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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

A dose-ranging study of selegiline in patients with Parkinson's disease: effect of platelet monoamine oxidase activity.

A dose-ranging study of selegiline was performed in patients with Parkinson's disease to determine the minimal dosage of the drug able to inhibit > or = 95% of platelet monoamine oxidase (MAO) activity. Different doses of selegiline (5 or 10 mg daily, 10 or 20 mg weekly) were studied in four groups of six patients with Parkinson's disease. Platelet MAO activity was measured before and after 1 month's treatment with selegiline. The doses of 5 or 10 mg daily and 20 mg (i.e., 10 mg x 2) weekly induced a complete inhibition of platelet MAO-B activity from day 7 to day 28 (96.0-99.5%). In contrast, platelet MAO-B inhibition was only 75.9% of the basal value after a dosage of 10 mg weekly. These results demonstrate that 20 mg weekly is the minimal dosage of selegiline able to induce a maximal and long-lasting inhibition of platelet MAO-B activity in patients with parkinsonism. Further clinical trials are needed to investigate the clinical efficacy of this dose.

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.