Vitiligo Treatment Impact score (VITs): development and validation of a vitiligo burden of treatment questionnaire using the ComPaRe Vitiligo e-cohort.

BACKGROUND: Vitiligo management is challenging and requires long-term adherence of patients who often complain of the burden associated with treatment. OBJECTIVE: To develop and validate a patient reported measurement of the burden of treatment in vitiligo. METHODS: The study was nested within the ComPaRe Vitiligo e-cohort, an online e-cohort of vitiligo patients in France. Items were derived from a literature review and from the qualitative analysis of a survey using open-ended questions of 204 patients with Vitiligo. Construct validity of the resulting instrument was assessed by comparing the instrument's score to the Dermatology Life Quality Index (DLQI), Vitiligo Impact Patient score (VIPs) and Treatment Burden Questionnaire (TBQ) scores. Reliability was assessed by test-retest with 15 ± 10 days of interval between both assessments. RESULTS: In total, 343 adult participants participated in the validation of the Vitiligo Treatment Impact score (VITs). The VITs is a 19-item questionnaire assessing the burden of treatment in patients with vitiligo with results suggesting four domains ('Finding a doctor', 'Phototherapy', 'Topical treatment' and 'Impact on outdoor activities and photoprotection'). The VITs total score was well correlated with the DLQI, VIP and TBQ scores. Agreement between test and retest was good (ICC 0.705, 95% CI 0.491-0.818). CONCLUSIONS: We developed a patient reported measurement of the burden of treatment in vitiligo with good psychometric properties.

XPS investigation of surface reactivity of electrode materials: effect of the transition metal.

The role of the transition metal nature and Al2O3 coating on the surface reactivity of LiCoO2 and LiNi(1/3)Mn(1/3)Co(1/3)O2 (NMC) materials were studied by coupling chemisorption of gaseous probes molecules and X-ray photoelectron (XPS) spectroscopy. The XPS analyses have put in evidence the low reactivity of the LiMO2 materials toward basic gaseous probe (NH3). The reactivity toward SO2 gaseous probe is much larger (roughly more than 10 times) and strongly influenced by the nature of metal. Only one adsorption mode (redox process producing adsorbed sulfate species) was observed at the LiCoO2 surface, while NMC materials exhibit sulfate and sulfite species at the surface. On the basis of XPS analysis of bare materials and previous theoretical work, we propose that the acid-base adsorption mode involving the Ni(2+) cation is responsible for the sulfite species on the NMC surface. After Al2O3 coating, the surface reactivity was clearly decreasing for both LiCoO2 and NMC materials. In addition, for LiCoO2, the coating modifies the surface reactivity with the identification of both sulfate and sulfite species. This result is in line with a change in the adsorption mode from redox toward acid-base after Al/Co substitution. In the case of NMC materials, the coating induced a decrease of the sulfite species content at the surface. This phenomenon can be related to the cation mixing effect in the NMC.

Identificación de genes clave implicados en el síndrome de Down mediante terapia génica / Identification of key genes involved in Down syndrome pathogenesis by gene therapy

La terapia génica nos ofrece la posibilidad de manipular los virus para convertir un agente infeccioso en un vehículo que transporta en su genoma secuencias de DNA con potencial terapéutico. En este trabajo hemos aprovechado la metodología que nos proporciona la terapia génica para desarrollar vectores virales derivados de virus adenoasociados y lentivirus con el objetivo de identificar genes clave (proteínas o microRNA [miRNA]) implicados en las alteraciones cognitivas presentes en el síndrome de Down (SD). Hemos demostrado que en un contexto de trisomía, como es el modelo de ratón Ts65Dn, la normalización de la expresión de Dyrk1A a través de la administración de los virus adenoasociados AAV2/1-shDyrk1A contribuye a restablecer la regulación de moléculas clave en los procesos de memoria y aprendizaje. Ello permite una atenuación de los defectos en plasticidad sináptica y facilita el desarrollo de una estrategia de aprendizaje visuoespacial más eficiente. Estos estudios refuerzan el papel destacado de Dyrk1A en los procesos cognitivos. Por otro lado, la estrategia de control de la expresión de miRNA desarrollada mediante los lentivirus Lv-anti-miR155-802 nos permite proponer a MeCP2 como un gen cuya desregulación en el síndrome de Down puede tener un papel clave en el deterioro cognitivo (AU)

Viruses have evolved ways of encapsulating and delivering their genes into human cells. Gene therapy takes advantage of this capability to manipulate the viral genome and convert an infectious agent into an efficient vector that delivers therapeutic genes. In the current work we have applied gene therapy approaches based on adeno-associated virus and lentivirus delivery to identify candidate genes (protein-coding or miRNAs) involved in the cognitive deficits in Down Syndrome. We show that the hippocampal injection of the adeno-associated virus AAV2/1-shDyrk1A normalized Dyrk1A expression in the trisomic Ts65Dn mice. As a consequence the regulation of key molecular players in memory and learning processes was rescued and mice showed an attenuation of synaptic plasticity defects and improved efficacy in learning strategies. All together these results reinforce the role of Dyrk1A in cognition. On the other hand, with the lentiviral strategydeveloped to specifically inhibit miR-155 and miR-802 (Lv-anti-miR155/802), we were able to show a tight control of the miRNAs target Mecp2 suggesting that the downregulation of MeCP2 in Down syndromecould be a contributing factor to the cognitive defects (AU)

Comparación de dos programas de rehabilitación tras artroplastia total de rodilla / Comparison of two rehabilitation programs following total knee arthroplasty

Objetivo: Comparar los resultados funcionales de dos programas de rehabilitación distintos tras Artroplastia Total de Rodilla (ATR). Material y métodos: Estudio prospectivo de 122 pacientes intervenidos de ATR, valorándolos en el preoperatorio, al 8º día y al 6º mes de la intervención. Al alta hospitalaria, dividimos a los pacientes en 2 grupos según el recorrido articular y la disponibilidad de acudir al tratamiento. El grupo A (40 pacientes) siguieron un programa de rehabilitación domiciliario y el grupo B (82 pacientes) ambulatorio. Se estudió: el dolor mediante la escala visual analógica (EVA), la funcionalidad usando el Hospital Special Surgery (HSS), la independencia para las actividades de la vida diaria mediante el Índice de Barthel, la capacidad de marcha con la Fuctional Ambulatory Clasification (FAC) y la calidad de vida con el cuestionario de salud SF-36. Comparamos los resultados usando el paquete estadístico SPSS 15.0. Resultados: La valoración global mostró un mejoría de: 7,2 a 2,4 en la EVA, 63 a 80,8 en el HSS, 27,9 a 37,2 en el SF36 físico y 43,4 a 46,9 entre la valoración inicial y al sexto mes en todos los pacientes, siendo estas mejorías estadísticamente significativas (p < 0,05). No hay una diferencia significativa en el Índice de Barthel y el FAC. En la comparación entre ambos grupos, no encontramos diferencias significativas en ninguna variable. Conclusiones: La ATR mejora el dolor, la funcionalidad y la calidad de vida en pacientes con gonartrosis con independencia de los dos programas de rehabilitación estudiados tras el alta hospitalaria (AU)

Objective: To compare the functional results obtained with two different rehabilitation programs following total knee arthroplasty (TKA). Material and methods: A retrospective study was made of 122 patients subjected to TKA, with evaluation before surgery, and on day 8 and 6 months after the operation. At discharge, the patients were divided into two groups according to the observed joint trajectory and patient availability for treatment. Group A (40 patients) followed a home rehabilitation program, while group B (82 patients) followed an outpatient rehabilitation program. The following was studied: pain as determined by the visual analog scale (VAS); functionality based on the Hospital Special Surgery (HSS) score; independency for activities of daily living based on the Barthel index; walking capacity according to the Functional Ambulatory Classification (FAC); and quality of life based on the SF 36 questionnaire. The results were compared using the SPSS version 15.0 statistical package. Results: The overall assessment showed improvement from 7.2 to 2.4 on the VAS, 63 to 80.8 on the HSS, 27.9 to 37.2 on the physical SF-36, and 43.4 to 46.9 between initial assessment and evaluation after 6 months in all the patients - these improvements being statistically significant (p<0.05). There were no significant differences in the Barthel index and FAC. No significant differences were observed for any variable on comparing the two patient groups. Conclusions: TKA improves pain, functionality and quality of life in patients with gonarthrosis, regardless of whether one or the other rehabilitation program is adopted after hospital discharge (AU)

Increased NR2A expression and prolonged decay of NMDA-induced calcium transient in cerebellum of TgDyrk1A mice, a mouse model of Down syndrome.

Transgenic mice overexpressing Dyrk1A (TgDyrk1A), a Down syndrome (DS) candidate gene, exhibit motor and cognitive alterations similar to those observed in DS individuals. To gain new insights into the molecular consequences of Dyrk1A overexpression underlying TgDyrk1A and possibly DS motor phenotypes, microarray studies were performed. Transcriptome analysis showed an upregulation of the NR2A subunit of the NMDA type of glutamate receptors in TgDyrk1A cerebellum. NR2A protein overexpression was also detected in TgDyrk1A cerebellar homogenates, in the synaptosome-enriched fraction and in TgDyrk1A primary cerebellar granular neuronal cultures (CGNs). In TgDyrk1A synaptosomes, calcium-imaging experiments showed a higher calcium uptake after NMDA stimulation. Similarly, NMDA administration promoted longer calcium transients in TgDyrk1A CGNs. Taken together, these results show that NMDA-induced calcium rise is altered in TgDyrk1A cerebellar neurons and indicate that calcium signaling is dysregulated in TgDyrk1A mice cerebella. These findings suggest that DYRK1A overexpression might contribute to the dysbalance in the excitatory transmission found in the cerebellum of DS individuals and DS mouse models.

Monitoring gene therapy by external imaging of mRNA: pilot study on murine erythropoietin.

Gene therapy is anticipated as being an important medical development. Essential to its effectiveness is the appropriate activity (protein expression) in the expected target cells. A noninvasive diagnostic procedure of successful gene expression will be of paramount importance to validate its use or its misuse (eg, sports gene doping). Externally detectable labeled oligonucleotide hybridizing with the messenger RNA generated by the transferred gene has been proposed as a possibility to monitor successful gene therapy. The authors selected the erythropoietin gene (Epo) for a pilot study on erythropoietin protein expression in mouse muscle. Oligonucleotides of peptide nucleic acid (PNA) type capable of antisense binding to unique murine Epo-mRNA sequences were synthesized by solid phase methods, and elongated at the N-terminus with the HIV Tat (48-60) cell penetrating peptide. They were labeled with fluorescence and radioactive tags to verify penetration and longer half-life properties in Epo gene transfected C2C12 mouse muscle cells as compared with corresponding wild-type cells. Downregulation of newly expressed erythropoietin protein in such cells additionally confirmed the penetration and hybridizing properties of the selected labeled oligonucleotide. I-labeled Tat-PNAs were intravenously injected into mice that had previously received the Epo gene into the right tibialis muscle by DNA electrotransfer. Preferential accumulation of radioactivity in the transferred limb as compared with the contralateral limb was ascertained, especially for I-Tat-CTA CGT AGA CCA CT (labeled Tat-PNA 1). This study provides experimental data to support the potential use of external noninvasive image detection to monitor gene therapy. The extension of the approach to more sensitive methods for whole-body external detection such as positron emission tomography appears feasible.

Identification of C15orf5, a heart-enriched transcript on chromosome 15q23-q24.

We have isolated C15orf5, a novel human gene lacking homology to any known protein. The C15orf5 gene encodes a transcript of 1,519 nt with an ORF of 94 amino acids and a predicted protein size of 11.5 kDa. Northern blot analysis showed enhanced expression of C15orf5 in heart. C15orf5 was mapped to chromosome 15q23-q24 using the Stanford TNG4 Radiation Hybrid panel.

PALML, a novel paralemmin-related gene mapping on human chromosome 1p21.

We describe PALML, a novel gene encoding a 551 amino acid protein with similarity to paralemmin and the paralemmin-like amino terminal domain of AKAP2, a protein kinase A anchor protein. PALML mRNA is expressed in many tissues and is most abundant in cardiac and skeletal muscle, while absent from brain and blood. Exogenously expressed PALML fusion protein has a widespread cytoplasmic localization, and it is excluded from the nucleus. Human PALML maps on human chromosome 1p21 (between D1S2767 and D1S223). SSCP-HD analysis of exonic sequences in patients with VUR (familial non-syndromic vesicoureteral reflux syndrome) excluded mutations in the PALML gene from causing this disease. PALML, paralemmin and AKAP2 share the presence of a conserved coiled coil region that may mediate protein interactions with shared partners. Based on its resemblance to paralemmin and AKAP2, PALML is hypothesized to be involved in regulating intracellular signaling and membrane-cytoskeletal interactions.

Engagement of right temporal cortex during processing of linguistic context.

Language processing involves the interplay of areas in both cerebral hemispheres. Whereas the left temporal lobe is necessary for most language tasks, the right hemisphere seems to be additionally activated during processing of paragraphs and metaphors. We studied the neural correlates of word generation and selection in a sentence context, using functional magnetic resonance imaging (fMRI). Cerebral activation was measured while seven healthy, right handed volunteers read and completed sentence stems, with relatively low Cloze frequency, out loud. During a GENERATION condition, subjects were required to generate a word which completed a sentence stem appropriately. During a DECISION condition, subjects selected and articulated one of two presented terminal words. A READING condition in which subjects read an appropriate completion aloud, served as baseline. When GENERATION was compared to READING or DECISION, the left middle frontal, anterior cingulate, precuneus and right lateral temporal cortex were activated. During DECISION relative to READING, the left inferior frontal and middle/superior temporal cortex bilaterally were activated. The prominent engagement of the right lateral temporal cortex during the GENERATION conditions may reflect the processing of linguistic context, and particularly the activation of multiple meanings in the course of producing an appropriate completion.

Avances en las técnicas de reproducción en parejas discordantes y en la prevención de la transmisión vertical en mujeres infectadas

La infección por el VIH en el mundo mediante transmisión vertical así como la infección pediátrica siguen siendo muy preocupantes. La prevalencia de la infección en gestantes en España es especialmente elevada (1,54 en 1999). En ausencia de estrategias preventivas, la transmisión vertical del VIH se produce en el 13-48 por ciento de los casos. Desde la aplicación de medidas preventivas tales como el uso de tratamiento antirretroviral combinado durante la gestación, evitar pruebas fetales invasivas, la finalización del embarazo mediante cesárea electiva y la inhibición de la lactancia materna, el riesgo de transmisión ha descendido de forma espectacular (1 por ciento). El uso de antirretrovirales en pautas supresoras es el factor que más ha contribuido a este descenso. No se dispone de mucha información respecto a la seguridad de estos fármacos. Afortunadamente, la mayoría de estudios a corto medio plazo son tranquilizadores. La cesárea es útil en pacientes no tratadas o tratadas con zidovudina sola, pero se desconoce su papel en pacientes que reciben pautas combinadas. Para que estas medidas sean eficaces, es obligado realizar el cribado sistemático de la infección durante la gestación. El manejo de cada gestante debe ser individualizado y llevado a cabo por un equipo multidisciplinario que idealmente debería incluir a ginecólogos, infectólogos y pediatras. En el caso de varones infectados, el 'lavado seminal' con comprobación posterior de la ausencia de virus en la muestra procesada permite obtener un embarazo en mujeres negativas con un riesgo mínimo de infección. Tanto en el caso de la mujer como en el del varón infectado que desea una gestación, el consejo preconcepcional es imprescindible. Su complejidad requiere que se realice de forma conjunta por el infectólogo a cargo del paciente y por un obstetra/ginecólogo con especial dedicación (AU)

Ausencia de relación entre insulinemia y afectación orgánica en hipertensos no tratados grados 1-2 / Absence of relationship between insulinemia and organic involvement in non treated hypertensive patients grades 1-2

Antecedentes. Aunque la hiperinsulinemia se comporta como un factor de riesgo independiente de enfermedad coronaria y cerebrovascular, sólo algunos estudios han investigado la relación entre la resistencia a la insulina y la afectación precoz de órganos diana en los sujetos hipertensos. Objetivo. Valorar si el nivel de insulinemia es un determinante independiente de afectación temprana cardíaca o renal en pacientes no tratados con hipertensión arterial grados 1-2.Pacientes y métodos. De la cohorte de pacientes hipertensos del estudio Hospitalet, 125 sujetos aceptaron participar en el estudio de la insulinemia que se determinó mediante radioinmunoensayo. A estos pacientes, formando parte del protocolo básico de la Unidad de Hipertensión Arterial, se les efectuó una determinación de la excreción urinaria de albúmina (EUA) de 24 horas por nefelometría y una ecocardiografía. Se consideró microalbuminuria una EUA entre 30 y 300 mg/24 horas. Se definió como hipertrofia ventricular izquierda un índice de masa ventricular izquierda superior o igual a 125 g/m2. Resultados. Los pacientes incluidos presentaron una edad media de 41,0 años (desviación estándar [DE]: 11,8). El 40,8 por ciento eran mujeres. La presión arterial diagnóstica media fue de 150,1 (DE: 10,5)/95,1 (DE: 5,0) mmHg. Se detectó hiperinsulinemia basal en un 8,8 por ciento de los pacientes, hipertrofia del ventrículo izquierdo en 26 sujetos (23,2 por ciento; IC 95 por ciento: 15,4 por ciento-31,0 por ciento) y microalbuminuria en 12 casos (13,3 por ciento; IC 95 por ciento: 7,1 por ciento-22,1 por ciento). Las determinaciones ecocardiográficas y la EUA no se correlacionaron de forma estadísticamente significativa con el nivel de insulinemia basal ni tras sobrecarga oral de glucosa. Tampoco se observaron diferencias en dichas variables al comparar únicamente a los pacientes en los terciles superior e inferior de los niveles de insulinemia. Conclusión. No se ha observado asociación entre la insuficiencia basal o tras sobrecarga oral de glucosa y la afectación ecocardiográfica o el nivel de excreción urinaria de albúmina en sujetos con hipertensión grados 1-2 no tratados farmacológicamente (AU)

PACSIN 3 is a novel SH3 domain cytoplasmic adapter protein of the pacsin-syndapin-FAP52 gene family.

Pacsins are cytoplasmic adapter proteins with an N-terminal FHC, a central coiled coil, and a C-terminal SH3 domain and several potential phosphorylation sites. Two murine Pacsin genes have been reported to date: Pacsin 1 (equivalent to rat Syndapin I), and Pacsin 2 (like rat Syndapin II and chicken focal adhesion protein FAP52). Rat syndapins have been well characterized as part of a synapse dynamin-associated protein complex involved in endocytosis and actin dynamics. Here we describe PACSIN 3, a third member of the pacsin gene family in humans and mice, which encodes a 424 amino acid cytoplasmic protein and has a ubiquitously expressed mRNA. Intracellular distribution was assessed by overexpression of exogenous tagged pacsin 3 protein. In addition, we report the cDNA sequence of human PACSIN 1, a gene encoding a 444 amino acid protein and its chromosome assignment to 6p21. PACSIN 1 mRNA is most abundant in brain, and is also present in heart, pancreas and liver. The close sequence conservation between the three pacsin gene products suggests they could be performing similar functions participating in the different tissues where these are expressed.

Identification and characterization of BTBD1, a novel BTB domain containing gene on human chromosome 15q24.

Working within the EUROIMAGE full-length cDNA sequencing project we have isolated BTBD1, a novel human gene with a BTB/POZ domain. This motif is found in developmentally regulated zinc finger proteins and in the kelch family of actin-associated proteins, and is thought to mediate protein-protein interactions. The BTBD1 gene encodes a transcript of 3188 nt with an ORF of 482 amino acids and a predicted protein product size of 52.7 kDa. Northern blot analysis revealed an enhanced BTBD1 expression in heart and skeletal muscle. We have identified a paralogous BTBD1 counterpart gene on chromosome 19, BTBD2. BTBD1 was mapped to chromosome 15q24. Conservation of multiple pairs of genes between 15q24 and 19p13.3-p12 suggests their possible common chromosomal origin. We show the existence of the murine BTBD1 and BTBD2 orthologous genes, as well as the partial rat and bovine homologs.

Cloning, mapping and expression analysis of C15orf4, a novel human gene with homology to the yeast mitochondrial ribosomal protein Ym130 gene.

We have identified C15orf4, a novel human gene showing homology to the yeast mitochondrial ribosomal protein YmL30. C15orf4 encodes a transcript of 1,006 nt with an ORF of 279 amino acids and a predicted protein size of 31.7 kDa. Expression of C15orf4 is enriched in testis. C15orf4 was positioned to chromosome 15q24 by radiation hybrid mapping. We have identified the C15orf4 mouse orthologue as well as homologues in other species.

Reliability of Chalmers' scale to assess quality in meta-analyses on pharmacological treatments for osteoporosis.

PURPOSE: This study estimates the inter-rater and test-retest reliability of Chalmers' quality score scale in the context of bone mass loss and fracture rate in postmenopausal women. METHODS: An exhaustive literature search was performed on Medline to locate clinical trials studying the effect of medication use on bone mass loss and fracture rate in postmenopausal women. Twenty articles were randomly selected and four raters independently assessed the quality of each article with Chalmers' scale. Among the 20 articles, 10 were blinded on authors' names, journal, year of publication and source of funding. Raters were also asked to assess all 20 articles one more time, two months after the first evaluation. Intraclass (ICC) and test-retest correlation coefficients were calculated. RESULTS: The overall inter-rater ICC was 0.66 [0.55, 0.79](95%). The overall test-retest reliability of Chalmers' scale was 0.81 [0.67, 0. 98](95%). When ratings were stratified according to articles' blinding status, blinded assessments generated a smaller inter-rater ICC than non-blinded assessments: 0.30 [0.17, 0.53](95%) vs. 0.80 [0. 71, 0.90](95%). In addition, analyzing sub-scales separately generated different estimates of reliability. CONCLUSIONS: This study shows that the reliability of the quality scale developed by Chalmers substantially varies between sub-scales, and is highly dependent on articles' blinding status. The possibility of bias in rating non-blinded articles can not be ruled out. The reliability of the scale can also be dependent on the outcome studied.

Cloning, mapping and expression analysis of VPS33B, the human orthologue of rat Vps33b.

We have identified VPS33B, the human ortholog of rat Vps33b. VPS33B encodes a transcript of 2482 nt with an ORF of 617 amino acids and a predicted protein size of 70.6 kDa. VPS33B contains a Sec-1 domain shared with a family of proteins involved in protein sorting and vesicular trafficking. Enriched expression of VPS33B was observed in testis. VPS33B was positioned at chromosome 15q26.1 by radiation hybrid mapping.

Identification and expression analysis of C15orf3, a novel gene on chromosome 15q21.1-->q21.2.

We have isolated C15orf3, a novel human gene that lacks homology to any known gene family. The C15orf3 gene encodes a transcript of 1676 nt with an ORF of 187 amino acids and a predicted protein product size of 20.8 kDa. Northern blot analysis showed ubiquitous expression in adult tissues. EST database searching revealed the presence of C15orf3 homologs in rat and mouse. C15orf3 was mapped to chromosome 15q21.1-->q21.2 using the Stanford G3 radiation hybrid panel.

L-Dopa-induced sedation: a double-blind cross-over controlled study versus triazolam and placebo in healthy volunteers.

Incidental case reports suggest that some parkinsonian patients treated with dopaminergic drugs complain of drowsiness but few controlled data are available. We compared the sedative effects of L-Dopa (200 mg + 50 mg benserazide, PO), triazolam (0.125 mg) and placebo in a randomized double-blind cross-over design in 22 healthy volunteers pretreated with domperidone (60 mg/day). Drowsiness was assessed using a visual analog scale (VAS), a computerized choice reaction time test (CRT) and an electro-oculogram (EOG). L-Dopa and triazolam induced significant drowsiness, compared to placebo, on VAS, CRT and some EOG parameters. After this first evaluation session, all subjects were chronically treated for 11 days with 600 mg/d of L-Dopa. Drowsiness induced by L-Dopa, triazolam or placebo was then tested again on three consecutive days to assess putative dopaminergic tolerance. After chronic L-Dopa treatment, triazolam-induced sedation remained unchanged while L-Dopa sedative effects were no longer significant except on the VAS, preventing the conclusion that tolerance occurred. These data suggest that an acute dose of L-Dopa induces sedation in L-Dopa-naive subjects. This sedative effect must be considered in clinical practice and when studying the effects of L-Dopa on motor or neuropsychological performance, especially in acute tests.