Experiences from the accident of Seveso

Provisional data on selected sanitary events which took place at Seveso after July 10 1976 are reported. 187 cases of chloracne, mostly in children, were detected, 50 just after the accident, the others within a year. Most polluted area (zone A) provided almost all "early" and most severe cases, but the territorial distribution of chloracne prevalence rates showed some inconsistencies with the soil TCDD pollution map; interpretations for such findings are discussed. Thirty-eight birth defects were detected in 1977 (none in zones A and B), more than in previous years, but still less than expected in a well controlled "normal" population: no clustering around a given type was observed. Spontaneous abortions, evaluated both as abortion rates and as pregnancy loss rates, showed scattered and statistically non-significant variations, inconsistent with the pollution map. No differences in birth and death rates compared to surrounding areas were observed. Data on ad hoc cytogenetic, neurological and immunological surveys are commented. Limitations of the presently available data are discussed and further research lines are anticipated.     

Electrofishing as a sampling technique for coastal stream fish populations and communities in the Southeast of Brazil

Electrofishing adequacy was tested as a technique to obtain quantitative data of coastal stream fish populations and communities in the Southeast of Brazil. Seven field trips, between July/94 and July/95, were done in 5 localities of the Ubatiba fluvial system (Maricá, RJ). Seventeen species, among the 22 collected, had their numbers estimated through the Zipping method, the model used to test the sampling methodology. At each field trip, three removals with electrofishing were done in each locality and, according to the number of obtained species at each locality/field trip, we analysed 315 cases. Nineteen cases, among 315, showed failure condition. Estimates were significant (p < 0.01) in 96% of the studied cases. Non-significant cases were obtained for rare species due to over and randomly efficient electrofishing in 63.3% and 36.4% of the cases, respectively. No correlation was found between catchability and the estimated number of individuals and/or environmental characteristics. High values for sampling efficiency (> 85%) were found for all estimates. An experimental analyses were done for one locality and, the comparison between the estimates for 3 and 6 successive removals showed a mean error and a standard deviation of 5.5% and 2.1% respectively. Therefore, it can be concluded that electrofishing was an efficient method for quantitative data analysis of fish populations and communities in the Ubatiba fluvial system.     

The Local Complement Activation on Vascular Bed of Patients with Systemic Sclerosis: A Hypothesis-Generating Study

ObjectiveThe role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region.MethodsC5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method.ResultsEven though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases.ConclusionsOur results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation.     

Identification of NF-κB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis

IntroductionSystemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility.MethodsSixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy).ResultsWe observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, P_adj = 7.22 × 10⁻⁵), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, P_adj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, P_adj = 2.49 × 10⁻⁴) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (P_adj = 4.45 × 10⁻⁴ and P_adj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (P_adj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10⁻⁴) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.ConclusionsAn analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0572-y) contains supplementary material, which is available to authorized users.     

Aggressive and non-aggressive personalities differ in oxidative status in selected lines of mice (Mus musculus)

Mice selected for aggression and coping (long attack latency (LAL), reactive coping strategy; short attack latency (SAL), pro-active coping strategy) are a useful model for studying the physiological background of animal personalities. These mice also show a differential stress responsiveness, especially in terms of hypothalamic-pituitary-adrenal axis reactivity, to various challenges. Since the stress response can increase the production of reactive oxygen species, we predicted that the basic oxidative status of the lines could differ. We found that LAL showed higher serum antioxidant capacity (OXY) than SAL, while no differences emerged for reactive oxygen metabolites (ROMs) or the balance between ROMs and OXY, reflecting oxidative stress. Moreover, the lines showed inverse relationships between ROMs or OXY and body mass corrected for age. The results indicate that variation in oxidative status is heritable and linked to personality. This suggests that different animal personalities may be accompanied by differences in oxidative status, which may predict differences in longevity.     

Anatomical features and histology of the digestive tract of two related neotropical omnivorous fishes (Characiformes; Anostomidae)

The estimated mean intestinal coefficients of Leporinus friderici Bloch, 1794 and L. taeniofasciatus Britski, 1997, from the Upper Tocantins River, central-western Brazil, were 1·25±0·15 and 1·14±0·07, respectively. The external surfaces of the lips have taste buds. The histological structure is composed of four layers: mucosa, submucosa, muscular, and serosa. No muscularis mucosa is detected. The oesophageal epithelium is stratified in L. friderici and pseudostratified in L. taeniofasciatus , the latter with PAS+ basal cells and eosinophilic apical cells. A thick layer of adipose tissue was found within the submucosa. Leporinus taeniofasciatus has a sphincter separating the cardiac and fundic portions of the stomach. In both species, gastric glands are present in the stomach, except in its pyloric portion. The pyloric caeca possess a simple columnar epithelium with brush border and three types of goblet cells. Rodlet cells were found in L. friderici . The three portions of the intestine showed no histological differences. Anatomical and histological features of the digestive tract are consistent with the omnivorous habit of both these species.     

Matrix metalloproteinase-12 inhibitors: synthesis,structure-activity relationships and intestinal absorption of novel sugar-based biphenylsulfonamide carboxylates

MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors. All the new derivatives were tested on human recombinant MMP-12 and MMP-9 in order to evaluate their affinity and the selectivity for the target enzyme. Among them, the four most promising compounds were selected to assess their intestinal permeability using an ex vivo everted gut sac model. Given the high polarity and structural similarity to glucose, compound 3 was demonstrated to cross the intestinal membrane by using the facilitative GLUT2 transport.     

Development of a fluorogenic ADAMTS-7 substrate

The extracellular protease ADAMTS-7 has been identified as a potential therapeutic target in atherosclerosis and associated diseases such as coronary artery disease (CAD). However, ADAMTS-7 inhibitors have not been reported so far. Screening of inhibitors has been hindered by the lack of a suitable peptide substrate and, consequently, a convenient activity assay. Here we describe the first fluorescence resonance energy transfer (FRET) substrate for ADAMTS-7, ATS7FP7. ATS7FP7 was used to measure inhibition constants for the endogenous ADAMTS-7 inhibitor, TIMP-4, as well as two hydroxamate-based zinc chelating inhibitors. These inhibition constants match well with IC₅₀ values obtained with our SDS-PAGE assay that uses the N-terminal fragment of latent TGF-β–binding protein 4 (LTBP4S-A) as a substrate. Our novel fluorogenic substrate ATS7FP7 is suitable for high throughput screening of ADAMTS-7 inhibitors, thus accelerating translational studies aiming at inhibition of ADAMTS-7 as a novel treatment for cardiovascular diseases such as atherosclerosis and CAD.     

Traditional approaches to estimate length at first maturity (L50) retrieve better results than alternative ones in a Neotropical heptapterid

Length at first maturity (L₅₀) is an important tool for the management and conservation of fish populations. Traditional approaches based on macroscopic and microscopic maturity staging exhibit high accuracy and precision, while alternative approaches (e.g., I_g-based staging, stanza changing point) are less resource-demanding. Herein, we compare four approaches to estimate L₅₀ in a population of the heptapterid Rhamdioglanis transfasciatus from Atlantic Forest streams. Fish were sampled monthly during a year by using electrofishing. We measured the length (cm), mass (g), and gonad mass (g) of each specimen, then classified their maturity status macroscopically and microscopically. Alternative approaches were strongly discordant from traditional ones. Logistic curves considering mature individuals as those displaying at least 1% of the maximum I_g in the sample greatly underestimated L₅₀ for females and overestimated L₅₀ for males. The stanza changing point derived from the polyphasic growth model underestimated L₅₀ in both cases. Despite the increasing development of less onerous approaches, it seems that they are not suitable for all fish populations and the requirements to use such approaches demand further investigation.