RESUMEN
Testosterone deficiency is commonly observed in male patients with chronic obstructive pulmonary disease (COPD), which is characterized by chronic inflammation of the airways and pulmonary emphysema. Although clinical trials have indicated that testosterone replacement therapy can improve respiratory function in patients with COPD, the role of testosterone in the pathogenesis of COPD remains unclear. The aim of this study was to explore the effect of testosterone deficiency on the development of pulmonary emphysema in orchiectomized (ORX) mice exposed to porcine pancreatic elastase (PPE). ORX mice developed more severe emphysematous changes 21 d after PPE inhalation than non-ORX mice. Testosterone propionate supplementation significantly reduced PPE-induced emphysematous changes in ORX mice. PPE exposure also increased the number of neutrophils and T cells in bronchoalveolar lavage fluid (BALF) of mice that had undergone ORX and sham surgery. T cell counts were significantly higher in the BALF of ORX mice than of sham mice. Testosterone supplementation reduced the infiltration of T cells into BALF and alleviated emphysematous changes in the lungs of ORX mice. Our findings suggest that testosterone, a male-specific hormone, may suppress the development of pulmonary emphysema through the regulation of T cell-mediated immunity.
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Enfisema Pulmonar/etiología , Testosterona/deficiencia , Administración por Inhalación , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Humanos , Inmunidad Celular/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/patología , Orquiectomía , Elastasa Pancreática/administración & dosificación , Elastasa Pancreática/toxicidad , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfisema Pulmonar/inmunología , Enfisema Pulmonar/patología , Porcinos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Testosterona/administración & dosificaciónRESUMEN
BACKGROUND: Neuroinflammation is associated with various chronic neurological diseases, including epilepsy; however, neuroimaging approaches for visualizing neuroinflammation have not been used in the clinical routine yet. In this study, we used the translocator protein positron emission tomography (PET) with [11C] DPA713 to investigate neuroinflammation in the epileptogenic zone in patients with child-onset focal epilepsy. METHODS: Patients with intractable focal epilepsy were recruited at the Epilepsy Center of Osaka University; those who were taking any immunosuppressants or steroids were excluded. PET images were acquired for 60 min after intravenous administration of [11C] DPA713. The PET image of [11C] DPA713 was co-registered to individual's magnetic resonance imaging (MRI), and the standardized uptake value ratio (SUVr) in regions of interest, which were created in non-lesions and lesions, was calculated using the cerebellum as a pseudo-reference region. In the case of epilepsy surgery, the correlation between SUVr in lesions and pathological findings was analyzed. RESULTS: Twenty-seven patients (mean age: 11.3 ± 6.2 years, male/female: 17/10) were included in this study. Of these, 85.1% showed increased uptake of [11C] DPA713 in the focal epileptic lesion. Three patients showed epileptic spasms, suggesting partial seizure onset, and all 18 patients with abnormal lesions on MRI were similarly highlighted by significant uptake of [11C] DPA713. DPA713-positive patients had a broad range of etiologies, including focal cortical dysplasia, tumors, infarction, and hippocampal sclerosis. Five out of nine MRI-negative patients showed abnormal [11C] DPA713 uptake. The SUVr of [11C] DPA713 in lesions was significantly higher than that in non-lesions. In seven patients who underwent epilepsy surgery, increased [11C] DPA713 uptake was associated with microglial activation. CONCLUSIONS: This study indicates that [11C] DPA713 uptake has valuable sensitivity in the identification of epileptic foci in child-onset focal epilepsy, and inflammation is implicated in the pathophysiology in the epileptic foci caused by various etiologies. Further research is required to establish diagnostic tools for identifying focal epileptogenic zones.
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Acetamidas/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/metabolismo , Tomografía de Emisión de Positrones/métodos , Pirazoles/metabolismo , Pirimidinas/metabolismo , Adolescente , Encéfalo/fisiopatología , Radioisótopos de Carbono/metabolismo , Niño , Preescolar , Electroencefalografía/métodos , Epilepsias Parciales/fisiopatología , Femenino , Humanos , Lactante , Inflamación/diagnóstico por imagen , Inflamación/metabolismo , Inflamación/fisiopatología , Imagen por Resonancia Magnética/métodos , Masculino , Receptores de GABA/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Aquaporin 4 (AQP4) is a water-selective transport protein expressed in astrocytes throughout the central nervous system. AQP4 level increases after cerebral ischemia and results in ischemic brain edema. Brain edema markedly influences mortality and motor function by elevating intracranial pressure that leads to secondary brain damage. Therefore, AQP4 is an important target to improve brain edema after cerebral ischemia. The Japanese herbal Kampo medicine, goreisan, is known to inhibit AQP4 activity. Here, we investigated whether goreisan prevents induction of brain edema by cerebral ischemia via AQP4 using 4-hour middle cerebral artery occlusion (4h MCAO) mice. METHODS: Goreisan was orally administered at a dose of 500 mg/kg twice a day for 5 days before MCAO. AQP4 expression and motor coordination were measured by Western blotting and rotarod test, respectively. RESULTS: Brain water content of 4h MCAO mice was significantly increased at 24 hours after MCAO. Treatment with goreisan significantly decreased both brain water content and AQP4 expression in the ischemic brain at 24 hours after MCAO. In addition, treatment with goreisan alleviated motor coordination deficits at 24 hours after MCAO. CONCLUSIONS: The results of this study suggested that goreisan may be a useful new therapeutic option for ischemic brain edema.
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Acuaporina 4/metabolismo , Edema Encefálico/prevención & control , Encéfalo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Animales , Conducta Animal/efectos de los fármacos , Agua Corporal/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Edema Encefálico/etiología , Edema Encefálico/metabolismo , Edema Encefálico/patología , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Masculino , Medicina Kampo , Ratones , Actividad Motora/efectos de los fármacos , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.
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Estudios de Asociación Genética , Discapacidad Intelectual/genética , Discapacidades para el Aprendizaje/genética , Proteínas de la Membrana/genética , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Exoma , Femenino , Genotipo , Células HEK293 , Humanos , Lactante , Discapacidad Intelectual/patología , Japón , Discapacidades para el Aprendizaje/patología , Masculino , Proteínas de la Membrana/deficiencia , Mutación , Linaje , Fenotipo , SíndromeRESUMEN
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene which encodes dystrophin protein. Dystrophin defect affects cardiac muscle as well as skeletal muscle. Cardiac dysfunction is observed in all patients with DMD over 18 years of age, but there is no curative treatment for DMD cardiomyopathy. To establish novel experimental platforms which reproduce the cardiac phenotype of DMD patients, here we established iPS cell lines from T lymphocytes donated from two DMD patients, with a protocol using Sendai virus vectors. We successfully conducted the differentiation of the DMD patient-specific iPS cells into beating cardiomyocytes. DMD patient-specific iPS cells and iPS cell-derived cardiomyocytes would be a useful in vitro experimental system with which to investigate DMD cardiomyopathy.
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Células Madre Pluripotentes Inducidas/fisiología , Distrofia Muscular de Duchenne/metabolismo , Miocitos Cardíacos/citología , Adolescente , Adulto , Diferenciación Celular , Células Cultivadas , Humanos , Células Madre Pluripotentes Inducidas/citología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Miocitos Cardíacos/metabolismo , ARN/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Chronic obstructive pulmonary disease (COPD) shows progressive, irreversible airflow limitation induced by emphysema and lung inflammation. The aim of the present study was to determine if COPD conditions induce blood-brain barrier (BBB) dysfunction. We found that the intratracheal administration of porcine pancreatic elastase (PPE; 3 U) induced alveolar enlargement, increased neutrophil number in bronchoalveolar lavage fluid, and decreased blood oxygen saturation in mice at 21 days after inhalation. In parallel with these lung damages, BBB permeability to sodium fluorescein and Evans blue albumin was markedly increased. Our findings demonstrate that COPD conditions are associated with risk for BBB impairment.
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Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiopatología , Elastasa Pancreática/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Administración por Inhalación , Animales , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Azul de Evans/metabolismo , Fluoresceína/metabolismo , Recuento de Leucocitos , Ratones , Neutrófilos , Oxígeno/sangre , Elastasa Pancreática/administración & dosificación , Permeabilidad , PorcinosRESUMEN
Sotos syndrome (OMIM #117550) is a congenital syndrome characterized by overgrowth with advanced bone age, macrocephaly, and learning difficulties. Endocrine complications of this syndrome have not yet been fully described in previous reports. We here investigated the clinical manifestations of Sotos syndrome in Japanese patients who presented with hyperinsulinemic hypoglycemia of infancy. We recruited patients diagnosed as having Sotos syndrome who presented with the complication of hyperinsulinemia during the neonatal period using a survey of the abstracts of Pediatric Meetings in domestic areas of Japan from 2007 to 2011. As a result, five patients (four females and one male) were recruited to evaluate the clinical presentation of Sotos syndrome by reference to the clinical record of each patient. A 5q35 deletion including the NSD1 gene was detected in all patients. Major anomalies in the central nervous, cardiovascular, and genito-urinary systems were frequently found. Hypoglycemia occurred between 0.5 and 3 hr after birth and high levels of insulin were initially found within 3 days of birth. The patients were treated with intravenous glucose infusion at a maximum rate of 4.6-11.0 mg/kg/min for 12-49 days. Three of the five patients required nasal tube feeding. One patient received medical treatment with diazoxide. This study shows that patients with Sotos syndrome may present with transient hyperinsulinemic hypoglycemia in the neonatal period.
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Hiperinsulinismo Congénito/genética , Síndrome del Maullido del Gato/genética , Síndrome de Sotos/genética , Trisomía/genética , Pueblo Asiatico/genética , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Hiperinsulinismo Congénito/fisiopatología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Estudios de Seguimiento , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Japón , Cariotipo , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/fisiopatología , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenotipo , Síndrome de Sotos/fisiopatologíaRESUMEN
Interstitial deletions of chromosome 3 are rare, and only one patient with a microdeletion of 3p21.31 has been reported to date. We identified two additional cases of patients with microdeletions of 3p21.31. The characteristic clinical features of developmental delay and distinctive facial features (including arched eyebrows, hypertelorism, epicanthus, and micrognathia) were seen both in the previously reported patient and in the two newly identified patients. In these two new cases, additional features, including elevated serum creatine kinase levels and characteristic neuroradiological features with white matter involvement, were seen. These features had not been described in the previous case in which the patient was examined during infancy, suggesting an age-dependent mechanism. The shortest region of overlap among the three deletions narrowed down the candidate genes that may be responsible for the common neurological features to the bassoon (presynaptic cytomatrix protein) gene (BSN), which has an important function in neuronal synapses. In this study, we confirmed common phenotypic features in the patients with microdeletions of 3p21.31 and identified additional features that have not been reported previously. Because the constellation of such characteristic features is quite unique, clinical manifestations of the patients with microdeletions of 3p21.31 would be clinically recognizable as a contiguous gene deletion syndrome.
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Deleción Cromosómica , Cromosomas Humanos Par 3/genética , Discapacidades del Desarrollo/fisiopatología , Leucoencefalopatías/fisiopatología , Anomalías Múltiples/sangre , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Preescolar , Creatina Quinasa/sangre , Discapacidades del Desarrollo/sangre , Femenino , Humanos , Leucoencefalopatías/sangre , Leucoencefalopatías/complicaciones , Proteínas del Tejido Nervioso/sangre , FenotipoRESUMEN
We report a case of a 15-year-old girl with relapsing-remitting multiple sclerosis (MS) who received cyclophosphamide pulse therapy. At the age of 5 years, she displayed symptoms such as headache and unconsciousness after varicella infection as the first episode of MS. She had been treated with methylprednisolone pulse therapy, intravenous immunoglobulin, interferon-beta1b, and azathioprine. However, she had relapsed 12 times by the age of 15 years. At this time, she showed weakness and severe paralysis of her left leg, and even 1 month after methylprednisolone pulse therapy, she still had gait impairment and showed gadolinium-enhanced lesion on brain magnetic resonance imaging. We then started cyclophosphamide pulse therapy (600 mg/m2) once a month for 12 months combined with interferon-beta1a. She had no serious side effects and she could walk again after 4 months on cyclophosphamide treatment. She has been free from relapse for 2 years and 8 months until the present time. Although only a few studies have indicated the efficacy of cyclophosphamide pulse therapy for childhood MS, we consider careful use of cyclophosphamide could be one of the options for refractory childhood MS.
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Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adolescente , Quimioterapia Combinada/métodos , Femenino , Humanos , Interferón beta-1a , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Prevención Secundaria , Resultado del TratamientoRESUMEN
Chronic obstructive pulmonary disease is an inflammatory lung disease characterized by chronic bronchitis and emphysema. Our previous study revealed that testosterone depletion induced T cell infiltration in the lungs and aggravated pulmonary emphysema in orchiectomized (ORX) mice exposed to porcine pancreatic elastase (PPE). However, the association between T cell infiltration and emphysema remains unclear. The aim of this study was to determine whether thymus and T cells are involved in the exacerbation of PPE-induced emphysema in ORX mice. The weight of thymus gland in ORX mice was significantly greater than that of sham mice. The pretreatment of anti-CD3 antibody suppressed PPE-induced thymic enlargement and T cell infiltration in the lungs in ORX mice, resulting in improved expansion of the alveolar diameter, a marker of emphysema exacerbation. These results suggest that increased thymic function due to testosterone deficiency and the associated increased pulmonary infiltration of T cells may trigger the development of emphysema.
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Successful surgery for drug-resistant pediatric epilepsy can facilitate motor and cognitive development and improve quality of life by resolution or reduction of epileptic seizures. Therefore, surgery should be considered early in the disease course. However, in some cases, the estimated surgical outcomes are not achieved, and additional surgical treatments are considered. In this study, we investigated the clinical factors related with such unsatisfactory outcomes.We reviewed the clinical data of 92 patients who underwent 112 surgical procedures (69 resection and 53 palliation procedures). Surgical outcomes were assessed according to the postoperative disease status, which was classified as good, controlled, and poor. The following clinical factors were analyzed in relation to surgical outcome: sex, age at onset, etiology (malformation of cortical development, tumor, temporal lobe epilepsy, scar, inflammation, and non-lesional epilepsy), presence of genetic cause, and history of developmental epileptic encephalopathy. At a median of 59 (30-81.25) months after the initial surgery, the disease status was good in 38 (41%), controlled in 39 (42%), and poor in 15 (16%) patients. Among the evaluated factors, etiology exhibited the strongest correlation with surgical outcomes. Tumor-induced and temporal lobe epilepsy were correlated with good, whereas malformation of cortical development, early seizure onset, and presence of genetic cause were correlated with poor disease status. Although epilepsy surgery for the patients who present with the latter factors is challenging, these patients demonstrate a greater need for surgical treatment. Hence, development of more effective surgical options is warranted, including palliative procedures.
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Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Epilepsia , Niño , Humanos , Epilepsia del Lóbulo Temporal/cirugía , Calidad de Vida , Resultado del Tratamiento , Epilepsia/cirugía , Convulsiones , Epilepsia Refractaria/cirugía , Electroencefalografía , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVES: Neuroinflammation contributes to the severity of various neurological disorders, including epilepsy. Tuberous sclerosis complex (TSC) is a condition that results in the overactivation of the mammalian target of rapamycin (mTOR) pathway, which has been linked to the activation of microglia responsible for neuroinflammation. To clarify the involvement of neuroinflammation in the neuropathophysiology of TSC, we performed a positron emission tomography (PET) study using the translocator protein (TSPO) radioligand, [11C] DPA713, and investigated microglial activation in relation to neurological manifestations, especially epilepsy and cognitive function. METHODS: This cross-sectional study included 18 patients with TSC (6 in the no-seizure group, 6 in the refractory seizure group, and 6 in the mTOR-inhibitor [mTOR-i] group). All participants underwent [11C] DPA713-PET. PET results were superimposed with a 3D T2-weighted fluid-attenuated inversion-recovery (FLAIR) and T1-weighted image (T1WI) to evaluate the location of cortical tubers. Microglial activation was assessed using the standardized uptake value ratio (SUVr) of DPA713 binding. The volume ratio of the DPA713-positive area to the intracranial volume (volume ratio of DPA713/ICV) was calculated to evaluate the extent of microglial activation. A correlation analysis was performed to examine the relationship between volume ratio of DPA713/ICV and severity of epilepsy and cognitive function. RESULTS: Most cortical tubers with hyperintensity on FLAIR and hypo- or isointensity on T1WI showed microglial activation. The extent of microglial activation was significantly greater in the refractory seizure group than in the no-seizure or mTOR-i groups (p < 0.001). The extent of microglial activation in subjects without mTOR-i treatment correlated positively with epilepsy severity (r = 0.822, P = 0.001) and negatively with cognitive function (r = -0.846, p = 0.001), but these correlations were not present in the mTOR-i group (r = 0.232, P = 0.658, r = 0.371, P = 0.469, respectively). CONCLUSION: Neuroinflammation is associated with the severity of epilepsy and cognitive dysfunction in brains with TSC. mTOR-i may suppress the extent of neuroinflammation in TSC. Investigating the spread of microglial activation using TSPO-PET in these patients may help to predict the progression of neuropathy by assessing the degree of neuroinflammation and therefore be useful for determining how aggressive the treatment should be and in assessing the effectiveness of such treatment in patients with TSC.
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Disfunción Cognitiva , Epilepsia , Esclerosis Tuberosa , Humanos , Microglía , Enfermedades Neuroinflamatorias , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/diagnóstico por imagen , Esclerosis Tuberosa/metabolismo , Estudios Transversales , Tomografía Computarizada por Rayos X , Epilepsia/etiología , Epilepsia/complicaciones , Tomografía de Emisión de Positrones/métodos , Convulsiones/complicaciones , Disfunción Cognitiva/etiología , Disfunción Cognitiva/complicaciones , Serina-Treonina Quinasas TOR/metabolismo , Receptores de GABA/metabolismoRESUMEN
OBJECTIVE: In glucose transporter 1 deficiency syndrome (Glut1DS), cerebrospinal fluid glucose (CSFG) and CSFG to blood glucose ratio (CBGR) show significant differences among groups classified by phenotype or genotype. The purpose of this study was to investigate the association between these biochemical parameters and Glut1DS severity. METHODS: The medical records of 45 patients who visited Osaka University Hospital between March 2004 and December 2021 were retrospectively examined. Neurological status was determined using the developmental quotient (DQ), assessed using the Kyoto Scale of Psychological Development 2001, and the Scale for the Assessment and Rating of Ataxia (SARA). CSF parameters included CSFG, CBGR, and CSF lactate (CSFL). RESULTS: CSF was collected from 41 patients, and DQ and SARA were assessed in 24 and 27 patients, respectively. Simple regression analysis showed moderate associations between neurological status and biochemical parameters. CSFG resulted in a higher R2 than CBGR in these analyses. CSF parameters acquired during the first year of life were not comparable to those acquired later. CSFL was measured in 16 patients (DQ and SARA in 11 and 14 patients, respectively). Although simple regression analysis also showed moderate associations between neurological status and CSFG and CSFL, the multiple regression analysis for DQ and SARA resulted in strong associations through the use of a combination of CSFG and CSFL as explanatory variables. CONCLUSION: The severity of Glut1DS can be predicted from CSF parameters. Glucose and lactate are independent contributors to the developmental and neurological status in Glut1DS.
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Glucemia , Glucosa , Estudios Retrospectivos , Transportador de Glucosa de Tipo 1/genética , Glucosa/líquido cefalorraquídeo , Ácido Láctico , Líquido CefalorraquídeoRESUMEN
Botulinum toxin A (BTX-A) therapy has been approved as a first-line therapy for spastic torticollis. However it has been suggested as that its use in patients with respiratory distress should be decided cautiously. We treated 5 patients with abnormal posture, cervical hypertonia and obstructive respiratory distress by BTX-A, and analyzed its efficacy for respiratory distress by their Tsui score and respiratory status after BTX-A therapy. All 5 patients clinically had some degree of dysphagia before BTX-A therapy. Cervical hypertonia and induced abnormal posture were improved in all patients. The youngest patient could control muscle tone after only 2 doses of BTX-A and subsequently maintained a good condition without additional BTX-A. BTX-A therapy can decrease torsion and hyperextension of the upper respiratory tract by reducing cervical hypertonia. Consequently, it may improve respiratory status. On the other hand, mild dysphagia and excessive salivation was noted in one patient for each symptom. It is safe to avoid BTX-A invasion to the anterior muscle of neck and rapid changes in the swallowing pattern.
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Toxinas Botulínicas Tipo A/administración & dosificación , Hipertonía Muscular/complicaciones , Hipertonía Muscular/tratamiento farmacológico , Músculos del Cuello/fisiopatología , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/etiología , Adolescente , Adulto , Niño , Femenino , Humanos , Lactante , Masculino , Resultado del TratamientoRESUMEN
This case concerns a 50-year-old male patient who was diagnosed with rectal cancer without any obvious distal metastasis. The patient underwent abdominoperineal resection of the rectum with lateral lymph node dissection exclusively on the lesion side. An obturator lymph node metastasis was found, and histopathological tests revealed that the patient was in Stage IIIb. FOLFOX4 therapy was performed as postoperative adjuvant chemotherapy, and although temporary discontinuation was necessary due to abscesses in the buttocks, the patient completed 10 courses of chemotherapy. Lung metastasis was diagnosed when a chest computed tomography revealed a nodule 12 mm in diameter immediately above the diaphragm in the left S8. Since the nodule was a solitary tumor, radiofrequency ablation (RFA) therapy was performed, after which postoperative adjuvant chemotherapy was changed to FOLFIRI therapy. No obvious adverse events occurred, making it possible to continue the therapy without withdrawal. The lesions tended to gradually shrink, and during the 50th course of the therapy, the patient converted from partial remission (PR) to complete remission (CR). The FOLFIRI therapy was continued for another 6 months and then suspended for a while. The patient received 62 courses of FOLFIRI therapy in total. No sign of recurrence has been found. This case demonstrates the successful treatment and CR of recurrent lung metastasis after surgery for rectal cancer using lung RFA therapy and long-term administration of FOLFIRI.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/terapia , Neoplasias del Recto/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Ablación por Catéter , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Recurrencia , Factores de TiempoRESUMEN
Objective: Tuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI). Methods: A total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers. Results: The TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC. Conclusion: The disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.
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OBJECTIVE: In a study using a mouse model of CDKL5 deficiency disorder (CDD), seizures are specific to female mice heterozygous for Cdkl5 mutations and not observed in hemizygous knockout males or homozygous knockout females. The aim of this study was to examine whether the clinical phenotype of patients with CDD can be impacted by the type of genetic variant. METHODS: Eleven CDD patients (six females and five males) were included in this study. The molecular diagnosis of hemizygous male patients was performed using digital PCR and their clinical phenotypes were compared with those of patients with mosaic or heterozygous CDKL5 variants. The severity of clinical phenotypes was graded by using CDKL5 Developmental Score and the adapted version of the CDKL5 Clinical Severity Assessment. The effect of cellular mosaicism on the severity of CDD was studied by comparing the clinical characteristics and comorbidities between individuals with hemizygous and mosaic or heterozygous CDKL5 variants. RESULTS: One of the five male patients was mosaic for the CDKL5 variant. All patients developed seizures irrespective of their genetic status of the pathogenic variant. However, cellular mosaicism of CDKL5 deficiency was associated with lesser severity of other comorbidities such as feeding, respiratory, and visual functional impairments. SIGNIFICANCE: This study provided evidence that cellular mosaicism of CDKL5 deficiency was not necessarily required for developing epilepsy. CDD patients not only exhibited clinical features of epilepsy but also exhibited the developmental consequences arising directly from the effect of the CDKL5 pathogenic variant.
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Epilepsia , Espasmos Infantiles , Femenino , Masculino , Humanos , Mosaicismo , Convulsiones/genética , Espasmos Infantiles/genética , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
BACKGROUND: Atypical sensory behavior disrupts behavioral adaptation in children with autism spectrum disorder (ASD); however, neural correlates of sensory dysfunction using magnetoencephalography (MEG) remain unclear. METHOD: We used MEG to measure the cortical activation elicited by visual (uni)/audiovisual (multisensory) movies in 46 children (7-14 years) were included in final analysis: 13 boys with atypical audiovisual behavior in ASD (AAV+), 10 without this condition, and 23 age-matched typically developing boys. RESULTS: The AAV+ group demonstrated an increase in the cortical activation in the bilateral insula in response to unisensory movies and in the left occipital, right superior temporal sulcus (rSTS), and temporal regions to multisensory movies. These increased responses were correlated with severity of the sensory impairment. Increased theta-low gamma oscillations were observed in the rSTS in AAV+. CONCLUSION: The findings suggest that AAV is attributed to atypical neural networks centered on the rSTS.
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Percepción Auditiva/fisiología , Trastorno del Espectro Autista/fisiopatología , Ondas Encefálicas/fisiología , Corteza Cerebral/fisiopatología , Trastornos de la Percepción/fisiopatología , Trastornos de la Sensación/fisiopatología , Percepción Visual/fisiología , Adolescente , Niño , Humanos , Magnetoencefalografía , Masculino , Películas CinematográficasRESUMEN
Glucose transporter 1 deficiency syndrome (Glut1-DS) is a congenital metabolic disorder characterized by refractory seizures with early infantile onset, developmental delay, movement disorders and acquired microcephaly. Glut1-DS is caused by heterozygous abnormalities of the SLC2A1 (Glut1) gene, whose product acts to transport glucose into the brain across the blood-brain barrier. We analyzed the SLC2A1 gene in 12 Japanese Glut1-DS patients who were diagnosed by characteristic clinical symptoms and hypoglycorrhachia as follows: all patients had infantile-onset seizures and mild to severe developmental delay, and ataxia was detected in 11 patients. For the 12 patients, we identified seven different mutations (three missense, one nonsense, two frameshift and one splice-site) in exons and exon-intron boundaries of the SLC2A1 gene by direct sequencing, of which six were novel mutations. Of the remaining five patients who had no point mutations and underwent investigation by multiplex ligation-dependent probe amplification, a complex abnormality with deletion and duplication was identified in one patient: this is the first case of such recombination of the SLC2A1 gene. Changes in regulatory sequences in the promoter region or genes other than SLC2A1 might be responsible for onset of Glut1-DS in the other four patients (33%) without SLC2A1 mutation.
Asunto(s)
Transportador de Glucosa de Tipo 1/deficiencia , Transportador de Glucosa de Tipo 1/genética , Adolescente , Pueblo Asiatico/genética , Niño , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Humanos , Japón , Masculino , Linaje , SíndromeRESUMEN
The metabolic syndrome, characterized by conditions such as obesity and insulin resistance, is more prevalent in postmenopausal women than in premenopausal women, and increases the risk of cardiovascular disease and type 2 diabetes. The main objective of the present study was to investigate the combined effects of ovariectomy (OVX) and high-fat diet (HFD) on metabolic parameters, vascular function and glucose homeostasis in mice. After OVX or sham operation (Sham), mice were fed with either a normal diet (ND) or a HFD. Mice were divided into ND+Sham, ND+OVX, HFD+Sham, and HFD+OVX groups. After 4weeks, HFD+OVX mice developed marked increases in body weight and plasma insulin levels, but not blood glucose levels. The area under the glucose tolerance curve (Δ AUC(glucose)) following an oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR) revealed that HFD+OVX mice had higher values than any other group. Concomitantly with these metabolic disturbances, decreased tail skin blood flow and augmented tail skin flushing, a marker of hot flashes, were observed in HFD+OVX mice. These vascular modulations likely result from vasomotor dysfunction. Furthermore, we investigated whether OVX and HFD affect the insulin signaling pathway in mice. Insulin-induced Akt phosphorylation in the livers of HFD+OVX mice was significantly downregulated compared with ND+Sham and HFD+Sham mice. Thus, the HFD+OVX mice used in the present study constitute an experimental animal model of postmenopausal metabolic syndrome. Herein, we provide experimental evidence that vascular dysfunction and impaired insulin signaling may contribute to the pathogenesis of postmenopausal metabolic syndrome.