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Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

BackgroundMaternal high blood glucose during pregnancy increases the risk for both maternal and fetal adverse outcomes. The mechanisms underlying the regulator effects of hyperglycemia on placental development and growth have not been fully illustrated yet. The placenta expresses high amounts of both insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R). It has been reported that the placenta of diabetic women has structural and functional alterations and the insulin/IGF system is likely to play a role in these changes. The aim of the present study was to measure the content of IR and IGF-1R and their phosphorylation in the placenta of women with type 1 diabetes mellitus (T1D) or with gestational diabetes mellitus (GDM) compared to women with normal glucose tolerance (NGT) during pregnancy.MethodsPlacental tissues were obtained from 80 Caucasian women with a singleton pregnancy. In particular, we collected placenta samples from 20 T1D patients, 20 GDM patients and 40 NGT women during pregnancy. Clinical characteristics and anthropometric measures of all women as well as delivery and newborn characteristics were recorded. Patients were also subdivided on the basis of peripartum glycemia either ≥90 mg/dl or ResultsIn T1D patients, a higher rate of adverse outcomes was observed. Compared to the GDM women, the T1D group showed significantly higher average capillary blood glucose levels at the third trimester of pregnancy and at peripartum, and higher third-trimester HbA1c values. In both T1D and GDM women, HbA1c values during pregnancy correlated with glucose values in the peripartum period (R-squared 0.14, p=0.02). A positive correlation was observed between phosphorylation of placental IR and the glucose levels during the third trimester of GDM and T1D pregnancy (R-squared 0.21, p=0.003). In the placenta of T1D patients, IGF-1R phosphorylation and IR isoform A (IR-A) expression were significantly increased (p=0.006 and p=0.040, respectively), compared to the NGT women. Moreover, IGF-1R phosphorylation was significantly increased (p90 mg/dl, while IR-A expression was increased in those with peripartum blood glucose higher than 120 mg/dl (p=0.046).ConclusionsTo the best of our knowledge, our study represents the first one in which an increased maternal blood glucose level during pregnancy is associated with an increased IGF-1R phosphorylation and IR-A expression in the placenta. Both these mechanisms can promote an excessive fetal growth.

The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell model deprived of the Insulin-like Growth Factor 1 Receptor (IGF1-R) we therefore generated cells exhibiting no IR (R-shIR cells), or only human IR-A (R-shIR-A), or exclusively human IR-B (R-shIR-B) and we studied the specific effect of the two isoforms on cell proliferation and cell apoptosis. In the absence of insulin both IR-A and IR-B similarly inhibited proliferation but IR-B was 2–3 fold more effective than IR-A in reducing resistance to etoposide-induced DNA damage. In the presence of insulin, IR-A and IR-B promoted proliferation with the former significantly more effective than the latter at increasing insulin concentrations. Moreover, only insulin-bound IR-A, but not IR-B, protected cells from etoposide-induced cytotoxicity. In conclusion, IR isoforms have different effects on cell proliferation and survival. When unoccupied, IR-A, which is predominantly expressed in undifferentiated and neoplastic cells, is less effective than IR-B in protecting cells from DNA damage. In the presence of insulin, particularly when present at high levels, IR-A provides a selective growth advantage.

Insulin degludec is an extra‐long‐acting insulin analog that allows for enhanced efficacy and flexibility in the injection time. However, it is not approved for use during pregnancy. We report the pregnancy outcome and newborn conditions in two women with type 1 diabetes who continued preconception degludec treatment during embryogenesis. No pregnancy complication or congenital neonatal malformation was observed. Both babies presented with hypoglycemia and required neonatal intensive care unit admission. Degludec treatment did not cause adverse effects in the mothers or malformations in the newborns. The observed neonatal complications were probably independent of early pregnancy degludec treatment.

The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.

TORCH complex, one of the potential infections that may occur during pregnancy, may contribute also to prenatal pregnant women's anxiety and depression. The aim of this study was to explore the presence of psychiatric symptoms, in relation with infection of TORCH agents, specifically the Toxoplasma gondii (T. gondii) and Cytomegalovirus (CMV). The study was conducted on 58 preg- nant women recruited from the Clinical Virology Unit, A.O.U. Policlinico-Vittorio Emanuele, P.O. "Gaspare Rodolico", from September 2012 to March 2014. Psychiatric symptoms were evaluated through the Symptom Checklist-90 Revised (SCL-90 R) in pregnant women with CMV or T. gondii infection. Moreover, pregnant women were invited to participate in a program of "Counseling about behavioral change", an effective psychotherapeutic training for the development of new motivational strategies to the infection acceptance, the greater self-confidence and greater adhe- rence to treatment. The age of the subjects was positively correlated with Depression (r = 0.119, p < 0.05) and negatively correlated with Phobic Anxiety (r = −0.178, p < 0.05). The same variables were also negatively correlated with the level of education (r = −0.231, r = −0.320, p < 0.05) and with the dimension Somatization (r = −0.208, p < 0.05). Somatization was positively correlated with unmarried patients (r = 0.141, p < 0.05), while Phobic Anxiety was negatively correlated with unmarried patients (r = −0.105, p < 0.05). Somatization, Phobic Anxiety and Depression were po- * Corresponding author.

Purpose Heart diseases can alter liver volume, morphology, and circulation. The Doppler pulsatility of the portal vein and its pulsatility ratio (PR) have been reported as being closely associated with the right atrial pressure and with the New York Heart Association (NYHA) class. We examined the relationships between measurements of liver and spleen dimensions and blood flow in portal and hepatic veins, assessed noninvasively by Doppler sonography, and compared them with echocardiographic data. Methods The study group comprised 87 inpatients with heart failure. The mean age was 64 ± 12 years. Patients underwent duplex Doppler sonography of the heart and portal and hepatic veins. Results Patients with more severe left ventricular failure (NYHA class III–IV) showed more dilatation of the left ventricle and atrium, reduced systolic function, and reduced portal vein mean velocity compared with patients with milder heart failure (NYHA class I–II); in addition, the hepatic vein diameter was increased and portal vein PR was reduced. Considering all patients, significant positive correlations were found between portal vein PR and left ventricular shortening fraction (r = 0.34, p < 0.01) and ejection fraction (r = 0.38, p < 0.001). Significant negative correlations were found between PR and hepatic vein diameter (r = −0.44, p < 0.001), right ventricle diameter (r = −0.38, p < 0.001), left ventricular end-diastolic volume (r = −0.31, p < 0.01), and left atrium diameter (r = −0.33, p < 0.01). Patients with hepatic vein dilatation had increased left ventricular volumes, reduced systolic function indices, and portal vein alterations (increased diameter, reduced mean velocity, and reduced PR). In patients with an ejection fraction of no more than 50%, only PR was significantly reduced, while other sonographic liver measurements were not significantly different. Conclusions The effects of cardiac failure on portal blood flow, which declines progressively with worsening cardiac function, is shown better by the pulsatility pattern of the portal vein than by morphologic caval and hepatic vein measurements. PR can be used as a reliable adjunctive sign of heart failure. © 1998 John Wiley & Sons, Inc. J Clin Ultrasound26: 27–31, 1998.