Discovery of a Neuroprotective Chemical, ( S )- N -(3-(3,6-Dibromo-9 H -carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(−)-P7C3-S243], with Improved Druglike Properties

(−)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinson’s disease. A short, enantioselective synthesis provides the neuroprotective agent in optically pure form. It is nontoxic, orally bioavailable, metabolically stable, and able to cross the blood–brain barrier. As such, it represents a valuable lead compound for the development of drugs to treat neurodegenerative diseases and traumatic brain injury

Arctic Flora and Fauna: Status and Conservation

What is the overall state of the Arctic environment? The aim of this report is to answer the many aspects of this seemingly straightforward question. Although several national and international efforts have looked at parts of the Arctic, this is the first attempt to assess the state of Arctic flora and fauna as a whole

Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by chorea, cognitive impairment, dementia and personality changes, caused by the expansion of a CAG repeat in the HD gene. Often, patients with a similar clinical presentation do not carry expansions of the CAG repeat in this gene [Huntington disease-like (HDL) patients]. We report the genetic analysis of 107 Portuguese patients with an HDL phenotype. The HDL genes PRNP and JPH3, encoding the prion protein and junctophilin-3, respectively, were screened for repeat expansions in these patients. Given the partial clinical overlap of SCA17, DRPLA and neuroferritinopathy with HD, their causative genes (TBP, ATN1, and FTL, respectively) were also analysed. Finally, repeat expansions in two candidate genes, CREBBP and POU3F2, which encode the nuclear transcriptional coactivator CREB-binding protein and the CNS-specific transcription factor N-Oct-3, respectively, were also studied. Expansions of the repetitive tracts of the PRNP, JPH3, TBP, ATN1, CREBBP and POU3F2 genes were excluded in all patients, as were sequence alterations in the FTL gene. Since none of the genes already included in the differential diagnosis of HD was responsible for the disease in our sample, the genetic heterogeneity of the HDL phenotype is still open for investigation.Fundação para a Ciência e a Tecnologia (FCT) and FEDER (grant CBO/33485/99). BIC included in grant CBO/33485/99, respectivel

Tracking Signals of Change in Mediterranean Fish Diversity Based on Local Ecological Knowledge

One of the expected effects of global change is increased variability in the abundance and distribution of living organisms, but information at the appropriate temporal and geographical scales is often lacking to observe these patterns. Here we use local knowledge as an alternative information source to study some emerging changes in Mediterranean fish diversity. A pilot study of thirty-two fishermen was conducted in 2009 from four Mediterranean locations along a south-north gradient. Semi-quantitative survey information on changes in species abundance was recorded by year and suggests that 59 fish species belonging to 35 families have experienced changes in their abundance. We distinguished species that increased from species that decreased or fluctuated. Multivariate analysis revealed significant differences between these three groups of species, as well as significant variation between the study locations. A trend for thermophilic taxa to increase was recorded at all the study locations. The Carangidae and the Sphyraenidae families typically were found to increase over time, while Scombridae and Clupeidae were generally identified as decreasing and Fistularidae and Scaridae appeared to fluctuate in abundance. Our initial findings strongly suggest the northward expansion of termophilic species whose occurrence in the northern Mediterranean has only been noted previously by occasional records in the scientific literature

Are oral health conditions associated with schoolchildren's performance and school attendance in the Kingdom of Bahrain? A life-course perspective

Background The link between oral diseases and school performance and school attendance remains unclear among Middle Eastern children. Aim To investigate the relationship of oral conditions with schoolchildren’s school performance and attendance using the life course approach. Design A cross-sectional study was conducted with 466 schoolchildren aged 7-8 years from Kingdom of Bahrain (KoB) and their parents. Questionnaire data on children’s current and at birth environmental characteristics were completed by their parents. Children’s oral health measures, including ICDAS (International Caries Detection and Assessment System), PUFA (Pulp, Ulcer, Fistula, Abscess), and DDE (Developmental Defects of Enamel) indices, were the exposure variables. School performance and school attendance data obtained from the school register were the outcome variables. The data were analysed using multivariate ordinal logistic regression. Results The odds of Excellent school performance were significantly lower for children with untreated dentine caries (OR = 0.98 CI 95%: 0.96-0.99). Children with caries-treated teeth showed greater odds of Excellent school performance (OR=1.41 CI 95%: 1.15-1.74). A permissive parental style was associated with poor school attendance (OR= 2.63 CI 95%: 1.08-6.42). Conclusion Dental caries was associated with poor school performance but not with school attendance. Treated caries was associated with good school performance

Assessment of the quality of measures of child oral health-related quality of life

Background Several measures of oral health-related quality of life have been developed for children. The most frequently used are the Child Perceptions Questionnaire (CPQ), the Child Oral Impacts on Daily Performances (C-OIDP) and the Child Oral Health Impact Profile (COHIP). The aim of this study was to assess the methodological quality of the development and testing of these three measures. Methods A systematic search strategy was used to identify eligible studies published up to December 2012, using both MEDLINE and Web of Science. Titles and abstracts were read independently by two investigators and full papers retrieved where the inclusion criteria were met. Data were extracted by two teams of two investigators using a piloted protocol. The data were used to describe the development of the measures and their use against existing criteria. The methodological quality and measurement properties of the measures were assessed using standards proposed by the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) group. Results The search strategy yielded 653 papers, of which 417 were duplicates. Following analysis of the abstracts, 119 papers met the inclusion criteria. The majority of papers reported cross-sectional studies (n = 117) with three of longitudinal design. Fifteen studies which had used the original version of the measures in their original language were included in the COSMIN analysis. The most frequently used measure was the CPQ. Reliability and construct validity appear to be adequate for all three measures. Children were not fully involved in item generation which may compromise their content validity. Internal consistency was measured using classic test theory with no evidence of modern psychometric techniques being used to test unidimensionality of the measures included in the COSMIN analysis. Conclusion The three measures evaluated appear to be able to discriminate between groups. CPQ has been most widely tested and several versions are available. COHIP employed a rigorous development strategy but has been tested in fewer populations. C-OIDP is shorter and has been used successfully in epidemiological studies. Further testing using modern psychometric techniques such as item response theory is recommended. Future developments should also focus on the development of measures which can evaluate longitudinal change

The Interleukin-2 Receptor γ Chain Maps to Xq13.1 and is Mutated in X-Linked Severe Combined Immunodeficiency, SCIDX1

The gene encoding the γ chain of the lymphocyte interleukin-2 receptor has been cloned and shown to be required to associate with the β chain in order for IL-2 internalization and cell activation to occur (1). We considered this gene, IL2RG, a candidate for the X-linked form of severe combined Immunodeficiency at the SCIDX1 locus, in which affected males have impaired lymphocyte development. Using fluorescence in situ hybridization and PCR amplification of somatic cell hybrid DNAs, we mapped IL2RG to human Xq13.1, a location within the SCIDX1 critical region established by linkage analysis. The 4.2 kb IL2RG gene was sequenced, and its genomlc organization was elucidated. Seven of 19 transformed B-lymphocyte cell lines with independent SCIDX1 mutations had absent or minimal IL2RG mRNA. Unique point mutations were documented to be specifically associated with the disease and the carrier state in four unrelated affected males and their family members: one in a boy with no detectable IL2RG mRNA, In which the mutation ablated a splice donor site; one causing premature chain termination; and two causing distinct amino acid changes. The demonstration of impaired IL2RG mRNA expression in males with X-linked SCID and of unique point mutations In SCIDX1 pedigrees constitutes powerful evidence that the SCIDX1 gene Is IL2RG. Noguchi et al. (2) have Independently published IL2RG mapping to Xq13 and discovery of mutations in three affected males. The specific pathogenesis of IL2RG mutations and approaches to gene therapy can now be addressed in the X-linked form of SCID