Exposure and effective dose biomarkers for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in infertile subjects: preliminary results of the PREVIENI project

Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been used as surfactants in various industry and consumer products. PFOS/PFOA are very persistent in the environment and bioaccumulate in humans. They are potential reproductive and developmental toxicants and are considered to be emerging endocrine disrupters (EDs). The Italian project PREVIENI, funded by the Italian Environment Ministry, aims to link environment and human health through the investigation of selected endocrine disrupters (EDs) exposure and associated biomarkers related to human infertility conditions. In the early PREVIENI phase, PFOS and PFOA were determined in 53 couples affected by an infertility status, enrolled in a metropolitan area, according to established inclusion criteria and informed consensus. Nuclear receptors related to chemical compounds interactions were selected as biomarkers of effect and their gene expression modulations were analyzed in human peripheral blood mononuclear cell (PBMC). Among couples, subjects not presenting infertility factors (IF--) were separated from affected subjects (IF++). Most IF-- serum samples showed PFOS and PFOA concentrations overlapping the limit of detection (LOD) of 0.5 ng/g wet weight (ww). A substantial percentage of IF++ serum samples showed PFOS concentrations >20-fold the LOD, i.e. from 3 to 50 ng/g ww. In male (50%, n=26) and from 3 to 144 ng/g ww in female (37%, n=30) samples. PFOA values were below the LOD levels in 90% of the total samples. Peroxisome proliferator-activated receptor-gamma (PPARγ) and aryl hydrocarbon receptor (AhR) showed a low level of expression in PBMC of both IF++ and IF-- groups. Whereas alpha and beta estrogen receptors (ERα and ERβ), androgen receptor (AR), and pregnane X receptor (PXR) were all upregulated in IF++ of both sexes with respect to IF-- group. Our preliminary results related to the metropolitan area indicate that subjects affected by infertility factors tend to have both higher PFOS levels and higher gene expression of specific nuclear receptors.     

A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment

Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 10(9)/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group-defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 10(9)/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET.     

Long-term effects of intensive B cell depletion therapy in severe cases of IgG4-related disease with renal involvement

Immunologic Research - IgG4-related disease (IgG4-RD) is an immune-mediated disorder often showing elevated serum IgG4 concentrations, dense T and B lymphocyte infiltration, and IgG4-positive...     

P2X7 activation enhances skeletal muscle metabolism and regeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis

Muscle weakness plays an important role in neuromuscular disorders comprising amyotrophic lateral sclerosis (ALS). However, it is not established whether muscle denervation originates from the motor neurons, the muscles or more likely both. Previous studies have shown that the expression of the SOD1G93A mutation in skeletal muscles causes denervation of the neuromuscular junctions, inability to regenerate and consequent atrophy, all clear symptoms of ALS. In this work, we used SOD1G93A mice, a model that best mimics some pathological features of both familial and sporadic ALS, and we investigated some biological effects induced by the activation of the P2X7 receptor in the skeletal muscles. The P2X7, belonging to the ionotropic family of purinergic receptors for extracellular ATP, is abundantly expressed in the healthy skeletal muscles, where it controls cell duplication, differentiation, regeneration or death. In particular, we evaluated whether an in vivo treatment in SOD1G93A mice with the P2X7 specific agonist 2′(3′)‐O‐(4‐Benzoylbenzoyl) adenosine5′‐triphosphate (BzATP) just before the onset of a pathological neuromuscular phenotype could exert beneficial effects in the skeletal muscles. Our findings indicate that stimulation of P2X7 improves the innervation and metabolism of myofibers, moreover elicits the proliferation/differentiation of satellite cells, thus preventing the denervation atrophy of skeletal muscles in SOD1G93A mice. Overall, this study suggests that a P2X7‐targeted and site‐specific modulation might be a strategy to interfere with the complex multifactorial and multisystem nature of ALS.     

TMEM16E/ANO5 mutations related to bone dysplasia or muscular dystrophy cause opposite effects on lipid scrambling

Mutations in the human TMEM16E/ANO5 gene are causative for gnathodiaphyseal dysplasia (GDD), a rare bone malformation and fragility disorder, and for two types of muscular dystrophy (MD). Previous studies have demonstrated that TMEM16E/ANO5 is a Ca²⁺‐activated phospholipid scramblase and that the mutation c.1538C>T (p.Thr513Ile) causing GDD leads to a gain‐of‐function phenotype. Here, using established HEK293‐based functional assays, we investigated the effects of MD‐related and further GDD‐related amino acid exchanges on TMEM16E/ANO5 function in the same expression system. These experiments also revealed that the gradual changes in HEK293 cell morphology observed upon expression of TMEM16E/ANO5^GDD mutants are a consequence of aberrant protein activity. Our results collectively demonstrate that, on the level of protein function, MD mutations are associated to loss‐of‐function and GDD mutations to gain‐of‐function phenotypes, confirming conjectures made on the basis of inheritance modes.     

Insulin resistance in the early stages of renal failure: implications for cardiovascular risk

An elevated risk of cardiovascular events is present in patients with mild-to-moderate renal function impairment. Similar to patients with end-stage renal disease, this elevated risk can be accounted for by high prevalence of classic and emergent cardiovascular risk factors and additional conditions that are more specifically related to the organ failure, such as anemia and electrolyte disturbances. Among emergent cardiovascular risk factors, insulin resistance has been demonstrated to contribute significantly to the cardiovascular risk in the general population and it is known that abnormalities of glucose metabolism and hyperinsulinemia due to insulin resistance are present in patients with renal failure. Because patients with more advanced disease stage have several abnormalities that might affect the cellular action of insulin acting as important confounders, the relationship between insulin sensitivity and renal function should be better evaluated in the early stages of renal failure. This article overviews the evidence supporting the presence of increased cardiovascular morbidity and mortality in patients with early stages of renal disease, and examines the potential for insulin resistance to contribute to cardiovascular risk in these patients.     

Phylodynamic and phylogeographic patterns of the HIV type 1 subtype F1 parenteral epidemic in Romania

In the late 1980s an HIV-1 epidemic emerged in Romania that was dominated by subtype F1. The main route of infection is believed to be parenteral transmission in children. We sequenced partial pol coding regions of 70 subtype F1 samples from children and adolescents from the PENTA-EPPICC network of which 67 were from Romania. Phylogenetic reconstruction using the sequences and other publically available global subtype F sequences showed that 79% of Romanian F1 sequences formed a statistically robust monophyletic cluster. The monophyletic cluster was epidemiologically linked to parenteral transmission in children. Coalescent-based analysis dated the origins of the parenteral epidemic to 1983 [1981-1987; 95% HPD]. The analysis also shows that the epidemic's effective population size has remained fairly constant since the early 1990s suggesting limited onward spread of the virus within the population. Furthermore, phylogeographic analysis suggests that the root location of the parenteral epidemic was Bucharest.