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1.
Sci Adv ; 6(51)2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33328224

RESUMEN

The assortment of cellular microRNAs ("microRNAome") is a vital readout of cellular homeostasis, but the mechanisms that regulate the microRNAome are poorly understood. The microRNAome of glioblastoma is substantially down-regulated in comparison to the normal brain. Here, we find malfunction of the posttranscriptional maturation of the glioblastoma microRNAome and link it to aberrant nuclear localization of DICER, the major enzymatic complex responsible for microRNA maturation. Analysis of DICER's nuclear interactome reveals the presence of an RNA binding protein, RBM3, and of a circular RNA, circ2082, within the complex. Targeting of this complex by knockdown of circ2082 results in the restoration of cytosolic localization of DICER and widespread derepression of the microRNAome, leading to transcriptome-wide rearrangements that mitigate the tumorigenicity of glioblastoma cells in vitro and in vivo with correlation to favorable outcomes in patients with glioblastoma. These findings uncover the mechanistic foundation of microRNAome deregulation in malignant cells.


Asunto(s)
Glioblastoma , MicroARNs , Glioblastoma/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular , Proteínas de Unión al ARN/genética
2.
J Extracell Vesicles ; 7(1): 1490144, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30034643

RESUMEN

We have previously uncovered the impact of oncogenic and differentiation processes on extracellular vesicles (EVs) in cancer. This is of interested in the context of glioma stem cells (GSC) that are responsible for recurrent nature of glioblastoma multiforme (GBM), while retaining the potential to undergo differentiation and self renewal.  GSCs reside in vascular niches where they interact with endothelial cells through a number of mediators including bioactive cargo of EVs. GSCs can be classified as proneural (PN) or mesenchymal (MES) subtypes on the basis of their gene expression profiles and distinct biological characteristics. In the present study we investigated how GSC diversity and differentiation programmes influence their EV-mediated communication potentials. Indeed, molecular subtypes of GBMs and GSCs differ with respect to their expression of EV-related genes (vesiculome) and GSCs with PN or MES phenotypes produce EVs with markedly different characteristics, marker profiles, proteomes and endothelial stimulating activities. For example, while EVs of PN GSC are largely devoid of exosomal markers their counterparts from MES GSCs express ample CD9, CD63 and CD81 tetraspanins. In both GSC subtypes serum-induced differentiation results in profound, but distinct changes of cellular phenotypes including the enhanced EV production, reconfiguration of their proteomes and the related functional pathways. Notably, the EV uptake was a function of both subtype and differentiation state of donor cells. Thus, while, EVs produced by differentiated MES GSCs were internalized less efficiently than those from undifferentiated cells they exhibited an increased stimulatory potential for human brain endothelial cells. Such stimulating activity was also observed for EVs derived from differentiated PN GSCs, despite their even weaker uptake by endothelial cells. These findings suggest that the role of EVs as biological mediators and biomarkers in GBM may depend on the molecular subtype and functional state of donor cancer cells, including cancer stem cells. Abbreviations: CryoTEM: cryo-transmission electron microscopy; DIFF: differentiated GSCs; EGF: epidermal growth factor; DUC: differential ultracentrifugation; EV: extracellular vesicle; FGF: fibroblast growth factor; GBM: glioblastoma multiforme; GFAP: glial fibrillary acidic protein; GO: gene ontology; GSC: glioma stem cells; HBEC-5i: human brain endothelial cells; MES: mesenchymal cells; MTS - [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; PMT1: proneural-to-mesenchyman transition cell line 1; PN: proneural cells; TEM: transmission electron microscopy; WB: western blotting.

3.
Oncogene ; 35(43): 5641-5652, 2016 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-27041571

RESUMEN

Gliomas are highly malignant brain tumors that are highly invasive and resistant to conventional therapy. Receptor tyrosine kinases (RTKs) such as PDGFRα (platelet-derived growth factor receptor-α), which show frequent aberrant activation in gliomas, are associated with a process of epithelial-mesenchymal transition (EMT), a cellular alteration that confers a more invasive and drug-resistant phenotype. Although this phenomenon is well documented in human cancers, the processes by which RTKs including PDGFRα mediate EMT are largely unknown. Here, we report that SHP-2 (encoded by PTPN11) upregulates an EMT inducer, ZEB1, to mediate PDGFRα-driven glioma EMT, invasion and growth in glioma cell lines and patient-derived glioma stem cells (GSCs) using cell culture and orthotopic xenograft models. ZEB1 and activated PDGFRα were coexpressed in invasive regions of mouse glioma xenografts and clinical glioma specimens. Glioma patients with high levels of both phospho-PDGFRα (p-PDGFRα) and ZEB1 had significantly shorter overall survival compared with those with low expression of p-PDGFRα and ZEB1. Knockdown of ZEB1 inhibited PDGFA/PDGFRα-stimulated glioma EMT, tumor growth and invasion in glioma cell lines and patient-derived GSCs. PDGFRα mutant deficient of SHP2 binding (PDGFRα-F720) or phosphoinositide 3-kinase (PI3K) binding (PDGFRα-F731/42), knockdown of SHP2 or treatments of pharmacological inhibitor for PDGFRα-signaling effectors attenuated PDGFA/PDGFRα-stimulated ZEB1 expression, cell migration and GSC proliferation. Importantly, SHP-2 acts together with PI3K/AKT to regulate a ZEB1-miR-200 feedback loop in PDGFRα-driven gliomas. Taken together, our findings uncover a new pathway in which ZEB1 functions as a key regulator for PDGFRα-driven glioma EMT, invasiveness and growth, suggesting that ZEB1 is a promising therapeutic target for treating gliomas with high PDGFRα activation.


Asunto(s)
Transición Epitelial-Mesenquimal , Glioma/metabolismo , Glioma/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Expresión Génica , Glioma/genética , Humanos , Ratones , MicroARNs/genética , Modelos Biológicos , Invasividad Neoplásica , Células Madre Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal , Ensayo de Tumor de Célula Madre , Regulación hacia Arriba
4.
Cell Death Differ ; 22(9): 1517-25, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25721045

RESUMEN

Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/patología , Glioblastoma/irrigación sanguínea , Glioblastoma/patología , Proteínas con Dominio LIM/biosíntesis , Proteínas con Dominio LIM/genética , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Animales , Apoptosis/fisiología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo
5.
Oncogene ; 34(29): 3770-9, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25241898

RESUMEN

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.


Asunto(s)
Neoplasias Cerebelosas/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Inhibidoras de la Apoptosis/deficiencia , Meduloblastoma/metabolismo , Proteínas Represoras/deficiencia , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Compuestos de Bifenilo/farmacología , Western Blotting , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , Quimioradioterapia , Niño , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Imidazoles/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/genética , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Antígeno Ki-67/metabolismo , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones Desnudos , Ratones SCID , Microscopía Confocal , Naftoquinonas/farmacología , Piridinas/farmacología , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Survivin , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Exp Mol Pathol ; 97(3): 484-91, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25303899

RESUMEN

Neuronal ceroid lipofuscinosis (NCL) diseases consist of a group of genetically inherited neurodegenerative disorders that share common symptoms such as seizures, psychomotor retardation, blindness, and premature death. Although gene defects behind the NCL diseases are well characterized, very little is known how these defects affect normal development of the brain and cause the pathology of the disease. To obtain understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN2, CLN3 and CLN5 genes was investigated in developing mouse brain. The relationship between the expression pattern and the developmental stage of the brain showed that these genes are co-expressed spatially and temporally during brain development. Throughout the development strong expression of the three mRNAs was detected in germinal epithelium and in ventricle regions, hippocampus and cerebellum, all representing regions that are known to be associated with the formation of new neurons. More specifically, RT-PCR studies on developing mouse cortices revealed that the CLN genes were temporally co-expressed in the neural progenitor cells together with known stem cell markers. This suggested that CLN2, CLN3 and CLN5 genes may play an important role in early embryonal neurogenesis.


Asunto(s)
Aminopeptidasas/biosíntesis , Encéfalo/embriología , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Chaperonas Moleculares/biosíntesis , Células-Madre Neurales/metabolismo , Serina Proteasas/biosíntesis , Animales , Encéfalo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Inmunohistoquímica , Hibridación in Situ , Proteínas de Membrana de los Lisosomas , Ratones , Ratones Endogámicos C57BL , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcriptoma , Tripeptidil Peptidasa 1
7.
Acta Neurol Scand ; 128(6): 386-90, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23802939

RESUMEN

OBJECTIVES: Creatinine (Cr) as a marker of renal function has limited value in amyotrophic lateral sclerosis (ALS) because patients with ALS have reduced muscle mass. Thus, there is a need for alternative methods of assessing renal function. Cystatin C (CysC), which is unaffected by muscle mass, is potentially an ideal biomarker of nephrotoxicity in ALS; however, its utility requires validation. MATERIAL AND METHODS: One hundred and six subjects were recruited for the study: 76 ALS patients and 30 healthy controls. We compared the Cr-based estimated glomerular filtration rate (eGFR) with the CysC-based eGFR in the ALS patients and healthy controls. The results were further analysed according to the severity of ALS in the patients. RESULTS: The mean Cr-based eGFRs were 257.2 ± 383.1 ml/min/1.73 m(2) in the ALS group and 98.1 ± 34.9 in the control group; however, the mean CysC-based eGFRs were not significantly different between both groups. Thus, the Cr-based eGFR in the ALS group was markedly higher than any of the other values. Although serum CysC levels did not correlate with the severity of ALS according to the ALS Functional Rating Scale-Revised, strong simple correlations were observed between serum Cr levels and the severity of ALS (correlation coefficient = 0.734, P < 0.001). CONCLUSIONS: This study demonstrates the potential usefulness of CysC as a biomarker of renal function in ALS patients. Furthermore, its applicability could be extended to other neuromuscular diseases.


Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Cistatina C/sangre , Enfermedades Renales , Anciano , Esclerosis Amiotrófica Lateral/sangre , Creatinina/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/diagnóstico , Enfermedades Renales/etiología , Modelos Lineales , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
8.
J Viral Hepat ; 18(4): 280-6, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20367792

RESUMEN

Mutations in two regions of hepatitis C virus (HCV) have been implicated in influencing response to interferon (IFN) therapy. Substitutions in the NS5A region of HCV have been associated with response to IFN therapy, and this region has been known as the IFN sensitivity-determining region (ISDR). The mutations in the core region of HCV have also been reported to predict IFN response. The aim of this study was to investigate whether amino acid substitutions in the core region and ISDR among patients with HCV genotype 1b affect the response to IFN therapy. A total of 213 patients who completed IFN treatment were randomly selected. All patients received pegylated-IFN-alpha 2b once each week, plus oral ribavirin daily for 48 weeks. Of the 213 patients, 117 (54.9%) showed early virologic response (EVR), with HCV-negativity, at 12 weeks. Factors related to EVR on multivariate analysis were non-Gln70 and Leu91 in the core region, and ISDR mutant-type. One hundred and two (47.9%) showed a sustained virologic response (SVR). SVR occurred more frequently in patients without Gln70 (55.4%) than in those with Gln70 (21.3%) (P < 0.0001). SVR was achieved in 43.6% of patients with wild-type ISDR and 62.5% of patients with mutant-type (P = 0.0227). Of the 34 patients who simultaneously had non-Gln70 and mutant-type ISDR, 26 (76.5%) achieved SVR. Factors related to SVR on multivariate analysis were non-Gln70 and ISDR mutant-type. In conclusion, amino acid substitutions in the core region and ISDR were useful for predicting the response to IFN in patients with HCV genotype 1b.


Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Mutación Missense , Polietilenglicoles/administración & dosificación , Ribavirina/administración & dosificación , Adulto , Anciano , Sustitución de Aminoácidos , Quimioterapia Combinada , Femenino , Genotipo , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Recombinantes , Resultado del Tratamiento , Proteínas del Núcleo Viral/genética , Proteínas no Estructurales Virales/genética
9.
J Neurol Sci ; 264(1-2): 73-6, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-17716690

RESUMEN

The authors describe the four patients in the first known Belgian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). A novel homozygous missense mutation, NM_014363.3: c.3491T>A in exon 9, of the SACS gene was identified in the present family, which results in an original amino acid of methionine to lysine substitution at amino acid residue 1164 (p.M1164K). Although the cardinal clinical features, i.e., spastic ataxia with peripheral neuropathy, in our patients were similar to those in Quebec patients, our patients exhibited some atypical clinical features, e.g., teenage-onset and absence of retinal hypermyelination. The present family is from Wallonia, and there could be shared ethnicity with the families of Charlevoix-Saguenay.


Asunto(s)
Ataxia/genética , Trastornos de los Cromosomas/genética , Genes Recesivos/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Choque Térmico/genética , Mutación/genética , Adulto , Edad de Inicio , Sustitución de Aminoácidos/genética , Ataxia/metabolismo , Ataxia/fisiopatología , Bélgica/etnología , Trastornos de los Cromosomas/metabolismo , Trastornos de los Cromosomas/fisiopatología , Análisis Mutacional de ADN , Femenino , Marcadores Genéticos/genética , Pruebas Genéticas , Genotipo , Humanos , Masculino , Mutación Missense/genética , Linaje , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Quebec/etnología , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Degeneración Retiniana/fisiopatología , Síndrome
10.
Acta Neurol Scand ; 116(5): 340-4, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17922728

RESUMEN

OBJECTIVES - We investigated the regional cerebral blood flow in amyotrophic lateral sclerosis with dementia (ALS-D) patients, using single photon emission computed tomography (SPECT). MATERIALS AND METHODS - The (123)I-IMP SPECT data for 5 ALS-D and 16 ALS patients were analyzed using three-dimensional stereotactic surface projection (3D-SSP). RESULTS - 3D-SSP demonstrated marked prefrontal hypoperfusion in all the five ALS-D cases and significant bilateral prefrontal hypoperfusion in group comparisons. CONCLUSIONS - This study revealed prefrontal hypoperfusion in ALS-D cases to be an obvious abnormality with scientific objectivity.


Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Demencia/complicaciones , Demencia/diagnóstico por imagen , Lóbulo Frontal/irrigación sanguínea , Lóbulo Frontal/diagnóstico por imagen , Anciano , Esclerosis Amiotrófica Lateral/fisiopatología , Mapeo Encefálico , Demencia/fisiopatología , Femenino , Lóbulo Frontal/fisiopatología , Lateralidad Funcional , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Corteza Motora/irrigación sanguínea , Corteza Motora/diagnóstico por imagen , Corteza Motora/fisiopatología , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Técnicas Estereotáxicas , Tomografía Computarizada de Emisión de Fotón Único
12.
Diabet Med ; 23(10): 1136-9, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16978380

RESUMEN

BACKGROUND: Aceruloplasminaemia is an autosomal recessive disorder caused by specific mutations in the ceruloplasmin gene. Aceruloplasminaemia is clinically characterized by diabetes mellitus, pigment degeneration of the retina, and neurological abnormalities, such as cerebellar ataxia, extrapyramidal signs, and dementia. We present a patient with aceruloplasminaemia who, until progressive neurological abnormalities were noticed, had been treated for more than 30 years as having Type 1 diabetes mellitus requiring multiple insulin injection therapy. CASE REPORT: The patient was a 58-year-old man. At the age of 23 years, he developed diabetes that required multiple insulin injection therapy. At the age of 39 years, he was commenced on continuous subcutaneous insulin infusion (CSII) therapy. Despite CSII therapy, the patient's blood glucose levels were poorly controlled (HbA(1c), approximately 9.5%). He was diagnosed as having aceruloplasminaemia at 58 years of age when he presented with progressive cerebellar ataxia, extrapyramidal signs of recent onset and pigment degeneration of the retina. CONCLUSIONS: It is possible that some diabetic patients with aceruloplasminaemia are mistakenly diagnosed as having Type 1 diabetes mellitus, as they have reduced insulin secretion and develop diabetes at a younger age, before neurological abnormalities associated with aceruloplasminaemia are apparent. Therefore, aceruloplasminaemia should be considered in patients with insulin-dependent diabetes mellitus who develop progressive neurological abnormalities of unknown aetiology along with a microcytic hypochromic anaemia and retinal degeneration.


Asunto(s)
Trastornos de las Proteínas Sanguíneas/tratamiento farmacológico , Ceruloplasmina/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/genética , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Trastornos de las Proteínas Sanguíneas/genética , Ceruloplasmina/genética , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
13.
Infection ; 34(4): 201-7, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16896578

RESUMEN

BACKGROUND: Recently genotype A which is rare in the patients in chronic hepatitis B (CHB) was frequently noted in patients with acute hepatitis B (AHB). To investigate their clinical and virological features, we studied the AHB patients in the past 5 years. PATIENTS AND METHODS: 98 patients with AHB and 80 patients with CHB admitted to our hospital between 1998 and 2003 were studied. RESULTS: Genotype A was not found in CHB but was frequently noted in AHB (p < 0.001). Comparison of the clinical features of acute hepatitis between the two major genotypes, A and C, homosexual and heterosexual with multiple partners were frequently seen among genotype A patients (p < 0.001). On the other hand, infection from steady partner showed a tendency to be more frequent in genotype C (p = 0.065). In genotype A, the levels of HBVDNA on admission was higher (p = 0.007) and AHB has significantly more frequently progress to chronic infection than in genotype C (p = 0.028). Phylogenetic analysis of genotype A revealed that almost all strains from homosexual men belonged not to the African type A1 but to the Western type A2. CONCLUSION: Genotype A has increased recently among AHB in Japan. This fact may correlate to promiscuous intercourse in high risk group. Prophylactic efforts should be considered to prevent the prevailing of genotype A.


Asunto(s)
Virus de la Hepatitis B/genética , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/transmisión , Hepatitis B Crónica/virología , Hepatitis B/transmisión , Hepatitis B/virología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Femenino , Genotipo , Hepatitis B/epidemiología , Hepatitis B Crónica/epidemiología , Homosexualidad Masculina , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Japón/epidemiología , Masculino , Persona de Mediana Edad , Filogenia
14.
J Neurol Sci ; 247(2): 180-6, 2006 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-16780885

RESUMEN

The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.


Asunto(s)
Ataxia Cerebelosa/genética , Cromosomas Humanos Par 16 , Genes Dominantes , Factores de Intercambio de Guanina Nucleótido/genética , Espectrina/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Ataxia Cerebelosa/patología , Análisis Mutacional de ADN/métodos , Salud de la Familia , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos
15.
Acta Neurochir Suppl ; 96: 239-43, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16671462

RESUMEN

We investigated, at both light and ultrastructural levels, the fate of swollen astrocytes and remodeling of neurites connected to disseminated, dying neurons in the ischemic neocortical penumbra. Specimens from left cerebral cortex were cut coronally at the infundibulum and observed by light and electron microscopy. We measured synapses and spines, and the thickness of neuritic trunks in the neuropil on electron microscopy photos. We also determined percent volume of axon terminals and spines by Weibel's point-counting method. Astrocytic swelling gradually subsided from day 4 after the ischemic insult, with increases in cytoplasmic glial fibrils and GFAP-positive astrocytes. Disseminated dying electron-dense neurons were fragmented by invading astrocytic cell processes and accumulated as granular pieces. The number of synapses and spines and total percent volume of axon terminals and spines decreased with an increasing sparsity of synaptic vesicles until day 4. One to 12 weeks after the ischemic insult, these values increased to or exceeded control values, and sprouting and increased synaptic vesicles were seen. Axons that had been attached to the dying neurons appeared to have shifted their connections to the spines and the neurites of the surviving neurons, increasing their thickness. Astrocytic restitution and neuronal remodeling processes started at 4 days continuing until 12 weeks after ischemic insult.


Asunto(s)
Astrocitos/ultraestructura , Axones/ultraestructura , Edema Encefálico/patología , Isquemia Encefálica/patología , Corteza Cerebral/ultraestructura , Neuritas/ultraestructura , Daño por Reperfusión/patología , Animales , Apoptosis , Edema Encefálico/etiología , Isquemia Encefálica/complicaciones , Células Cultivadas , Corteza Cerebral/irrigación sanguínea , Gerbillinae , Regeneración Nerviosa , Neuronas/ultraestructura , Daño por Reperfusión/complicaciones
16.
Neurology ; 66(7): 1103-4, 2006 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-16606928

RESUMEN

The authors describe a Japanese autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patient with a compound heterozygous mutation (32627-32636delACACTGTTAC and 31760delT) in a new exon of the SACS gene. The new exons upstream of the gigantic one should be analyzed when a case is clinically compatible with ARSACS, even without any mutation in the gigantic exon.


Asunto(s)
Ataxia/genética , Proteínas de Choque Térmico/genética , Adulto , Edad de Inicio , ADN/sangre , ADN/genética , ADN/aislamiento & purificación , Disartria/genética , Exones , Femenino , Genotipo , Humanos
17.
J Neurosci ; 25(46): 10773-85, 2005 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-16291951

RESUMEN

We performed genomic subtraction coupled to microarray-based gene expression profiling and identified the PDZ (postsynaptic density-95/Discs large/zona occludens-1)-binding kinase/T-LAK (lymphokine-activated killer T cell) cell originating protein kinase (PBK/TOPK) as a gene highly enriched in neural stem cell cultures. Previous studies have identified PBK/TOPK as a mitogen-activated protein kinase (MAPK) kinase that phosphorylated P38 MAPK but with no known expression or function in the nervous system. First, using a novel, bioinformatics-based approach to assess cross-correlation in large microarray datasets, we generated the hypothesis of a cell-cycle-related role for PBK/TOPK in neural cells. We then demonstrated that both PBK/TOPK and P38 are activated in a cell-cycle-dependent manner in neuronal progenitor cells in vitro, and inhibition of this pathway disrupts progenitor proliferation and self-renewal, a core feature of progenitors. In vivo, PBK/TOPK is expressed in rapidly proliferating cells in the adult subependymal zone (SEZ) and early postnatal cerebellar external granular layer. Using an approach based on transgenically targeted ablation and lineage tracing in mice, we show that PBK/TOPK-positive cells in the SEZ are GFAP negative but arise from GFAP-positive neural stem cells during adult neurogenesis. Furthermore, ablation of the adult stem cell population leads to concomitant loss of PBK/TOPK-positive cells in the SEZ. Together, these studies demonstrate that PBK/TOPK is a marker for transiently amplifying neural progenitors in the SEZ. Additionally, they suggest that PBK/TOPK plays an important role in these progenitors, and further implicates the P38 MAPK pathway in general, as an important regulator of progenitor proliferation and self-renewal.


Asunto(s)
Proliferación Celular , Sistema de Señalización de MAP Quinasas/fisiología , Neuronas/citología , Neuronas/enzimología , Proteínas Serina-Treonina Quinasas/fisiología , Células Madre/citología , Células Madre/enzimología , Animales , Bovinos , Células Cultivadas , Pollos , Perros , Humanos , Ratones , Ratones Transgénicos , Quinasas de Proteína Quinasa Activadas por Mitógenos , Oncorhynchus mykiss , Pan troglodytes , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Ratas , Tetraodontiformes , Xenopus laevis , Pez Cebra , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología
19.
Neurology ; 62(1): 107-9, 2004 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-14718708

RESUMEN

The authors describe two patients in a Japanese family with autosomal recessive spastic ataxia of Charlevoix-Saguenay. They presented early onset spastic ataxia, sensorimotor neuropathy, nystagmus, slurred speech, and hypermyelinated retinal nerve fibers. The authors identified a homozygous missense mutation (T7492C) in the SACS gene, which resulted in the substitution of arginine for tryptophan at amino acid residue 2498 (W2498R).


Asunto(s)
Ataxia/genética , Proteínas de Choque Térmico/genética , Espasticidad Muscular/genética , Mutación Missense , Adulto , Ataxia/complicaciones , Ataxia/diagnóstico , Cerebelo/patología , Análisis Mutacional de ADN , Disartria/diagnóstico , Disartria/etiología , Disartria/genética , Femenino , Trastornos Neurológicos de la Marcha/diagnóstico , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/genética , Genes Recesivos , Homocigoto , Humanos , Japón , Imagen por Resonancia Magnética , Masculino , Espasticidad Muscular/complicaciones , Espasticidad Muscular/diagnóstico , Fibras Nerviosas Mielínicas/patología , Conducción Nerviosa , Pruebas Neuropsicológicas , Retina/patología , Hermanos , Nervio Sural/patología , Nervio Sural/fisiopatología
20.
Acta Neurochir Suppl ; 86: 131-5, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-14753420

RESUMEN

When a threshold amount of temporary ischemic insult to induce focal infarction was given to the unilateral cerebral hemisphere of gerbils, a small focal infarct surrounded by a wide penumbra developed in the rostral portion of the cerebral cortex. During the first 5 hours following recirculation, whole astrocytic cell bodies and processes in the ischemic hemisphere were swollen, with an increase in the number of glycogen granules and in number and size of mitochondria. This swelling was an active reaction of astrocytes for neuronal protection, scavenging potassium, glutamate, and other neuronal metabolic products, and for generating fuels for neurons (cyto-reactive edema). This reactive astrocytic swelling continued in the penumbra, but some dead neurons were found disseminated among the surviving neurons. Whereas, at 12 approximately 48 hours, focal infarction developed in which all cell membranes lost their Gibbs-Donnan's equilibrium due to energetic failure of their membranous Na+/K+ ATPase. This is the cytotoxic edema (cyto-necrotic edema). In the infarct focus, when pericapillary astrocytic end-feet were damaged, the capillary BBB was broken; and thus vasogenic edema was superimposed on the cytotoxic edema.


Asunto(s)
Edema Encefálico/complicaciones , Isquemia Encefálica/complicaciones , Infarto Cerebral/etiología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Edema Encefálico/patología , Isquemia Encefálica/patología , Infarto Cerebral/metabolismo , Infarto Cerebral/patología , Colorantes/farmacocinética , Azul de Evans/farmacocinética , Gerbillinae , Microscopía Electrónica , Necrosis , Factores de Tiempo
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