 3D-DSA at Hokkaido University Hospital from January 2005 to December 2016. We selected 9 patients in whom we could obtain data of multi-planar reconstruction of 3D-DSA. We measured the computed tomography (CT) values of feeding arteries and draining veins. The CT values represented the averages of maximum CT values of 5 continuous axial slices. The ratio of the CT value of feeders to that of drainers (F/D ratio) was calculated. The correlation between the F/D ratio and the number of feeders was examined with Pearson's correlation coefficient. RESULTS: The average number of feeders was 2.3 (1-4), and the number of feeders was significantly positively correlated with the F/D ratio (r = 0.855, P = .003). CONCLUSIONS: We conclude that the number of feeding arteries of spinal intra-dural AVMs can be estimated by using the F/D ratio obtained from 3D-DSA. These slides can be retrieved under Electronic Supplementary Material.
Assuntos
Angiografia Digital/métodos , Malformações Arteriovenosas/diagnóstico , Imageamento Tridimensional/métodos , Adolescente , Adulto , Idoso , Artérias/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
Leucine-rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of familial and idiopathic Parkinson's disease (PD). We have identified two novel LRRK2-associated proteins, a HECT-type ubiquitin ligase, HERC2, and an adaptor-like protein with six repeated Neuralized domains, NEURL4. LRRK2 binds to NEURL4 and HERC2 via the LRRK2 Ras of complex proteins (ROC) domain and NEURL4, respectively. HERC2 and NEURL4 link LRRK2 to the cellular vesicle transport pathway and Notch signaling, through which the LRRK2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. This process negatively regulates Notch signaling through cis-inhibition by stabilizing Dll1/Dl, which accelerates neural stem cell differentiation and modulates the function and survival of differentiated dopaminergic neurons. These effects are strengthened by the R1441G ROC domain-mutant of LRRK2. These findings suggest that the alteration of Notch signaling in mature neurons is a component of PD etiology linked to LRRK2.
Assuntos
Endossomos/metabolismo , Doença de Parkinson/enzimologia , Proteínas Serina-Treonina Quinases/fisiologia , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Animais , Proteínas de Transporte/metabolismo , Dopamina/metabolismo , Drosophila , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitina-Proteína LigasesRESUMO
Bilateral complex vertebral artery aneurysms (BCoVAAns) have no established strategy of management. We retrospectively reviewed five consecutive patients with unruptured BCoVAAns between January 2006 and December 2012. Considering surgical risks of lower cranial nerve (LCN) injuries and eventual growth of an opposite side lesion after unilateral vertebral artery (VA) occlusion, we proposed a strategy of combined open and interventional treatment using revascularization. We applied the following several specific techniques: (1) proximal clipping and occipital artery-posterior inferior cerebellar artery (OA-PICA) and/or superficial temporary artery (STA)-superior cerebellar artery (SCA) bypasses; (2) Distal blood pressure, motor evoked potentials (MEPs), and somatosensory evoked potentials (SEPs) monitoring after parent artery temporary occlusion for safe permanent occlusion of the proximal portions of VA and PICA; (3) V3 to V4 bypass using radial artery (RA) graft with proximal clipping or trapping, two of them combined with OA-PICA bypass; (4) VA fenestration as an opportunity to preserve the flow of the parent artery. Two patients were treated bilaterally and 3 unilaterally, with modified Rankin scale assessed at 39 months postoperatively in average 0 in 2, 1 in 2, and 2 in 1, respectively, and the untreated opposite side lesions without regrowth or bleeding. Two patients with patent V3-RA-V4 bypass complained of dysphagia due to LCN palsies. One of them however suffered a cerebellar infarction due to occlusion of the OA-PICA bypass. When BCoVAAns require surgical treatment, revascularization or preservation of the VA should be considered at the first operation. By doing so, the opposite aneurysm can be effectively occluded by coil embolization, even with VA sacrifice if required.
Assuntos
Aneurisma/cirurgia , Cerebelo/cirurgia , Artérias Cerebrais/cirurgia , Procedimentos Neurocirúrgicos , Artéria Vertebral/cirurgia , Anastomose Cirúrgica/métodos , Artéria Basilar/cirurgia , Angiografia Cerebral/métodos , Revascularização Cerebral/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Dissecação da Artéria Vertebral/cirurgiaRESUMO
PURPOSE: To examine the validity of our treatment strategy for spinal dural arteriovenous fistulae (SDAVF), based on the treatment results and the long-term outcome. METHODS: This study included 50 SDAVF patients (38 men, 12 women, mean age 63.2 years) with progressive myelopathy. The treatment strategy involved embolization as the initial management tool and surgery if embolization was considered unsuitable. Their medical records were evaluated to identify the treatment results and functional outcomes. The mean follow-up period was 81.2 months (range 27-184 months). RESULTS: Complete obliteration was achieved in 22 (71.0%) of 31 embolized patients and in 18 of 19 (94.7%) operated patients. The initial success rate was significantly lower in embolized than operated patients. At the last follow-up, 33 of the 50 patients (66%) manifested improved gait and 16 (32%) improved micturition. The activity of daily living (ADL) was improved in 33 (66%). When we compared the rates of functional improvement at the last follow-up, there was no significant difference between patients treated initially by embolization or surgery. CONCLUSIONS: The long-term outcomes in SDAVF patients treated by multidisciplinary management with first-line embolization were comparable to those in earlier surgical series. However, our results were unable to demonstrate the superiority of endovascular embolization to surgical treatment for SDAVF. For the purpose of justifying endovascular embolization as a first-line treatment for SDAVF, it will be necessary to show further improvement in both the initial treatment success and the complication rates.
Assuntos
Malformações Vasculares do Sistema Nervoso Central/terapia , Embolização Terapêutica/métodos , Procedimentos Neurocirúrgicos/métodos , Doenças da Medula Espinal/terapia , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Malformações Vasculares do Sistema Nervoso Central/complicações , Procedimentos Endovasculares/métodos , Feminino , Marcha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças da Medula Espinal/etiologia , Resultado do Tratamento , MicçãoRESUMO
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective dopaminergic cell loss in the substantia nigra, but its pathogenesis remains unclear. The recessively inherited familial PD genes PARK2 and PARK6 have been attributed to mutations in the Parkin and PTEN-induced kinase 1 (PINK1) genes, respectively. Recent reports suggest that PINK1 works upstream of Parkin in the same pathway to regulate mitochondrial dynamics and/or conduct autophagic clearance of damaged mitochondria. This phenomenon is preserved from Drosophila to human cell lines but has not been demonstrated in a vertebrate animal model in vivo. Here, we developed a medaka fish (Oryzias latipes) model that is deficient in Pink1 and Parkin. We found that despite the lack of a conspicuous phenotype in single mutants for Pink1 or Parkin, medaka that are deficient in both genes developed phenotypes similar to that of human PD: late-onset locomotor dysfunction, a decrease in dopamine levels and a selective degeneration of dopaminergic neurons. Further analysis also revealed defects in mitochondrial enzymatic activity as well as cell death. Consistently, PINK1 and Parkin double-deficient MEF showed a further decrease in mitochondrial membrane potential and mitochondrial complex I activity as well as apoptosis compared with single-deficient MEF. Interestingly, these mitochondrial abnormalities in Parkin-deficient MEF were compensated by exogenous PINK1, but not by disease-related mutants. These results suggest that PINK1 and Parkin work in a complementary way to protect dopaminergic neurons by maintaining mitochondrial function in vertebrates.
Assuntos
Dopamina/metabolismo , Proteínas de Peixes/metabolismo , Neurônios/metabolismo , Oryzias/metabolismo , Doença de Parkinson/metabolismo , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose , Modelos Animais de Doenças , Drosophila , Proteínas de Peixes/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neurônios/citologia , Oryzias/genética , Doença de Parkinson/genética , Fenótipo , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Vertebrados/genética , Vertebrados/metabolismoRESUMO
BACKGROUND: In acute encephalopathy, deterioration of the condition can be rapid, and early intervention is essential to prevent progression of the disease. However, in the acute period, differentiating acute encephalopathy from febrile seizures is difficult. Thus, an early diagnostic marker has been sought to enable early intervention. Proton nuclear magnetic resonance ((1)H NMR) spectroscopy is used to study the chemical characteristics of biological fluids such as cerebrospinal fluid (CSF). The purpose of this study was to ascertain if pattern recognition of (1)H NMR spectra could differentiate CSF obtained from patients with acute encephalopathy and febrile seizures. METHODS: CSF was obtained from patients with acute encephalopathy (n = 4), complex febrile seizures (n = 9), and simple febrile seizures (n = 9). RESULTS: NMR spectra of CSF did not visually differ across the three groups. Spectral data were analyzed by partial least squares discriminant analysis and visualized by plotting the partial least squares scores of each sample. The three patient groups clustered separately on the plots. CONCLUSION: In this preliminary study, we were able to visualize different characteristics of CSF obtained from patients with acute encephalopathy and simple and complex febrile seizures using pattern recognition analysis of (1)H NMR data.
Assuntos
Encefalopatias/líquido cefalorraquidiano , Convulsões Febris/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Encefalopatias/imunologia , Líquido Cefalorraquidiano , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Reconhecimento Automatizado de Padrão , Análise de Componente Principal , Espectroscopia de Prótons por Ressonância Magnética , Processamento de Sinais Assistido por ComputadorRESUMO
A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Edema/tratamento farmacológico , Pirimidinonas/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Ésteres de Forbol , Pirimidinonas/síntese química , Pirimidinonas/química , Solubilidade , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Inibidores de Fosfodiesterase/química , Pirimidinas/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/metabolismo , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
Although thrombotic thrombocytopenic purpura (TTP) is rare, early diagnosis and treatment are important for decreasing the mortality rate. Acquired vitamin B12 deficiency is frequently overlooked because of its rarity in developed countries, particularly in children and adolescents. The hematological changes in vitamin B12 deficiency present as megaloblastic anemia, increased lactate dehydrogenase, vasoconstriction, increased platelet aggregation, and abnormal activation of the coagulation followed by microangiopathy as well as neutropenia and thrombocytopenia. We report herein the case of a 15-year-old girl who had been neglected, which might have caused pseudo-TTP through malnutrition, particularly vitamin B12 deficiency. When we encounter cases of TTP in children, clinicians must be aware of the possibility of malnutrition, particularly with vitamin B12 deficiency, even in developed countries, and investigate the cause of malnutrition including neglect.
Assuntos
Diagnóstico Tardio , Desnutrição/complicações , Doenças Negligenciadas , Púrpura Trombocitopênica Trombótica/etiologia , Deficiência de Vitamina B 12/complicações , Adolescente , Biópsia , Diagnóstico Diferencial , Feminino , Humanos , Desnutrição/sangue , Desnutrição/diagnóstico , Púrpura Trombocitopênica Trombótica/diagnóstico , Fatores de Tempo , Tomografia Computadorizada por Raios X , Deficiência de Vitamina B 12/sangueRESUMO
BACKGROUND: Despite several advances in the treatment of Epstein-Barr virus (EBV) in recent years, patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) do not always show satisfactory outcomes. We here conducted a nationwide survey in Japan to identify prognostic factors of EBV-HLH in children with this disease in an effort to improve the management and the outcomes of these patients. PROCEDURE: Between January 2003 and June 2008, we enrolled 98 children younger than 18 years of age who were diagnosed with EBV-HLH. We then studied the clinical characteristics and laboratory findings at the time of diagnosis with the aim to identify prognostic factors for EBV-HLH. RESULTS: The mean age of onset of EBV-HLH was 3.9 ± 2.8 years. Most of our patients presented with fever, hepatosplenomegaly, lymphadenopathy, and hemophagocytosis of bone marrow. Sixty-two percent of patients showed T cell clonality, and 97% had EBV infection in either T or natural killer cells. Most patients (60%) were treated with a multi-agent chemotherapeutic regimen, including corticosteroid, etoposide, and cyclosporine. After initial treatment, 90.3% of patients were in remission, and 7 patients (8.2%) experienced recurrence of EBV infection. Among several prognostic factors, patients with both hyperbilirubinemia (>1.8 mg/dl) and hyperferritinemia (>20,300 ng/ml) at the time of diagnosis had significantly poorer outcomes than those with low serum bilirubin and ferritin levels. CONCLUSIONS: These findings suggest that the therapeutic strategy for children with EBV-HLH could be tailored according to the laboratory findings at diagnosis.
Assuntos
Coleta de Dados , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica , Corticosteroides/administração & dosagem , Idade de Início , Antineoplásicos Fitogênicos/administração & dosagem , Povo Asiático , Bilirrubina/sangue , Criança , Pré-Escolar , Ciclosporina/administração & dosagem , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/mortalidade , Etoposídeo/administração & dosagem , Humanos , Hiperbilirrubinemia/sangue , Hiperbilirrubinemia/diagnóstico , Hiperbilirrubinemia/tratamento farmacológico , Hiperbilirrubinemia/mortalidade , Imunossupressores/administração & dosagem , Lactente , Japão/epidemiologia , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/mortalidade , Indução de Remissão , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Since the introduction of carotid stenting (CAS), a combined treatment for bilateral lesions using carotid endarterectomy (CEA) and CAS has been developed. However, there has been only 1 report about CEA then CAS. Herein we describe 2 patients with bilateral severe carotid stenosis who were treated by CEA for the symptomatic side and CAS for the contralateral asymptomatic side. A 71-year-old man underwent CEA for the symptomatic side. Although the patient suffered hyperperfusion syndrome after CEA, he recovered fully after 3 weeks of rehabilitation. Two months later, CAS was performed for the asymptomatic side, and he was discharged with no deficit. A 67-year-old man underwent CEA for the symptomatic side. The patient developed no postoperative neurologic deficits except for hoarseness. Four weeks later, CAS was performed for the contralateral asymptomatic side. After the procedure, however, severe hypotension occurred, and treatment by continuous injection of catecholamine was necessary to maintain systematic blood pressure. The patient was ultimately discharged with no deficit. The combined therapy of CAS for the asymptomatic side and then CEA for the symptomatic side has been recommended by several authors. However, one of the problems of this strategy is the higher incidence of postprocedural hemodynamic complications, and hypotension after CAS may be dangerous for the symptomatic hemisphere. We suggest a combined therapy using CEA for the symptomatic side and then CAS for the asymptomatic side can be 1 beneficial treatment option for patients with bilateral carotid stenosis without coronary artery disease.
Assuntos
Angioplastia/instrumentação , Estenose das Carótidas/terapia , Endarterectomia das Carótidas , Stents , Idoso , Angioplastia/efeitos adversos , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico , Estenose das Carótidas/fisiopatologia , Angiografia Cerebral/métodos , Circulação Cerebrovascular , Imagem de Difusão por Ressonância Magnética , Endarterectomia das Carótidas/efeitos adversos , Hemodinâmica , Humanos , Hipotensão/tratamento farmacológico , Hipotensão/etiologia , Hipotensão/fisiopatologia , Angiografia por Ressonância Magnética , Masculino , Imagem de Perfusão/métodos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Vasoconstritores/uso terapêuticoRESUMO
INTRODUCTION: Previous reports have suggested that endovascular parent artery occlusion is an effective and safe procedure for the treatment of vertebral artery dissection (VAD). However, the results of long-term outcomes are still unclear. This study reviewed the clinical and imaging outcomes of patients with VAD treated by endovascular internal trapping. METHODS: A total of 73 patients were treated for VAD by endovascular internal trapping between March 1998 and March 2011. Patients were regularly followed up by magnetic resonance imaging, magnetic resonance angiography, and clinical examinations. Clinical outcomes were evaluated using the modified Rankin Scale. RESULTS: Forty-five patients had ruptured VADs, and 28 had unruptured VADs. Clinical follow-up of at least 6 months data was obtained for 61 patients (83.6 %). The follow-up period ranged from 6 to 145 months (mean ± SD, 55.6 ± 8.9 months). Two patients with ruptured VADs had recurrence (2.74 %). Cranial nerve paresis (CNP) was observed in six patients (8.21 %), spinal cord infarction in two patients (2.74 %), and a perforating artery ischemia was diagnosed in seven patients (9.59 %); all patients with CNP and five of the patients with partial Wallenberg syndrome experienced only temporary symptoms; two of the patients with partial Wallenberg syndrome had permanent neurological deficits. Despite their symptoms, most patients were in good general condition, as shown by their clinical scores. CONCLUSIONS: The results of this study have proven that endovascular internal trapping is a stable and durable treatment for closure of VADs. Recanalization is rather rare and occurred only in ruptured cases, both within 3 months after initial treatment without rupture. CNPs were observed in 8.21 %, perforating ischemia in 9.59 %, and spinal cord infarction in 2.74 %. The former two are temporary, while the last can be a factor that affects the modified Rankin Scale. Patients rated their quality of life as good, as corroborated by their posttreatment clinical score. Endovascular internal trapping for VAD is a therapy with a satisfactory long-term outcome.
Assuntos
Procedimentos Endovasculares/estatística & dados numéricos , Angiografia por Ressonância Magnética/estatística & dados numéricos , Dissecação da Artéria Vertebral/diagnóstico , Dissecação da Artéria Vertebral/cirurgia , Feminino , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Resultado do Tratamento , Dissecação da Artéria Vertebral/epidemiologiaRESUMO
Markedly expanded tandem repeats (TRs) have been correlated with ~60 diseases. TR diversity has been considered a clue toward understanding missing heritability. However, haplotype-resolved long TRs remain mostly hidden or blacked out because their complex structures (TRs composed of various units and minisatellites containing >10-bp units) make them difficult to determine accurately with existing methods. Here, using a high-precision algorithm to determine complex TR structures from long, accurate reads of PacBio HiFi, an investigation of 270 Japanese control samples yields several genome-wide findings. Approximately 322,000 TRs are difficult to impute from the surrounding single-nucleotide variants. Greater genetic divergence of TR loci is significantly correlated with more events of younger replication slippage. Complex TRs are more abundant than single-unit TRs, and a tendency for complex TRs to consist of <10-bp units and single-unit TRs to be minisatellites is statistically significant at loci with ≥500-bp TRs. Of note, 8909 loci with extended TRs (>100b longer than the mode) contain several known disease-associated TRs and are considered candidates for association with disorders. Overall, complex TRs and minisatellites are found to be abundant and diverse, even in genetically small Japanese populations, yielding insights into the landscape of long TRs.
Assuntos
Genoma Humano , Sequências de Repetição em Tandem , Humanos , Genoma Humano/genética , Repetições Minissatélites , Algoritmos , Deriva GenéticaRESUMO
BACKGROUND: Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for non-Hodgkin' s lymphoma and mantle cell lymphoma, the mechanisms of resistance to BH are not yet fully understood. Our study focuses on elucidating the mechanisms behind bendamustine resistance in leukemia cells, with a specific emphasis on epigenetics. METHODS: Bendamustine-resistant cells were cultivated from human B cell lymphoblastic leukemia cell lines through systematic and sustained exposure to bendamustine, using the limiting dilution method. Gene expression was assessed via real-time polymerase chain reaction, while the expression of the multidrug resistance protein 1 (MDR1) was evaluated using flow cytometry. RESULTS: Bendamustine-resistant leukemia cells exhibited a decreased RNA expression level for Polo-like kinase-1 (PLK-1). Notably, after treatment with the demethylating agent 5-aza-2'-deoxycytidine, PLK-1 gene expression surged significantly, enhancing bendamustine's cytotoxicity in the resistant leukemia cells. However, MDR1 expression, as determined by flow cytometry, remained consistent between parental and bendamustine-resistant leukemia cells. CONCLUSIONS: Our findings indicate that the methylation of the PLK-1 gene plays a pivotal role in modulating PLK-1 expression and is central to the development of bendamustine resistance in leukemia cells.
RESUMO
Invasive neonatal infection with Group B Streptococcus (GBS) is a disease of concern that can lead to neurological sequelae. Guidelines for preventing mother-to-child transmission have been introduced to reduce the incidence of early-onset infection, but guidelines for controlling the late-onset form are lacking. Recently, the trans-breastfeeding route of transmission has been highlighted as an example of late-onset infection, but no consensus on how to manage such infections has been reached. In this report, we describe a case of late-onset bacteremia/meningitis in a neonate suspected to have been infected with GBS via breastfeeding. A vaginal culture test of the mother at 35 weeks' gestation was negative for GBS. Since she had symptoms of mastitis, breast milk and nipple cultures were also tested and found to be positive for the strain of GBS identified in the neonate on genetic analysis. Diagnosis of trans-mammary GBS infection is challenging because breastfeeding-related events are difficult to identify. In our case, the diagnosis was based on the mother's history of mastitis, and the patient was treated without escalation to sequelae. When a neonate develops a fever, physicians should consider GBS infection and examine the mother's medical history to facilitate accurate diagnosis, especially if the history includes mastitis. A breast milk culture should be performed if the mother has mastitis, especially in cases of infection in preterm infants and in recurrent cases.
RESUMO
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is associated with hypercytokinemia in children. Although HLH can be also observed after hematopoietic stem cell transplantation (HSCT), the incidence and clinical features of HLH after HSCT remain obscure. PROCEDURE: The clinical features of HLH after HSCT (post-HSCT HLH) were investigated in children with malignancies, immune deficiencies, or aplastic anemia. The HLH/Langerhans Cell Histiocytosis (LCH) Committee of the Japanese Society of Pediatric Hematology (JSPH) sent questionnaires to hospitals with JPSH members asking for details of cases in which HLH occurred after HSCT between 1998 and 2008. RESULTS: Among 42 children who were diagnosed with post-HSCT HLH between 1998 and 2008 in Japan, 37 fulfilled our inclusion criteria; of these, 26 were classified as early-onset (onset <30 days after HSCT) and 11 were classified as late-onset (onset >30 days after HSCT). In the early-onset group, the presence of respiratory symptoms, high levels of total bilirubin, and triglycerides at onset and the lack of control of GVHD with tacrolimus were significantly associated with non-resolution of HLH (P < 0.05). The survival rate was significantly higher in patients with resolution of HLH than in those without resolution (59% vs. 14%, P < 0.05). CONCLUSIONS: These findings suggest that early-onset post-HSCT HLH is a specific entity of HLH, and appropriate diagnosis and prompt management need to be established.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica/mortalidade , Inquéritos e Questionários , Anemia Aplástica/sangue , Anemia Aplástica/mortalidade , Anemia Aplástica/terapia , Bilirrubina/sangue , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/mortalidade , Imunodeficiência de Variável Comum/terapia , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Lactente , Recém-Nascido , Japão/epidemiologia , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Neoplasias/sangue , Neoplasias/mortalidade , Neoplasias/terapia , Taxa de Sobrevida , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos , Transplante Homólogo , Triglicerídeos/sangueRESUMO
Preoperative embolization for hypervascular tumors is typically performed using particle agents such as polyvinyl alcohol, gelfoam powder, and fibrin glue. Furthermore, n-butyl-2-cyanoacrylate (NBCA) is used in patients with cerebral arteriovenous malformation (AVM) or an AV shunt. However, few reports have described the efficacy of NBCA in treating hypervascular tumors. Here, we report cases of hypervascular tumors in which preoperative embolization was performed using NBCA. We also discuss the difference between the efficacy of a liquid agent and a particle agent for hypervascular tumor embolization. We analyzed 10 cases encountered at our institution since 2004 in which preoperative embolization was performed using NBCA. In all cases, NBCA was injected through the tumor-feeding artery. In eight of these cases, preoperative embolization decreased intraoperative bleeding and markedly reduced the tumor stain. In the remaining two cases, complications occurred but without any permanent sequel. Thus, NBCA is useful for preoperative embolization.
Assuntos
Embolização Terapêutica , Embucrilato/uso terapêutico , Neoplasias Vasculares/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Embucrilato/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Neoplasias Vasculares/patologia , Adulto JovemRESUMO
We report a case of longstanding asymptomatic direct carotid-cavernous fistula (CCF) which caused fatal subarachnoid hemorrhage (SAH). A 91-year-old female with no history of previous head trauma and optic symptoms presented acute subarachnoid hemorrhage. Angiography revealed a left direct carotid-cavernous fistula draining only into the contralateral cavernous sinus with leptomeningeal venous reflux and small varix on the pontine bridging vein. The affected cavernous sinus was markedly dilated and there was no septum between the left cavernous sinus and the internal carotid artery. The patient underwent transvenous coil embolization for intercavernous sinus and leptomeningeal venous reflux was successfully obliterated and opacification of the varix was diminished. The past history of this patient and angiographical findings strongly suggest long standing asymptomatic CCF caused SAH.