Perfluorooctanoic acid disrupts gap junction intercellular communication and induces reactive oxygen species formation and apoptosis in mouse ovaries

Perfluorooctanoic acid (PFOA) is a member of the perfluoroalkyl acid family of compounds. Due to the presence of strong carbon–fluorine bonds, it is practically nonbiodegradable and highly persistent in the environment. PFOA has been detected in the follicular fluid of women, and positively associated with reduced fecundability and infertility. However, there are no reports concerning the experimental evaluation of PFOA on oocyte toxicity in mammals. The aim of the present study was to determine if PFOA is able to induce oxidative stress in fetal ovaries and cause apoptosis in oocytes in vitro. In addition, since inhibition of the gap junction intercellular communication (GJIC) by PFOA has been demonstrated in liver cells in vivo and in vitro, the effect of PFOA on the GJIC between the oocyte and its supportive cumulus cells was studied. Results show that PFOA induced oocyte apoptosis and necrosis in vitro (medium lethal concentration, LC₅₀ = 112.8 μM), as evaluated with Annexin‐V‐Alexa 508 in combination with BOBO‐1 staining. Reactive oxygen species (ROS) levels, as assessed by DCFH‐DA, increased significantly in fetal ovaries exposed to ¼ LC₅₀ (28.2 μM, a noncytotoxic and relevant occupational exposure concentration) and LC₅₀ PFOA ex vivo. This perfluorinated compound also caused the blockage of GJIC in cumulus cells‐oocyte complexes (COCs) obtained from female mice exposed in vivo, as evaluated by calcein transfer from cumulus cells to the oocyte. The ability of PFOA of disrupting the GJIC in COCs, generating ROS in the fetal ovary and causing apoptosis and necrosis in mammal's oocytes, might account for the reported association between increasing maternal plasma concentrations of PFOA with reduced fertility in women.     

Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma

Objective: Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma. Methods: In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n?=?25?975, follow-up 3.0?±?1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV and heart failure) and four conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates. Results: HIV followed by alcoholism and mental disorders among 18–45-years old, and heart failure, diabetes, IHD and cancer among those ≥65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18–45 years old, and chronic sinusitis, mental disorder and IHD among those ≥65-years old. GERD was associated with decreased risk for asthma exacerbation in all ages. Conclusions: Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.     

Pregnancy complications predict thrombotic events in young women with essential thrombocythemia

Although Philadelphia‐negative myeloproliferative neoplasms (MPNs) occur typically in middle to advanced age, any age group may be affected, posing a challenge for their management during pregnancy when they occur in young females. There is a high incidence of thromboembolic events and pregnancy complications in patients with myeloproliferative neoplasms, and a possible relationship between these complications is a matter of concern. The aim of this article was to correlate thrombosis and pregnancy outcome in 158 females with ET experiencing 237 pregnancies. Seven patients had a thrombotic event before their first pregnancy, one of them ended (14.3%) in a miscarriage. Among the 151 patients with no history of thrombosis before they became pregnant, 40 (26.5%) had a miscarriage (P = NS). Eighteen patients (11.4%) developed major thrombotic complications (12 splanchnic vein, 1 cerebral vein, 2 coronary syndromes, and 3 strokes) after at least one pregnancy (4 uneventful and 14 complicated). The occurrence of thrombosis was significantly more frequent (P < 0.001) in patients with a history of pregnancy complications (28%) than in those experiencing a normal pregnancy and delivery (3.7%). Pregnancy complications in women with ET are associated with a higher risk of subsequent thromboses, so pregnant women with this neoplasm who miscarry need to be carefully monitored. Am. J. Hematol. 89:306–309, 2014. © 2013 Wiley Periodicals, Inc.     

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).     

Left-Atrial-Appendage Occluder Migrates in an Asymptomatic Patient

Percutaneous closure of the left atrial appendage (LAA) is a new approach to the prevention of cardioembolic events in patients with atrial fibrillation. We implanted an LAA occlusion device (Amplatzer™ Cardiac Plug) in a 70-year-old woman via a transseptal approach. Upon her discharge from the hospital, a transthoracic echocardiogram showed stable anchoring of the device; 6 months after implantation, a routine transthoracic echocardiogram revealed migration of the occluder into the left ventricular outflow tract, in the absence of symptoms. We surgically removed the device from the mitral subvalvular apparatus and closed the LAA with sutures. This case shows that percutaneous LAA occlusion can result in serious adverse events, including device migration in the absence of signs or symptoms; therefore, careful follow-up monitoring is mandatory.