Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009.

BACKGROUND: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification, typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. OBJECTIVE: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. METHODS: The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Sorèze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. RESULTS: It was agreed that currently the nosology should remain clinically based. "Syndromic" versus "nonsyndromic" forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, "keratinopathic ichthyosis"-under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. "Autosomal recessive congenital ichthyosis" is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. LIMITATIONS: As more becomes known about these diseases in the future, modifications will be needed. CONCLUSION: We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research.

Blood pressure in relation to coffee and caffeine consumption.

The relationship between blood pressure (BP) and coffee is of major interest given its widespread consumption and the public health burden of high BP. Yet, there is no specific recommendation regarding coffee intake in existing hypertension guidelines. The lack of a definitive understanding of the BP-coffee relationship is partially attributable to issues that we discuss in this review, issues such as acute vs. chronic effects, genetic and smoking effect modifications, and coffee vs. caffeine effects. We also present evidence from meta-analyses of studies on the association of BP with coffee intake. The scope of this review is limited to the latest advances published with a specific focus on caffeine, acknowledging that caffeine is only one among numerous components in coffee that may influence BP. Finally, considering the state of the research, we propose a mechanism by which the CYP1A2 gene and enzyme influence BP via inhibition of the adenosine receptor differentially in smokers and non-smokers.

Cell entry of Lassa virus induces tyrosine phosphorylation of dystroglycan.

The extracellular matrix (ECM) receptor dystroglycan (DG) serves as a cellular receptor for the highly pathogenic arenavirus Lassa virus (LASV) that causes a haemorrhagic fever with high mortality in human. In the host cell, DG provides a molecular link between the ECM and the actin cytoskeleton via the adapter proteins utrophin or dystrophin. Here we investigated post-translational modifications of DG in the context of LASV cell entry. Using the tyrosine kinase inhibitor genistein, we found that tyrosine kinases are required for efficient internalization of virus particles, but not virus-receptor binding. Engagement of cellular DG by LASV envelope glycoprotein (LASV GP) in human epithelial cells induced tyrosine phosphorylation of the cytoplasmic domain of DG. LASV GP binding to DG further resulted in dissociation of the adapter protein utrophin from virus-bound DG. This virus-induced dissociation of utrophin was affected by genistein treatment, suggesting a role of receptor tyrosine phosphorylation in the process.

Role of Sam68 in post-transcriptional gene regulation.

The STAR family of proteins links signaling pathways to various aspects of post-transcriptional regulation and processing of RNAs. Sam68 belongs to this class of heteronuclear ribonucleoprotein particle K (hnRNP K) homology (KH) single domain-containing family of RNA-binding proteins that also contains some domains predicted to bind critical components in signal transduction pathways. In response to phosphorylation and other post-transcriptional modifications, Sam68 has been shown to have the ability to link signal transduction pathways to downstream effects regulating RNA metabolism, including transcription, alternative splicing or RNA transport. In addition to its function as a docking protein in some signaling pathways, this prototypic STAR protein has been identified to have a nuclear localization and to take part in the formation of both nuclear and cytosolic multi-molecular complexes such as Sam68 nuclear bodies and stress granules. Coupling with other proteins and RNA targets, Sam68 may play a role in the regulation of differential expression and mRNA processing and translation according to internal and external signals, thus mediating important physiological functions, such as cell death, proliferation or cell differentiation.

Anopheles darlingi polytene chromosomes: revised maps including newly described inversions and evidence for population structure in Manaus

Salivary gland polytene chromosomes of 4th instar Anopheles darlingi Root were examined from multiple locations in the Brazilian Amazon. Minor modifications were made to existing polytene photomaps. These included changes to the breakpoint positions of several previously described paracentric inversions and descriptions of four new paracentric inversions, two on the right arm of chromosome 3 and two on the left arm of chromosome 3 that were found in multiple locations. A total of 18 inversions on the X (n = 1) chromosome, chromosome 2 (n = 7) and 3 (n = 11) were scored for 83 individuals from Manaus, Macapá and Porto Velho municipalities. The frequency of 2Ra inversion karyotypes in Manaus shows significant deficiency of heterozygotes (p < 0.0009). No significant linkage disequilibrium was found between inversions on chromosome 2 and 3. We hypothesize that at least two sympatric subpopulations exist within the An. darlingi population at Manaus based on inversion frequencies.

Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.

Composition and cost of drugs stored at home by elderly patients.

BACKGROUND: Elderly people often have multiple chronic diseases, are frequently treated by several physicians, and also use over-the-counter medications. Excessive prescribing, imperfect therapeutic adherence, treatment modifications after hospitalization, and oversized drug packages result in home storage of leftover drugs, resulting in a waste of healthcare resources. PATIENTS AND METHODS: All patients aged >/=75 years hospitalized for >24 hours during a 6-month period in an urban teaching hospital in Switzerland were eligible for inclusion in a study collecting sociodemographics, medical, functional, and psychosocial characteristics. Six months later, a research nurse visited the patients at home and recorded the names, number of tablets, and expiration dates of all open or intact drug packages, and the doses actually taken. Acquisition costs of these drugs were computed. RESULTS: One hundred ninety-five patients were included (127 women; mean age 82.2 +/- 4.8 y, range 75-96). They had a total of 2059 drugs (mean per patient 10.3 +/- 6.7, range per patient 1-42), corresponding to a total cost of (US) $62 826 (mean per patient 322 +/- 275, range per patient 10-1571). Self-reported drug intake was regular for 36% of the drugs (46.5% of total costs) and occasional for 11% (6.1%), whereas 35.7% (30.1%) had been stopped during the last month. Cardiovascular drugs amounted to 36.6% of the drugs and 55.5% of the costs. None of the patients' characteristics was significantly associated with a greater number of drugs and higher costs. CONCLUSIONS: Drugs stored at home by elderly patients were worth about $320 per patient. Only about one-third of these drugs were regularly taken. In the context of resources shortage, innovative solutions should be found to reduce the waste linked with drugs stopped in previous months.

Validation transculturelle de l'Oswestry disability index en français [Cross-cultural validation of the Oswestry disability index in French]

AIM: The aim of this study was to interpret and validate a French version of the Oswestry disability index (ODI), using a cross-cultural validation method. The validity and reliability of the questionnaire was assessed in order to ensure the psychometric characteristics. METHOD: The cross-cultural validation was carried out according to Beaton's methodology. The study was conducted with 41 patients suffering from low back pain. The correlation between the ODI and the Roland-Morris disability questionnaire (RMDQ), the medical outcome survey short form-36 (MOS SF-36) and a pain visual analogical scale (VAS) was assessed. RESULTS: The validity of the Oswestry questionnaire was studied using the Cronbach Alpha coefficient calculation: 0.87 (n=36). The significant correlation between the ODI and RMDQ was 0.8 (P<0.001, n=41) and 0.71 (P<0.001, n=36) for the pain VAS. The correlation between the ODI and certain subscales (physical functioning 0.7 (P<0.001, n=41), physical role 0.49 et bodily pain 0.73 (P<0.001, n=41)) of the MOS SF-36 were equally significant. The reproducibility of the ODI was calculated using the Wilcoxon matched pairs test: there was no significant difference for eight out of ten sections or for the final score. CONCLUSION: This French translation of the ODI should be considered as valid and reliable. It should be used for any future clinical studies carried out using French language patients. Complimentary studies must be completed in order to assess its sensitivity to change in the event of any modifications in the patients functional capacity.

Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field.

Non-alcoholic fatty liver disease (NAFLD) is an emerging health concern in both developed and non-developed world, encompassing from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Incidence and prevalence of this disease are increasing due to the socioeconomic transition and change to harmful diet. Currently, gold standard method in NAFLD diagnosis is liver biopsy, despite complications and lack of accuracy due to sampling error. Further, pathogenesis of NAFLD is not fully understood, but is well-known that obesity, diabetes and metabolic derangements played a major role in disease development and progression. Besides, gut microbioma and host genetic and epigenetic background could explain considerable interindividual variability. Knowledge that epigenetics, heritable events not caused by changes in DNA sequence, contribute to development of diseases has been a revolution in the last few years. Recently, evidences are accumulating revealing the important role of epigenetics in NAFLD pathogenesis and in NASH genesis. Histone modifications, changes in DNA methylation and aberrant profiles or microRNAs could boost development of NAFLD and transition into clinical relevant status. PNPLA3 genotype GG has been associated with a more progressive disease and epigenetics could modulate this effect. The impact of epigenetic on NAFLD progression could deserve further applications on therapeutic targets together with future non-invasive methods useful for the diagnosis and staging of NAFLD.

Tau and neurofilaments in a family with frontotemporal dementia unlinked to chromosome 17q21-22.

A Swiss frontotemporal dementia (FTD) kindred with extrapyramidal-like features and without motor neuron disease shows a brain pathology with ubiquitin-positive but tau-negative inclusions. Tau and neurofilament modifications are now studied here in three recently deceased family members. No major and specific decrease of tau was observed as described by others in, e.g., sporadic cases of FTD with absence of tau-positive inclusions. However, a slight decrease of tau, neurofilament, and synaptic proteins, resulting from frontal atrophy was detected. In parallel, polymorphic markers on chromosome 17q21-22, the centromeric region of chromosome 3 and chromosome 9, were tested. Haplotype analysis showed several recombination events for chromosomes 3 and 17, but patients shared a haplotype on chromosome 9q21-22. However as one of the patients exhibited Alzheimer and vascular dementia pathology with uncertain concomitant FTD, this locus is questionable. Altogether, these data indicate principally that the Swiss kindred is unlinked to locus 17q21-22, and that tau is not at the origin of FTD in this family.

SwissBioisostere: a database of molecular replacements for ligand design.

The SwissBioisostere database (http://www.swissbioisostere.ch) contains information on molecular replacements and their performance in biochemical assays. It is meant to provide researchers in drug discovery projects with ideas for bioisosteric modifications of their current lead molecule, as well as to give interested scientists access to the details on particular molecular replacements. As of August 2012, the database contains 21 293 355 datapoints corresponding to 5 586 462 unique replacements that have been measured in 35 039 assays against 1948 molecular targets representing 30 target classes. The accessible data were created through detection of matched molecular pairs and mining bioactivity data in the ChEMBL database. The SwissBioisostere database is hosted by the Swiss Institute of Bioinformatics and available via a web-based interface.

Quantifying ChIP-seq data: a spiking method providing an internal reference for sample-to-sample normalization.

Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments are widely used to determine, within entire genomes, the occupancy sites of any protein of interest, including, for example, transcription factors, RNA polymerases, or histones with or without various modifications. In addition to allowing the determination of occupancy sites within one cell type and under one condition, this method allows, in principle, the establishment and comparison of occupancy maps in various cell types, tissues, and conditions. Such comparisons require, however, that samples be normalized. Widely used normalization methods that include a quantile normalization step perform well when factor occupancy varies at a subset of sites, but may miss uniform genome-wide increases or decreases in site occupancy. We describe a spike adjustment procedure (SAP) that, unlike commonly used normalization methods intervening at the analysis stage, entails an experimental step prior to immunoprecipitation. A constant, low amount from a single batch of chromatin of a foreign genome is added to the experimental chromatin. This "spike" chromatin then serves as an internal control to which the experimental signals can be adjusted. We show that the method improves similarity between replicates and reveals biological differences including global and largely uniform changes.

Type II and IIIA thumb hypoplasia reconstruction.

Thumb hypoplasia treatment requires considering every component of the maldevelopment. Types II and IIIA hypoplasia share common features such as first web space narrowing, hypoplasia or absence of thenar muscles and metacarpophalangeal joint instability. Many surgical techniques to correct the malformation have been described. We report our surgical strategy that includes modifications of the usual technique that we found useful in reducing morbidity while optimizing the results. A diamond-shape kite flap was used to widen the first web space. Its design allowed primary closure of the donor site using a Dufourmentel flap. The ring finger flexor digitorum superficialis was transferred for opposition transfer, and the same tendon was used to stabilize the metacarpophalangeal joint on its ulnar and/or radial side depending on a uniplanar or more global instability. An omega-shaped K-wire was placed between the first and second metacarpals to maintain a wide opening of the first web space without stressing the reconstructed ulnar collateral ligament of the MCP joint. We report a clinical series of 15 patients (18 thumbs) who had this reconstructive program.

The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines.

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p&lt;0.05), IL-1beta-induced apoptosis (p&lt;0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.

Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase.

The cellular response to an inflammatory stressor requires a proinflammatory cellular activation followed by a controlled resolution of the response to restore homeostasis. We hypothesized that biliverdin reductase (BVR) by binding biliverdin (BV) quells the cellular response to endotoxin-induced inflammation through phosphorylation of endothelial nitric oxide synthase (eNOS). The generated NO, in turn, nitrosylates BVR, leading to nuclear translocation where BVR binds to the Toll-like receptor-4 (TLR4) promoter at the Ap-1 sites to block transcription. We show in macrophages that BV-induced eNOS phosphorylation (Ser-1177) and NO production are mediated in part by Ca(2+)/calmodulin-dependent kinase kinase. Furthermore, we show that BVR is S-nitrosylated on one of three cysteines and that this posttranslational modification is required for BVR-mediated signaling. BV-induced nuclear translocation of BVR and inhibition of TLR4 expression is lost in macrophages derived from Enos(-/-) mice. In vivo in mice, BV provides protection from acute liver damage and is dependent on the availability of NO. Collectively, we elucidate a mechanism for BVR in regulating the inflammatory response to endotoxin that requires eNOS-derived NO and TLR4 signaling in macrophages.