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AIM: The purpose of this study was to evaluate the long-term safety and efficacy of aripiprazole in treating irritability in pediatric patients (6-17 years) with autistic disorder (AD) in Japan. METHODS: In this open-label extension study, patients who had completed a previous randomized, double-blind, placebo-controlled 8-week study were enrolled and were flexibly dosed with aripiprazole (1-15 mg/day) until the new indication of irritability in pediatric autism spectrum disorder was approved in Japan. RESULTS: Seventy (81%) out of 86 enrolled patients completed week-48 assessments. The mean duration of treatment was 694.9 days. The mean daily dose of aripiprazole over the treatment period was 7.2 mg and the mean of the final dose was 8.5 mg. The most common treatment-emergent adverse events (TEAE; ≥20%) included nasopharyngitis, somnolence, influenza, and increased weight. The majority of these TEAE were mild or moderate in severity, and there were no deaths, and no clinically relevant findings in laboratory values except prolactin decrease, vital signs, height, or ECG parameters. At week 48 (observed case), the mean change from baseline in the Irritability subscale score for the Aberrant Behavior Checklist Japanese Version was -6.3 in prior placebo patients and -2.6 in prior aripiprazole patients. CONCLUSION: Aripiprazole was generally safe, well tolerated, and effective in the long-term treatment of irritability associated with AD in Japanese pediatric patients.
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Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Transtorno do Espectro Autista/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Transtorno do Espectro Autista/fisiopatologia , Criança , Feminino , Humanos , Japão , MasculinoRESUMO
Introduction: Post-synaptic dopamine receptor supersensitivity (DARSS) has been extensively researched by Dr. Masaya Segawa, who has investigated the efficacy of very-low-dose levodopa therapy (VLDT; 0.5-1 mg/kg/day). Considerable Japanese research supports the possibility that VLDT could be used to treat pediatric neurological disorders. We conducted an on-line survey in 2014 to collect real-world data on the use of VLDT to treat DARSS. Methods: A two-step survey, including a screening test and questionnaire, was posted on a private internet site that could be accessed via the VLDT Research Group home page, and 1,165 pediatric neurologists across Japan were invited to complete it. Results: A total of 25 respondents reported prescribing VLDT; 19 used VLDT to treat autism spectrum disorder, 14 for tics, 12 for speech delay, 9 for Rett syndrome, 7 for attention-deficit/hyperactivity disorder, intellectual disability, and 6 for sleep problems. Twelve respondents reported prescribing a dose of 0.5 mg/kg. Twenty-two reported that VLDT was effective for treating behavioral problems, and twenty reported a good efficacy for treating motor symptoms. Adverse events had a low incidence. Notably, respondents chose VLDT for its possible action in DARSS and for its safety. VLDT was commonly used for behavioral problems in patients younger than 5 years, and for motor symptoms in aged 5-9 years. Conclusion: VLDT could safely treat behavioral and motor symptoms in pediatric neurological disorders. In contrast, dopamine antagonists are associated with potent efficacy, but with adverse effects such as sleepiness and obesity. Further surveys should be conducted with a broader participants.
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BACKGROUND: Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1alpha and -1beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins. METHODS AND RESULTS: Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 micromol/L aldosterone in mIMCD-3 cells. CONCLUSIONS: Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension.
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Colectinas/biossíntese , Hipertensão/induzido quimicamente , Complexos Multiproteicos/metabolismo , Proteínas SNARE/metabolismo , Cloreto de Sódio/toxicidade , Regulação para Cima/efeitos dos fármacos , Aldosterona/urina , Animais , Aquaporina 2/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Canais Epiteliais de Sódio , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-beta Nuclear de Hepatócito/metabolismo , Hipertensão/metabolismo , Células Secretoras de Insulina/metabolismo , Túbulos Renais Coletores/metabolismo , Túbulos Renais Proximais/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Proteínas Qa-SNARE/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Proteína 2 Associada à Membrana da Vesícula/metabolismoRESUMO
BACKGROUND: Neutrophils of patients with Down syndrome (DS) are known to have numerous abnormalities associated with diminished resistance to infection. The intracellular calcium (Ca(2+)i) acts as a second messenger and regulates diverse functions in many cell types. The purpose of the present study was to compare the intracellular calcium concentration ([Ca(2+)]i) at baseline and stimulated conditions in DS patients and in normal subjects to investigate [Ca(2+)]i regulation in neutrophils. METHODS: The study group consisted of 27 subjects with DS (age, 8.6 +/- 4.6 years) and 14 healthy subjects (age, 12.0 +/- 3.9 years). Using a fluorescent probe, fura-2, the baseline levels and changes in [Ca(2+)]i were examined after stimulation of neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP). RESULTS: At baseline, the [Ca(2+)]i of neutrophils from DS subjects was significantly higher than that of the controls (70.6 +/- 28.0 nmol/L vs 44.4 +/- 16.0 nmol/L, P < 0.01). The absolute [Ca(2+)]i after addition of fMLP in the DS subjects was also significantly higher than that of the control group (250 +/- 91 nmol/L vs 167 +/- 60 nmol/L, respectively: P < 0.01). The neutrophils from the DS subjects had a consistently and significantly prolonged response to fMLP as compared to the neutrophils of control subjects. CONCLUSIONS: The higher [Ca(2+)]i and the prolonged response of [Ca(2+)]i to fMLP appear to be phenotypic traits of neutrophils in subjects with DS. This suggests intrinsic cellular defects in DS.
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Cálcio/análise , Síndrome de Down/metabolismo , Neutrófilos/química , Adolescente , Cálcio/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Neutrófilos/metabolismoRESUMO
Dialysis related amyloidosis (DRA) is a progressive and serious complication in patients under long-term hemodialysis and mainly leads to osteo-articular diseases. Although beta(2)-microglobulin (beta2-m) is the major structural component of beta2-m amyloid fibrils, the initiation of amyloid formation is not clearly understood. Here, we have identified procollagen C-proteinase enhancer-1 (PCPE-1) as a new interacting protein with beta2-m by screening a human synovium cDNA library. The interaction of beta2-m with full-length PCPE-1 was confirmed by immunoprecipitation, solid-phase binding and pull-down assays. By yeast two-hybrid analysis and pull-down assay, beta2-m appeared to interact with PCPE-1 via the NTR (netrin-like) domain and not via the CUB (C1r/C1s, Uegf and BMP-1) domain region. In synovial tissues derived from hemodialysis patients with DRA, beta2-m co-localized and formed a complex with PCPE-1. beta2-m did not alter the basal activity of bone morphogenetic protein-1/procollagen C-proteinase (BMP-1/PCP) nor BMP-1/PCP activity enhanced by PCPE-1. PCPE-1 did not stimulate beta2-m amyloid fibril formation from monomeric beta2-m in vitro under acidic and neutral conditions as revealed by thioflavin T fluorescence spectroscopy and electron microscopy. Since PCPE-1 is abundantly expressed in connective tissues rich in type I collagen, it may be involved in the initial accumulation of beta2-m in selected tissues such as tendon, synovium and bone. Furthermore, since such preferential deposition of beta2-m may be linked to subsequent beta2-m amyloid fibril formation, the disruption of the interaction between beta2-m and PCPE-1 may prevent beta2-m amyloid fibril formation and therefore PCPE-1 could be a new target for the treatment of DRA.
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Amiloide/química , Proteínas da Matriz Extracelular/metabolismo , Glicoproteínas/metabolismo , Microglobulina beta-2/química , Sequência de Aminoácidos , Proteína Morfogenética Óssea 1 , Proteínas Morfogenéticas Ósseas/química , Relação Dose-Resposta a Droga , Elementos Facilitadores Genéticos , Biblioteca Gênica , Humanos , Metaloendopeptidases/química , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Técnicas do Sistema de Duplo-HíbridoRESUMO
We investigated whether machine learning methods could potentially identify a subgroup of persons with autism spectrum disorder (ASD) who show vitamin B6 responsiveness by selected phenotype variables. We analyzed the existing data from our intervention study with 17 persons. First, we focused on signs and biomarkers that have been identified as candidates for vitamin B6 responsiveness indicators. Second, we conducted hypothesis testing among these selected variables and their combinations. Finally, we further investigated the results by conducting cluster analyses with two different algorithms, affinity propagation and k-medoids. Statistically significant variables for vitamin B6 responsiveness, including combination of hypersensitivity to sound and clumsiness, and plasma glutamine level, were included. As an a priori variable, the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores was also included. The affinity propagation analysis showed good classification of three potential vitamin B6-responsive persons with ASD. The k-medoids analysis also showed good classification. To our knowledge, this is the first study to attempt to identify subgroup of persons with ASD who show specific treatment responsiveness using selected phenotype variables. We applied machine learning methods to further investigate these variables' ability to identify this subgroup of ASD, even when only a small sample size was available.
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Transtorno do Espectro Autista/tratamento farmacológico , Aprendizado de Máquina , Vitamina B 6/uso terapêutico , Aminoácidos/sangue , Transtorno do Espectro Autista/sangue , Criança , Análise por Conglomerados , Feminino , Humanos , Masculino , Fenótipo , Análise de Componente PrincipalRESUMO
Thiazolidinediones are ligands for peroxisome proliferator-activated receptor (PPAR)-gamma, widely used as insulin sensitizer in type 2 diabetic patients and implicated in apoptosis, cell proliferation, and cell cycle regulation. Here, the effect of thiazolidinediones on G1-phase cell cycle arrest, the hallmark in diabetic nephropathy, was investigated. Eight-week-old male Otsuka Long-Evans Tokushima fatty rats were treated with pioglitazone (1 mg x kg body wt(-1) x day(-1)) until 50 weeks of age and compared with insulin treatment. Although similar HbA(1c) levels were observed in both groups, pioglitazone significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion compared with the insulin-treated group. In addition, pioglitazone significantly reduced the number of glomerular p27(Kip1)-positive cells. Because prominent expression of PPAR-gamma was observed in podocytes in glomeruli and cultured cells, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mmol/l D-glucose supplemented with pioglitazone. Pioglitazone inhibited cell hypertrophy revealed by [(3)H]thymidine and [(3)H]proline incorporation, and pioglitazone reversed high glucose-induced G1-phase cell cycle arrest, i.e., an increase in G0/G1 phase and decrease in S and G2 phases. Pioglitazone suppressed high glucose-induced phosphorylation of p44/42 mitogen-activated protein kinase and reduced Bcl-2 and p27(Kip1) protein levels. Besides glucose-lowering action, pioglitazone ameliorates diabetic nephropathy via cell cycle-dependent mechanisms.
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Ciclo Celular/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Tiazolidinedionas/farmacologia , Albuminúria/tratamento farmacológico , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Ciclo Celular/fisiologia , Linhagem Celular , Colágeno Tipo IV/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Glucose/farmacologia , Hipoglicemiantes/farmacologia , Imuno-Histoquímica , Insulina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Pioglitazona , Podócitos/citologia , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Ratos , Ratos Long-Evans , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVE: To investigate the time course for resolution of symptoms from recurrent herpes simplex viral infections after treatment with the herbal mixture WTTCGE [Wisteria floribunda, Trapa natans, Terminalia chebulae, Coicis lachryma-jobi, Ganoderma lucidum, Elfuinga applanata]. METHODS: Fifteen (15) patients with herpes genitalis (49.3+/-12.0: mean+/-standard deviation age in years), and 13 patients with herpes labialis (43.7+/-12.9), were studied. All had been suffering from recurrent herpes outbreaks for more than 1 year, and had received regular outpatient treatment at other medical institutions without improvement. RESULTS: The herbal mixture, WTTCGE appeared to provide fast, effective relief from the symptoms of recurrent herpes genitalis and labialis. The mean duration before relief from herpes genitalis occurred was 10.9+/-6.3 days without WTTCGE treatment and 4.9+/-1.3 days with it (p<0.002). Similarly, the time required to obtain relief from herpes labialis was 7.8+/-4.3 days without WTTCGE treatment and 4.0+/-1.1 days with it (p<0.005). CONCLUSIONS: Administration of WTTCGE to patients suffering from herpes genitalis and labialis appears to shorten the time required to obtain symptom relief as has been shown in a previous report.
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Antivirais/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Herpes Genital/tratamento farmacológico , Herpes Labial/tratamento farmacológico , Reishi , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the effectiveness of traditional Chinese medicine, specifically the traditional herbal formulation Bu-yang-huan-wu-tang, for treating epilepsy stemming from cerebrovascular dysfunction. SUBJECTS: Three adult patients with epilepsy refractory to standard antiepileptic medications were involved. RESULTS: All three showed substantial improvement in the frequency and severity of seizures after Bu-yanghuan- wu-tang was added to conventional medical treatment. CONCLUSIONS: Decrease of seizure frequency and severity in three epileptic patients was achieved by adding Bu-yang-huan-wu-tang to conventional therapy according to the principles of Traditional Chinese Medicine (TCM) theory. This treatment mainly relied on the resolution of blood stagnation in cerebrovascular systems. Blood stagnation is an important underlying pathology of many disease processes according to TCM theory.
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Anticonvulsivantes/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Epilepsias Parciais/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Fitoterapia , Adulto , Feminino , Humanos , Masculino , Plantas Medicinais , Qualidade de Vida , Resultado do TratamentoRESUMO
Methyl-CpG binding protein 2 gene (MECP2), the gene implicated in Rett syndrome, was also reported to be involved in mental retardation and autism. MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a nuclear protein family sharing the methyl-CpG binding domain (MBD) and are related to transcriptional repression. In 65 Japanese autistic patients, all the exons of each gene were screened for mutations by DHPLC, and the results were confirmed by direct sequencing. An R269C mutation that resulted in the addition of cysteine near a cysteine rich region was found in the MBD1 gene in one patient. This mutation was also detected in the patient's father with some phenotypes of autism and his normal sister, but not in 151 controls. Two repeat length polymorphisms, (GGGGCC)2 to 3 and (GGC)4 to 5, were detected in MBD2, and several polymorphisms were detected in each gene. Although our findings could not confirm that the genes of this family are responsible for the etiology in the majority of autistic patients, the R269C mutation in the MBD1 gene may relate to autism. The potential association of the high-polymorphic gene variants with autism needs to be studied further. Furthermore, these polymorphisms are useful for linkage analysis.
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Transtorno Autístico/genética , Proteínas de Ligação a DNA/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Ilhas de CpG/genética , Análise Mutacional de DNA , Primers do DNA , Feminino , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Homologia de SequênciaRESUMO
Administration of hot water extracts of a herbal formula containing Ganoderma lucidum, WTMCGEPP (Wisteria floribunda 0.38, Trapa natans 0.38, Miristica agrans 0.38, Coix lachryma-jobi 0.75, cultivated Ganoderma lucidum 0.75, Elfuinga applanata 0.38, tissue cultured Panax ginseng 0.3, and Punica granatum 0.38: numerals designate dry weight gram/dose), decreased herpes zoster pain for five Japanese patients suffering from shingles. Pain relief started within a few days of intake and was almost complete within 10 days. Two acute herpes zoster with manifestations including trigeminal nerve ophthalmia (both 74 years old), lower body zoster (70 years old), herpes zoster oticus (17 years old), and leg herpes (28 years old), responded quickly to treatment and no patient developed post-herpetic neuralgia (PHN) after more than one year of follow-up.
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Medicamentos de Ervas Chinesas/administração & dosagem , Herpes Zoster/complicações , Neuralgia/tratamento farmacológico , Neuralgia/virologia , Reishi , Adolescente , Idoso , Endoftalmite/virologia , Feminino , Humanos , Masculino , Otite/virologia , Projetos Piloto , Resultado do TratamentoRESUMO
For measurement of neural activity in the brainstem auditory pathway, the conventional two-dimensional (2D) auditory brainstem response (ABR) does not provide a true response, because the equivalent dipoles originate from the stereoregularity pathway. It is thus necessary to use three-dimensional (3D) ABR to estimate the true response of the brainstem. We recorded 3D ABR in a group of children and adults, and compared the results with those of the conventional 2D ABR. The subjects were 22 children (age range 3-10 years) and 10 adults with no neurological disorders, and three patients: a boy and a girl who had experienced sudden brainstem dysfunction, and a girl who had sudden deafness. 3D ABR was recorded for all subjects, and the results were displayed on a computer screen for off-line analysis using an original 3D ABR analysis program. Four leaf-like vector segments of 3D ABR existed during the first 8 ms after stimulation. Each vector segment corresponded to a peak of the conventional ABR, and showed the original directivity. The amplitudes of waves II and IV of the 3D ABR were significantly larger than those of the conventional ABR. 3D ABR was shown to be superior to the conventional ABR in obtaining absolute amplitude. We were able to clarify the development of brainstem function using 3D ABR. In one patient in whom only one wave was obtained, 3D ABR was able to identify the wave as wave V. These results indicate that ABR is useful both for identifying the kind of wave produced and for suggesting the wave origin.
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Audiometria de Resposta Evocada/métodos , Vias Auditivas/fisiologia , Tronco Encefálico/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Estimulação Acústica , Audiometria de Resposta Evocada/instrumentação , Vias Auditivas/crescimento & desenvolvimento , Tronco Encefálico/crescimento & desenvolvimento , Paralisia Cerebral/fisiopatologia , Criança , Pré-Escolar , Feminino , Lateralidade Funcional/fisiologia , Perda Auditiva Súbita/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , MasculinoRESUMO
OBJECTIVE: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. METHODS: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. RESULTS: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. CONCLUSIONS: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.
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Hemiplegia/genética , Transtornos das Habilidades Motoras/genética , Paralisia Respiratória/genética , ATPase Trocadora de Sódio-Potássio/genética , Estado Epiléptico/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Hemiplegia/complicações , Hemiplegia/fisiopatologia , Heterozigoto , Humanos , Lactente , Masculino , Transtornos das Habilidades Motoras/etiologia , Transtornos das Habilidades Motoras/fisiopatologia , Mutação de Sentido Incorreto/genética , Paralisia Respiratória/etiologia , Paralisia Respiratória/fisiopatologia , Índice de Gravidade de Doença , Estado Epiléptico/etiologia , Estado Epiléptico/fisiopatologia , Adulto JovemRESUMO
AIMS/INTRODUCTION: The safety and efficacy of insulin-to-liraglutide switch in type 2 diabetes has not been studied adequately. Here, we retrospectively characterize clinical parameters that might predict insulin-to-liraglutide treatment switch without termination due to hyperglycemia, and examine the effects of switching the therapies on glycated hemoglobin (HbA1c) and bodyweight in Japanese type 2 diabetes. MATERIALS AND METHODS: Japanese type 2 diabetes patients who underwent the switch of therapy were evaluated for their clinical data including ß-cell function-related indices, such as increment of serum C-peptide during glucagon stimulation test (GST-ΔCPR). HbA1c and bodyweight were analyzed in patients continuing with liraglutide after switching from insulin for 12 weeks. RESULTS: Of 147 patients, 28 failed in the switch due to hyperglycemia, nine failed because of other reasons and 110 continued with liraglutide for the 12-week period. Patients failing in the switch due to hyperglycemia showed longer duration and higher daily insulin dose, as well as lower GST-ΔCPR. Receiver-operating characteristic analysis showed that GST-ΔCPR of 1.34 ng/mL is a cut-off point for insulin-to-liraglutide switch without termination due to hyperglycemia. In patients continuing liraglutide for 12 weeks, the switch significantly reduced HbA1c and bodyweight with no severe hypoglycemia, irrespective of sulfonylurea co-administration, body mass index, duration and total daily insulin dose. The switch also significantly reduced the percentage of body fat and visceral fat areas. CONCLUSIONS: Insulin-to-liraglutide switch can improve glycemic control and reduce bodyweight in Japanese type 2 diabetes patients. However, caution must be taken with the switch in patients with reduced insulin secretory capacity as predicted by GST-ΔCPR.
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Children with ASD often suffer from epilepsy and paroxysmal EEG abnormality. Purposes of this study are the confirmation of incidence of epileptic seizures and EEG abnormalities in children with autism using a high performance digital EEG, to examine the nature of EEG abnormalities such as locus or modality, and to determine if the development of children with ASD, who have experienced developmental delay, improves when their epilepsy has been treated and maintained under control. A total of 1014 autistic children that have been treated and followed-up for more than 3 years at Yasuhara Children's Clinic in Osaka, Japan, were included in this study. Each participant's EEG had been recorded approximately every 6 months under sleep conditions. Epilepsy was diagnosed in 37% (375/1014) of the study participants. Almost all patients diagnosed with epilepsy presented with symptomatic epilepsy. The data showed that the participants with lower IQ had a higher incidence of epileptic seizures. Epileptic EEG discharges occurred in 85.8% (870/1014) of the patients. There was also a very high incidence of spike discharges in participants whose intellectual quotient was very low or low. Epileptic seizure waves most frequently developed from the frontal lobe (65.6%), including the front pole (Fp1 and Fp2), frontal part (F3, F4, F7 and F8) and central part (C3, Cz and C4). The occurrence rate of spike discharges in other locations, including temporal lobe (T3, T4, T5, T6), parietal lobe (P3, Pz, P4), occipital lobe (O1, O2) and multifocal spikes was less than 10%. These results support the notion that there is a relationship between ASD and dysfunction of the mirror neuron system. The management of seizure waves in children diagnosed with ASD may result in improves function and reduction of autistic symptoms.
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Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Eletroencefalografia , Adolescente , Idade de Início , Envelhecimento/fisiologia , Envelhecimento/psicologia , Anticonvulsivantes/uso terapêutico , Síndrome de Asperger/fisiopatologia , Síndrome de Asperger/psicologia , Mapeamento Encefálico , Criança , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Epilepsia/complicações , Epilepsia/fisiopatologia , Feminino , Humanos , Testes de Inteligência , Japão , Masculino , Desempenho Psicomotor/fisiologia , Convulsões/epidemiologia , Sono/fisiologia , Comportamento Social , Ácido Valproico/uso terapêuticoAssuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Herpesvirus Humano 4 , Mononucleose Infecciosa/tratamento farmacológico , Criança , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Herpesvirus Humano 4/efeitos dos fármacos , Humanos , Lactente , Mononucleose Infecciosa/diagnóstico , Japão , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: Diabetic hemichorea-hemiballismus is a rare complication of type 2 diabetes. Here, we report a case with type 1 diabetes, with hemichorea and bilateral dystonia manifested as hyperglycemia-induced involuntary movement. CASE PRESENTATION: A 62-year-old Japanese women with body weight loss of 30 kg during the past year developed symptoms of thirst, polydipsia and polyuria. She also presented with hemichorea and bilateral dystonia for 5 days and extremely high plasma glucose (774 mg/dl), hemoglobin A1c (21.2%) and glycated albumin (100%) with ketosis. Based on the presence of glutamic acid decarboxylase antibodies (18,000 U/ml; normal <1.3 U/ml), low daily urinary excretion of C-peptide (7.8 micro), ketosis and human leucocyte antigen typing DR-4, we diagnosed type 1 diabetes mellitus. We treated the patient with a continuous intravenous regular insulin infusion and medication with haloperidol, and dystonia completely disappeared within 3 days. CONCLUSION: Hyperglycemia-induced involuntary movement is one of the manifestations of dystonia and hemichorea-hemiballism.
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Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1alpha, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1beta and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to gamma-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1beta and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1beta regulated genes.
Assuntos
Polaridade Celular , Cílios/fisiologia , Fator 1-beta Nuclear de Hepatócito/fisiologia , Túbulos Renais Coletores/citologia , Glicoproteínas de Membrana/fisiologia , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Imunoprecipitação , Camundongos , Camundongos Transgênicos , RNA Interferente PequenoRESUMO
Hyperglycemia-induced overproduction of mitochondrial reactive oxygen species has emerged as a major player in diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane 44 (TIM44) was identified by upregulation in diabetic mouse kidneys. TIM44 functions as a membrane anchor of mitochondrial heat-shock protein 70 (mtHsp70) to TIM23 complex and is involved in the import of mitochondria-targeted preproteins into mitochondrial matrix. The process is dependent on inner membrane potential and ATP hydrolysis on ATPase domain of mitochondrial heat-shock protein 70. Hemagglutination virus of Japan-envelope vector that carries pcDNA3.1 plasmid that contains the full-length cDNA of TIM44 and control plasmid were injected weekly into the tail vein of uninephrectomized streptozotocin-induced diabetic CD-1 mice. The gene delivery alleviated proteinuria and renal hypertrophy at 8 wk after the injection, inhibited renal cell proliferation and apoptosis, and suppressed superoxide production. In vitro experiments, using human proximal tubular (HK2) cells, revealed that the gene delivery of TIM44 reversed high glucose-induced metabolic and cellular abnormalities such as enhanced reactive oxygen species production, increased ATP contents, alterations in inner membrane potential, increased cell proliferation, and apoptosis. Transfection with siRNA and expressing vector of TIM44 revealed that TIM44 facilitates import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase into mitochondria. The gene delivery of TIM44 therefore seems to be beneficial for the maintenance of mitochondrial function and is a novel therapeutic approach for diabetic nephropathy.