RESUMEN
Sleep disorders are very common in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Several parameters of polysomnography seem to correlate with cognitive scores and amyloid biomarkers in the different stages of AD. However, there is limited evidence for the relationship between self-reported sleep impairment and disease biomarkers. In this study, we assessed the relationship between self-reported sleep complaints, with the Pittsburgh Sleep Quality Index, and both cognitive function and cerebrospinal fluid biomarkers in 70 patients with MCI and 78 patients with AD. Sleep duration and daytime dysfunction were higher in AD. Daytime dysfunction had a negative correlation with cognitive scores (Mini-Mental-State Examination and Montreal Cognitive Assessment) and with amyloid-beta1-42 protein, and a positive correlation with total tau protein. However, daytime dysfunction was an independent predictor only of t-tau values (F=57.162; 95% CI: [18.118; 96.207], P=0.004). These findings support a relationship between daytime dysfunction, cognitive scores and neurodegeneration, further expanding recent findings that it may signal a risk of dementia.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Calidad del Sueño , Autoinforme , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Proteínas tau , Péptidos beta-Amiloides/líquido cefalorraquídeo , BiomarcadoresRESUMEN
OBJECTIVE: To detect and graduate endolymphatic hydrops or endolymphatic space dilations in patients with suspected Meniere's disease or immune-mediated inner ear disease by magnetic resonance imaging. MATERIAL AND METHODS: A prospective study was performed including all the patients with clinical suspicion of Meniere's disease or immune-mediated inner ear disease treated at the Otolaryngology department during a one year period. In all cases, magnetic resonance imaging (MRI) was performed in a 3T scanner. IR sequence was performed after 24 to 28h prior intratimpanic injection of gadolinium on both ears. Two neurorradiologist graduated endolymphatic space volume as agreed on normal, moderate and significant in the obtained images. RESULTS: The presence of hydrops was documented by MRI in six patients with definite or probable Meniere's disease. In two of the four cases without vertigo hydrops was not demonstrated. In the other two cases with a high clinical suspicion of immune-mediated disease but with negative autoimmune tests hydrops was proved. There was only disagreement on cochlear hydrops presence on two patients. CONCLUSION: The detection of endolymphatic hydrops in patients with definite or probable Meniere's disease served to confirm the final diagnosis. Moreover, hydrops was detected in patients with suspected immune-mediated inner ear disease, which could have an impact on the diagnosis and treatment of these patients. Therefore, we suggest that this test could be included for the diagnosis of these inner ear diseases.
Asunto(s)
Hidropesía Endolinfática/diagnóstico por imagen , Gadolinio/administración & dosificación , Imagen por Resonancia Magnética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Inyección Intratimpánica , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfused ex vivo for 90 min with maraviroc (600 ng/ml) either in the maternal-to-fetal (n = 10 placentas) or fetal-to-maternal (n = 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ± 3.0 and 0.26 ± 0.07, respectively, whereas the mean CLI was 0.52 ± 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and ABCC2, ABCC10, and ABCC11 placental gene expression levels (P < 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by in vivo data obtained from paired maternal and cord blood samples.
Asunto(s)
Ciclohexanos/metabolismo , Expresión Génica , Inhibidores de Fusión de VIH/metabolismo , Modelos Biológicos , Placenta/metabolismo , Triazoles/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Cromatografía Liquida , Ciclohexanos/farmacología , Cámaras de Difusión de Cultivos , Femenino , Feto , Inhibidores de Fusión de VIH/farmacología , Humanos , Cinética , Maraviroc , Intercambio Materno-Fetal , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Técnicas de Cultivo de Órganos , Perfusión , Placenta/efectos de los fármacos , Embarazo , Espectrometría de Masas en Tándem , Triazoles/farmacologíaRESUMEN
Human herpesvirus-8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus, encodes a protein, referred to as HHV8-Vcyc, with sequence similarity to human G1 cyclins, in particular of the D type. HHV8-Vcyc is expressed in Kaposi's sarcoma and functional analysis suggests that it can activate cyclin-dependent kinases (cdk) and thereby trigger inactivation of the retinoblastoma protein (pRb), indicating that HHV8-Vcyc may contribute to the oncogenic potential of HHV-8. We show here that HHV8-Vcyc can activate transcription of the human cyclin A gene in quiescent cells, a property shared with known transforming oncogenes. Transcriptional activation by HHV8-Vcyc depends on an E2F-binding site in the cyclin A promoter, and cdk6 kinase activity is required. The ability of HHV8-Vcyc to activate cyclin A gene expression is shared by D-type cyclins and cyclin E. Unlike D-type cyclins, HHV8-Vcyc is unable to trigger phosphorylation of the pRb-related protein p107 and fails to induce dissociation of p107 from E2F. Unlike cyclin E, HHV8-Vcyc fails to interact physically with E2F complexes on the cyclin A promoter. These results provide additional evidence for the notion that the HHV-8-encoded cyclin differs in several properties from cellular G1 cyclins.
Asunto(s)
Ciclina A/genética , Quinasas Ciclina-Dependientes , Ciclinas/fisiología , Herpesvirus Humano 8/fisiología , Activación Transcripcional , Proteínas Virales/fisiología , Células 3T3 , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Ciclina A/metabolismo , Quinasa 6 Dependiente de la Ciclina , Ciclinas/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Factor de Transcripción E2F4 , Herpesvirus Humano 8/genética , Humanos , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilación , Pruebas de Precipitina , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Proteína p107 Similar a la del Retinoblastoma , Homología de Secuencia de Aminoácido , Factor de Transcripción DP1 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Proteínas Virales/genéticaRESUMEN
The p16/MTS1/CDKN2 gene on human chromosome band 9p21 encodes two unrelated proteins: p16INK4a, a specific inhibitor of the cyclin D-dependent kinases CKD4 and CDK6, and the structurally unrelated p19ARF protein that arrests cell growth in G1/S and also in G2/M. By use of polyclonal antibodies, the human p19ARF (hp19ARF) protein has been identified in the nucleus of various cells including normal cultured fibroblasts. The level of this protein did not fluctuate throughout the cell cycle and was more elevated in fibroblasts with limited or arrested growth, suggesting that p19ARF accumulated in presenescent or senescent cells. Interestingly, hp19ARF was not detected in several hemopoietic tumor cell lines (mainly of B-type lymphoid origin) that expressed abundant amounts of the p16beta transcript. This finding indicates that in certain tumors, the expression of hp19ARF RNA and protein may be uncoupled. Furthermore, it suggests that disruption of a translational mechanism may be involved in the inactivation of hp19ARF.
Asunto(s)
Cromosomas Humanos Par 9/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Proteínas/análisis , ARN Mensajero/biosíntesis , Animales , Linfoma de Burkitt/patología , Células COS , Senescencia Celular , Niño , Fibroblastos/metabolismo , Genes , Humanos , Leucemia/patología , Leucemia Eritroblástica Aguda/patología , Masculino , Megacariocitos/metabolismo , Ratones , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Biosíntesis de Proteínas , Proteínas/genética , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Transfección , Células Tumorales Cultivadas , Proteína p14ARF Supresora de TumorRESUMEN
We have reported previously a preliminary study of a t(9;14)(p21-22; q11) in B-cell acute lymphoblastic leukemia. This translocation had rearranged the TCRA/D locus on chromosome band 14q11 and the locus encoding the tumor suppressor gene P16INK4/MTS1 (P16) on band 9p21 (D. Duro et al., Oncogene, 11: 21-29, 1995). In the present report, the breakpoints were precisely localized on each chromosome partner. On the 14q- derivative, the sequence derived from chromosome 9 was interrupted at 1.0 kb upstream of the first exon of P16, close to a consensus recombination heptamer, CACTGTG. In addition, the chromosome 14 breakpoint was localized at the end of the TCRD2 (delta 2) segment, and 22 residues with unknown origin were present at the translocation junction. On the 9p+ derivative, chromosome 9 sequences were in continuity with those displaced onto chromosome 14, and the 14q11 breakpoint was located within TCRJA29 segment. These features are consistent with aberrant activity of the TCR gene recombinase complex. Although all three coding exons of P16 were displaced onto the chromosome 14q-derivative, no P16 transcript was detected in the leukemic cells. Because the region spanning the P16 exon 1 was not inactivated by methylation and because the other P16 allele was deleted, the implication is that the chromosome breakpoint was likely to disrupt regulatory elements involved in the normal expression of the gene. As a whole, then, our results show that translocations affecting band 9p21 can participate to the inactivation of P16, thus justifying a systematic survey of translocations of the 9p21 band in acute lymphoblastic leukemia.
Asunto(s)
Linfoma de Burkitt/genética , Proteínas Portadoras/genética , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 9 , Genes Supresores de Tumor , Translocación Genética , Secuencia de Bases , Médula Ósea/patología , Linfoma de Burkitt/sangre , Linfoma de Burkitt/patología , Niño , Mapeo Cromosómico , Secuencia de Consenso , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Cartilla de ADN , Sondas de ADN , Exones , Humanos , Cariotipificación , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Mapeo RestrictivoRESUMEN
Chromosome band 9p21-22 is frequently altered by nonrandom abnormalities, mainly deletions, in hemopoietic malignancies of the lymphoid lineage. We have analysed a translocation t(9;14)(p21-p22;q11) in a B-cell type acute lymphoblastic leukemia. Location of the 14q11 breakpoint within the TCR-alpha/delta locus allowed the isolation of a fusion transcript composed of a 3' segment containing part of the constant region of the TCR-alpha gene and a 5' segment from chromosome 9, designated 0.18. This 0.18 segment was also part of cDNAs isolated from two tumoral B-cell lines (RPMI-8226, Raji). In both cases, 0.18 was juxtaposed 5' to a sequence corresponding to exons 2 and 3 of the p16INK4/MTS1 gene which is located on band 9p21-22. Unexpectedly, none of the two ATG codons found in 0.18 was in phase with that of the exons 2 and 3 of p16INK4/MTS1. Furthermore, in vitro translation product of a RPMI-8226 cDNA clone generated a product that was not immunoprecipitated by antibodies specific of the C-terminal end of the p16INK4/MTS1 protein. Evidence for similar transcripts in non tumoral lymphoid B cells (unstimulated peripheral blood lymphocytes (PBL) and lymphoblastoid cell lines) were obtained by using amplimers representative of the 0.18 segment and the p16INK4/MTS1 exon 2. Altogether, these data are consistent with the existence of a new type of p16INK4/MTS1 transcript whose significance is discussed.
Asunto(s)
Linfoma de Burkitt/genética , Proteínas Portadoras/genética , Secuencia de Bases , Línea Celular , Niño , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 9 , Clonación Molecular , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Sondas de ADN , ADN Complementario , Reordenamiento Génico de la Cadena alfa de los Receptores de Antígenos de los Linfocitos T , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Genes Supresores de Tumor , Humanos , Masculino , Datos de Secuencia Molecular , ARN Mensajero/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Translocación GenéticaRESUMEN
Human cDNAs encoding Krüppel-type zinc finger domains, designated KOX 1-32, have been cloned from human T lymphocyte cell line libraries. We report here the regional localizations by in situ hybridization of KOX 18 and KOX 25 on chromosome bands 7q21q22. Pulse-field gel electrophoresis (PFGE) analysis showed that these genes are physically located within a DNA fragment of 250 kb. The genes KOX 4 and KOX 9, mapped on chromosome 8q24, were found to be located within a DNA fragment of 450 kb. From the present and previous data, eighteen different KOX genes have been located at least two by two within nine DNA fragments of 200 to 580 kb.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 7 , Genes Homeobox , Proteínas Represoras , Dedos de Zinc/genética , Animales , Cromosomas Humanos Par 8 , ADN Complementario/genética , Proteínas de Unión al ADN/genética , Proteínas de Drosophila , Drosophila melanogaster/genética , Electroforesis en Gel de Campo Pulsado , Evolución Molecular , Humanos , Hibridación in Situ , Factores de Transcripción de Tipo Kruppel , Datos de Secuencia Molecular , Linfocitos T , Factores de Transcripción/genéticaRESUMEN
The chromosome band 9p21-22 is frequently rearranged or deleted in a variety of tumors including hematological malignancies. This supports the notion of a tumor suppressor gene in this chromosome region. Indeed, the p16/MTS1 gene encoding a cyclin-dependent kinase (CDK) inhibitor has been shown to be frequently deleted and/or inactivated by nonsense mutations in a number of tumors. We have examined 98 DNA samples from blood, bone marrow cells and lymph node biopsies of patients with leukemia (ALL and AML) or lymphoma (follicular lymphoma and T-cell lymphoma), using Southern blot hybridization and a p16/MTS1-specific probe. Molecular abnormalities, mainly homozygous deletions, were found principally in ALL (8 out of 22 patients), much less frequently in AML (2/32) and lymphoma (2/32). While these data argue in favor of a large involvement of p16/MTS1 in ALL, AML and lymphomas appear to be less frequently implicated.