The psoriasis genetics as a model of complex disease

Psoriasis [OMIM*177900] is a common, chronic and papulosquamous inflammatory skin disease affecting approximately 2% of Caucasian. However, this disorder is rare among Japanese, Eskimos, West Africans and North American blacks and very uncommon in North American and South American natives. The causes for these variations are likely to be both genetic and environmental. Population-based studies and twin studies indicate that psoriasis is a heritable disease with a polygenic mode of inheritance with variable penetrance. Independent genome-wide scans have suggested the involvement of a large number of chromosomal regions (loci), and many candidate genes have been proposed. We discuss genetic approaches to the disease, results and interpretations of relevant studies, as well as future perspectives. Understanding the genetic basis of psoriasis will represent a major advance in our understanding of the disease and will reveal novel disease-specific biologic pathways.     

Isocyanide terpene metabolites of Phyllidiella pustulosa, a nudibranch from the South China Sea

A series of isocyanides, compounds 4-11, including diterpenes never before found in Phyllidiid nudibranchs, have been isolated from a Chinese population of the nudibranch Phyllidiella pustulosa. Three new sesquiterpenes (8, 10, and 11), with eudesmane, guaiane, and bisabolane skeletons, respectively, have been characterized by spectral methods and chemical comparison with known related molecules. The absolute stereochemistry of the major metabolite, the isocyanide 8, an enantiomer of the known sponge metabolite stylotelline (12), has also been determined.     

Anxiety-related behaviour in C57BL/6 <--> BALB/c chimeric mice

In a previous study on anxiety-related behaviours of the genetically and behaviourally distant inbred mouse strains C57BL/6 and BALB/c using the Elevated plus-maze (EPM) and Open-field (OF) apparatuses, we identified a number of variables, the factorial scores of which were grouped by principal component analysis (PCA) into factors specifically describing each inbred strain [4]. We have now studied the effect of C57BL/6 and BALB/c haploid sets of genes on this behaviour by comparing EPM and OF variables of C57BL/6 and BALB/c versus C57BL/6×BALB/c F1 hybrids (B6CBF1) and chimeric C57BL/6×BALB/c (CHIM) mice. CHIM mice were made by embryo aggregation and the chimerism degree of their brain was inferred from coat black/white distribution. Discriminant analysis of EPM and OF factorial scores of C57BL/6, BALB/c and CHIM mice showed that CHIM mice with an exceeding (≥80%) C57BL/6 or BALB/c coat component had behaviours similar to those of the predominant strain, whereas CHIM mice with intermediate chimerism differed from both inbred strains. Additional MANOVA analysis showed that the anxiety behaviour of CHIM mice with intermediate chimerism was similar to that of B6CBF1 mice as for factors not describing the inbred strains, including a motor activity mostly limited to protected areas, with attempts to approach the anxiogenic areas while processing/storing the external information. We conclude that the balanced presence of both C57BL/6 and BALB/c genetic backgrounds, either when carried by the same cell or by different cells, gives rise to a novel stress coping strategy described by factors different from those of the inbred strains.     

Nerve growth factor (NGF) and lenses: effects of NGF in an in vitro rat model of cataract

Background The aims of this study are to investigate the presence and production of nerve growth factor (NGF) in the rat lens in basal conditions and to evaluate, in vitro, the role of NGF in a model of xylose-induced cataract.Methods Rat lenses were dissected and the expression of NGF, NGF mRNA and high-affinity NGF-receptor (TrkA) was evaluated by immunohistochemistry, immunoenzymatic assay (ELISA) and in-situ hybridization (ISH) techniques. To investigate the role of NGF in cataract formation we used an in vitro model of sugar-induced cataract by culturing rat lenses for 48 h in Eagle's minimum essential medium (MEM) supplemented with xylose. To evaluate the potential protective effect of NGF on xylose-induced cataract formation, exogenous NGF at different concentrations or antibodies neutralizing endogenous NGF (NGF-Ab) or aspecific antibodies were added to xylose-cultured lenses, and the following cataract-related parameters were evaluated and compared to xylose-treated lenses. Cataract formation was evaluated using three different parameters: staging of the cataract by lens photography, quantification of lens transparency in terms of gray level medium (GLM) and evaluation of the hydration percentage (H%) of the lens. To investigate the role of endogenous NGF in cataract onset, NGF levels were evaluated and compared in lenses cultured in xylose supplemented medium versus lenses cultured in control culture medium.Results The epithelium from fresh rat lenses expresses NGF-receptor, NGF protein and NGF-mRNA. NGF levels in fresh lens were 54.0±24.5 pg/g as quantified by ELISA. Xylose-cultured lenses develop cataract changes, including a decrease of GLM and an increase in hydration percentage, associated with a decrease in NGF levels when compared to lenses cultured in the control culture medium. The addition of NGF to xylose-cultured lenses reduces cataract formation, increasing GLM and decreasing the hydration percentage as compared to xylose-treated lenses. On the other hand, the addition of NGF-Ab induces an increase in cataract formation and lens hydration.Conclusions This study demonstrates that rat lens epithelium expresses and synthesizes NGF. Moreover, immunohistochemistry shows that lens epithelial cells also express the NGF receptor. Although the functional significance of TrkA on lens epithelium is at present not clear, the expression of NGF and its high-affinity receptor on the same cells together with our experimental results suggest that NGF is involved in supporting trophism and/or the function of the lens epithelium.     

Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer

OBJECTIVE: Paclitaxel-cisplatin is considered to be a standard therapy for metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the activity and toxicity of this combination with vinorelbine or gemcitabine as front-line therapy in brain metastases from NSCLC. METHODS: Twenty-six chemotherapy-naive patients with an ECOG performance status of 0-2 were treated with paclitaxel (135 mg/m(2)) on day 1, cisplatin (120 mg/m(2)) on day 1, and either vinorelbine (30 mg/m(2)) on days 1 and 15 or gemcitabine (800 mg/m(2)) on days 1 and 8. Whole-brain irradiation was offered early in case of progression and later as consolidation treatment. RESULTS: All patients were evaluated for toxicity and 25 for response. An intracranial response rate was observed in 38% of the patients (95% CI: 22-59%). WHO grade 3-4 neutropenia and thrombocytopenia occurred in 31 and 4% of the patients, respectively. There was one treatment-related death. Non-hematological toxicities were mild. After a median follow-up of 46 months, the median overall survival for all patients was 21.4 weeks and the median time to progression was 12.8 weeks. CONCLUSIONS: Paclitaxel and cisplatin combined with vinorelbine or gemcitabine as front-line therapy in brain metastases seem to achieve responses similar to those for extracranial disease, suggesting a meaningful role in this setting.     

Functional neuroanatomy of language without speech: An ALE meta‐analysis of sign language

Sign language (SL) conveys linguistic information using gestures instead of sounds. Here, we apply a meta‐analytic estimation approach to neuroimaging studies (N = 23; subjects = 316) and ask whether SL comprehension in deaf signers relies on the same primarily left‐hemispheric cortical network implicated in spoken and written language (SWL) comprehension in hearing speakers. We show that: (a) SL recruits bilateral fronto‐temporo‐occipital regions with strong left‐lateralization in the posterior inferior frontal gyrus known as Broca''s area, mirroring functional asymmetries observed for SWL. (b) Within this SL network, Broca''s area constitutes a hub which attributes abstract linguistic information to gestures. (c) SL‐specific voxels in Broca''s area are also crucially involved in SWL, as confirmed by meta‐analytic connectivity modeling using an independent large‐scale neuroimaging database. This strongly suggests that the human brain evolved a lateralized language network with a supramodal hub in Broca''s area which computes linguistic information independent of speech.     

Human genomics of acute liver failure due to hepatitis B virus infection: An exome sequencing study in liver transplant recipients

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life‐threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen‐specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti‐HBc and anti‐HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis‐driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case‐control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV‐related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.