Echinoderms as blueprints for biocalcification: regulation of skeletogenic genes and matrices.

Echinoderms have an extensive endoskeleton composed of magnesian calcite, a form of calcium carbonate that contains small amounts of magnesium carbonate and occluded matrix proteins. Adult sea urchins have several calcified structures, including test, teeth, and spines, composed of numerous ossicles which form a three-dimensional meshwork of mineral trabeculae, the stereom. The biomineral development begins in 24-hour-old embryos within the primary mesenchyme cells (PMCs), the only cells producing a set of necessary matrix proteins. The deposition of the biomineral occurs in a privileged extracellular space produced by the fused filopodial processes of the PMCs. We showed for the first time that signals from ectoderm cells overlying PMCs play an important role in the regulation of biomineralization-related genes. It is believed that growth factors are produced by ectoderm cells and released into the blastocoel where they interact with cognate receptor tyrosine kinases restricted to PMCs, which activate signaling cascades regulating the expression of biomineralization-related genes. We demonstrated the implication of a TGF-beta family factor by a perturbation model in which skeleton elongation was indirectly blocked by monoclonal antibodies to an extracellular matrix (ECM) protein located on the apical surface of ectoderm. Thus, it was inferred that interfering with the binding of the ECM ligand, a member of the discoidin family, to its cell surface receptor, a ßC integrin, disrupts the ectodermal cell signaling cascade, resulting in reduced or aberrant skeletons. During the last few years, we analyzed the expression of biomineralization-related genes in other examples of experimentally induced skeleton malformations, produced by the exposure to toxic metals, such as Cd and Mn or ionizing radiations, such as UV-B and X-rays. Besides the obvious toxicological implication, since the mis-expression of spicule matrix genes paralleled skeleton defects, we believe that by means of these studies we can dissect the molecular steps taking place and possibly understand the physiological events regulating embryonic biomineralization.

Simultaneous abdominal wall defect repair and Tenckhoff catheter placement in candidates for peritoneal dialysis.

INTRODUCTION: The presence of pre-existing abdominal wall defect (AWD) could represent a potential contraindication for peritoneal dialysis (PD) treatment. We report the results of our 6-year experience involving simultaneous repair of pre-existing AWD and catheter insertion for PD. METHODS: Patients with estimated glomerular filtration rate (e-GFR) 7-10 ml/min attending a single nephrology clinic between January 2008 and December 2014 were evaluated. Simultaneous AWD repair and catheter placement was performed. For inguinal (IH) or umbilical hernia (UH), a prolene mesh repair technique was adopted. Except for one case of total anaesthesia, the surgical procedure was performed under either spinal or local anaesthesia. Ceftazidime alone or in association with quinolones was administered 1 h before surgery in a single dose. Patients were discharged 2 days after surgery, and returned to the clinic twice during the 1st week for peritoneum washing (first volume of peritoneal dialysis solution: 300 ml). From week 3, volume (2000 ml) and dwells were personalized according to the patient's clinical condition; options were: incremental PD, standard PD, or continuous cycling PD. Surgical follow-up was planned at 1, 6, and 12 months. RESULTS: Peritoneal catheters were inserted in 170 patients. IH, UH and incisional hernia were found in 18, 2 and 1 patients, respectively. IH was bilateral in 4 patients; concomitant IH and UH occurred in 1 patient. There were no deaths, nor intra-operative complications apart from scrotal haematoma in 1 patient. Over a mean follow-up of 551 days (range 342-1274) no hernia recurrence was registered and the peritoneal catheter continued functioning without problems. CONCLUSIONS: Simultaneous AWD repair and peritoneal catheter placement seems a reliable and safe surgical procedure that allows patients with AWD to benefit from PD treatment.

Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II.

Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases. CDA type II (CDAII) is the most frequent CDA. It is characterized by ineffective erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance. Other features of the peripheral red blood cells are protein and lipid dysglycosylation and endoplasmic reticulum double-membrane remnants. Development of other hematopoietic lineages is normal. Individuals with CDAII show progressive splenomegaly, gallstones and iron overload potentially with liver cirrhosis or cardiac failure. Here we show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)-mediated suppression of SEC23B expression recapitulates the cytokinesis defect. Knockdown of zebrafish sec23b also leads to aberrant erythrocyte development. Our results provide in vivo evidence for SEC23B selectivity in erythroid differentiation and show that SEC23A and SEC23B, although highly related paralogous secretory COPII components, are nonredundant in erythrocyte maturation.

Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy.

UNLABELLED: The response to antiviral therapy is lower in hepatitis C virus (HCV) patients with genotype 1 than in those with genotype 2. Overexpression of the suppressor of cytokine signaling 3 (SOCS3) gene in liver tissue is associated with a poorer treatment outcome in patients with chronic hepatitis C viral genotype 1. Also, insulin resistance has been implicated in nonresponse to an anti-HCV treatment. To understand why HCV genotype 1 patients respond differently, we investigated SOCS3 gene expression, metabolic syndrome (MS), and the response to therapy in a cohort of patients with HCV-related hepatitis. A total of 198 patients (108 with genotype 1 and 90 with genotype 2) treated with pegylated interferon plus ribavirin were consecutively enrolled in the study. We measured SOCS3 expression in Epstein-Barr virus-transformed lymphoblastoid cell lines derived from peripheral lymphocytes of a subset of 130 patients. MS was more frequent in genotype 1 patients than in genotype 2 patients (P < 0.01). Nonresponders (P < 0.01), MS (P < 0.001), and genotype 1 (P < 0.001) were significantly related to SOCS3 overexpression. However, SOCS3 levels were higher in nonresponders also, regardless of the genotype (P < 0.01). In a univariate analysis, the genotype (P < 0.001), age (P < 0.001), SOCS3 (P < 0.001), and MS (P < 0.001) were significantly related to the response to therapy. However, in a multivariate analysis, SOCS3 was the only independent predictor of the response (odds ratio = 6.7; P < 0.005). CONCLUSION: We speculate that SOCS3 expression per se may influence the response to antiviral therapy and that the genotype 1b virus might induce its up-regulation. This may account for the different responses to therapy between genotype 1-infected and genotype 2-infected patients.