Hypo-methylation mediates chromosomal instability in pancreatic NET.

DAXX and or ATRX loss occur in 40% of pancreatic neuroendocrine tumors (PanNETs). PanNETs negative for DAXX or ATRX show an increased risk of relapse. The tumor-associated pathways activated upon DAXX or ATRX loss and how this event may induce chromosomal instability (CIN) and alternative lengthening telomeres (ALT) are still unknown. Both DAXX and ATRX are involved in DNA methylation regulation. DNA methylation of heterochromatin and of non-coding sequences is extremely important for the maintenance of genomic stability. We analyzed the association of DAXX and/or ATRX loss and CIN with global DNA methylation in human PanNET samples and the effect of DAXX knock-down on methylation and cell proliferation. We assessed LINE1 as well as global DNA methylation in 167 PanNETs, and we found that DAXX and or ATRX-negative tumors and tumors with CIN were hypomethylated. DAXX knock-down in PanNET cell lines blocked cells in G1/G0 phase and seemed to increase CIN in QGP-1 cells. However, no direct changes in DNA methylation were observed after DAXX knock-down in vitro In conclusion, our data indicate that epigenetic changes are crucial steps in the progression of PanNETs loss and suggest that DNA methylation is the mechanism via which CIN is induced, allowing clonal expansion and selection.

Occupational exposure to PCDDs, PCDFs, and DL-PCBs in metallurgical plants of the Brescia (Lombardy Region, northern Italy) area.

The concentration values of polychlorodibenzodioxins (PCDDs), polychlorodibenzofurans (PCDFs), and dioxin-like polychlorobiphenyls (DL-PCBs) in blood serum samples (pools) of metallurgical workers in the area of the city of Brescia (northern Italy) were statistically processed. As to workers' exposure characteristics, pools were divided into 34 professionally exposed (PE) and 11 non-professionally exposed (NPE). A further subdivision of PE pools was according to workplaces in which ferrous (N = 24) and non-ferrous (N = 10) materials were handled. To evaluate the aforesaid differences we applied the age-adjusted Generalized Linear Models. We identified significant (P ≤ 0.05) exposure models of the classification groups. The first subdivision was confirmed by the concentrations of 1,2,3,4,6,7,8-H7CDF, DL-PCB 105, and DL-PCB 189; the second was confirmed by the concentrations of PCDF TEQ97, PCDD + PCDF + DL-PCB (TEQTOT) TEQ97, 2,3,4,7,8-P5CDF, 1,2,3,6,7,8-H6CDD, 1,2,3,4,6,7,8-H7CDD, and PCB 189. Based on the literature, all mentioned congeners have been found in stack gas and fly ash samples of metallurgical plants: therefore, these indicators indicate the exposure to such work environments. Specifically, the concentrations measured in the workers' blood serum appear to depend on the type of material processed during work.

Hemispheric lateralization in top-down attention during spatial relation processing: a Granger causal model approach.

Magnetoencephalography was recorded during a matching-to-sample plus cueing paradigm, in which participants judged the occurrence of changes in either categorical (CAT) or coordinate (COO) spatial relations. Previously, parietal and frontal lobes were identified as key areas in processing spatial relations and it was shown that each hemisphere was differently involved and modulated by the scope of the attention window (e.g. a large and small cue). In this study, Granger analysis highlighted the patterns of causality among involved brain areas--the direction of information transfer ran from the frontal to the visual cortex in the right hemisphere, whereas it ran in the opposite direction in the left side. Thus, the right frontal area seems to exert top-down influence, supporting the idea that, in this task, top-down signals are selectively related to the right side. Additionally, for CAT change preceded by a small cue, the right frontal gyrus was not involved in the information transfer, indicating a selective specialization of the left hemisphere for this condition. The present findings strengthen the conclusion of the presence of a remarkable hemispheric specialization for spatial relation processing and illustrate the complex interactions between the lateralized parts of the neural network. Moreover, they illustrate how focusing attention over large or small regions of the visual field engages these lateralized networks differently, particularly in the frontal regions of each hemisphere, consistent with the theory that spatial relation judgements require a fronto-parietal network in the left hemisphere for categorical relations and on the right hemisphere for coordinate spatial processing.

Registered Replication Report: Schooler and Engstler-Schooler (1990).

Trying to remember something now typically improves your ability to remember it later. However, after watching a video of a simulated bank robbery, participants who verbally described the robber were 25% worse at identifying the robber in a lineup than were participants who instead listed U.S. states and capitals-this has been termed the "verbal overshadowing" effect (Schooler & Engstler-Schooler, 1990). More recent studies suggested that this effect might be substantially smaller than first reported. Given uncertainty about the effect size, the influence of this finding in the memory literature, and its practical importance for police procedures, we conducted two collections of preregistered direct replications (RRR1 and RRR2) that differed only in the order of the description task and a filler task. In RRR1, when the description task immediately followed the robbery, participants who provided a description were 4% less likely to select the robber than were those in the control condition. In RRR2, when the description was delayed by 20 min, they were 16% less likely to select the robber. These findings reveal a robust verbal overshadowing effect that is strongly influenced by the relative timing of the tasks. The discussion considers further implications of these replications for our understanding of verbal overshadowing.

Are collapse models testable with quantum oscillating systems? The case of neutrinos, kaons, chiral molecules.

Collapse models provide a theoretical framework for understanding how classical world emerges from quantum mechanics. Their dynamics preserves (practically) quantum linearity for microscopic systems, while it becomes strongly nonlinear when moving towards macroscopic scale. The conventional approach to test collapse models is to create spatial superpositions of mesoscopic systems and then examine the loss of interference, while environmental noises are engineered carefully. Here we investigate a different approach: We study systems that naturally oscillate-creating quantum superpositions-and thus represent a natural case-study for testing quantum linearity: neutrinos, neutral mesons, and chiral molecules. We will show how spontaneous collapses affect their oscillatory behavior, and will compare them with environmental decoherence effects. We will show that, contrary to what previously predicted, collapse models cannot be tested with neutrinos. The effect is stronger for neutral mesons, but still beyond experimental reach. Instead, chiral molecules can offer promising candidates for testing collapse models.

Polychlorinated dibenzodioxins, dibenzofurans, and biphenyls in fresh water fish from Campania Region, southern Italy.

Twenty-eight fish muscle specimens from the main water bodies of the Campania Region were analyzed in our laboratory. On average, results showed a low contamination by PCDDs+PCDFs and a relatively more important presence of DL-PCBs. All specimens were compliant with EU regulatory maximum levels. Cumulative PCDD+PCDF+DL-PCB concentrations (TEQ(TOT)) were comprised in the range 0.223-11.4 pgWHO(97)-TEQ g(-1) fresh weight (fw). DL-PCB contribution to TEQ(TOT) was on average greater than 86% (range, 50.2-97.1%). The cumulative concentrations of 30 non-dioxin-like PCB congeners (Σ(30)(NDL-PCBs)) and of the six indicators (Σ(6)(NDL-PCBs)) were respectively in the ranges 3.30-515 and 1.30-195 ng g(-1) fw. The hybrid clustering approach adopted to analyze the sample-specific congener profiles indentified the main analytical patterns present in the database and, in particular, two main diverse exposure macro-areas that seem to exist north and south of the city of Naples. The distribution of PCDD and PCDF congeners among different species showed significant variations from chub (Leuciscus cephalus), characterized by a higher proportion of low-chlorinated congeners (e.g. 2,3,7,8-T(4)CDD), to eel (Anguilla anguilla), whose contamination consisted mainly of highly chlorinated congeners (e.g. O(8)CDD). To have a more complete perspective in relation to the contaminants present in the environment, the study suggestion is to use benthic as well as pelagic species to obtain an integrated characterization of fish tissue contamination.

Suppression of the GnRH pulse generator by neurokinin B involves a κ-opioid receptor-dependent mechanism.

Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and κ-opioid receptor (KOR), respectively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebroventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons. We performed a series of in vivo neuropharmacological experiments aiming to determine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the interaction between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons. First, we investigated the effect of intra-ARC administration of the selective NK3R agonist, senktide, on pulsatile LH secretion using a frequent automated serial sampling method to obtain blood samples from freely moving ovariectomized 17ß-estradiol-replaced rats. Our results show that senktide suppresses LH pulses in a dose-dependent manner. Intra-ARC administration of U50488, a selective KOR agonist, also caused a dose-dependent, albeit more modest, decrease in LH pulse frequency. Thus we tested the hypothesis that Dyn/KOR signaling localized to the ARC mediates the senktide-induced suppression of the LH pulse by profiling pulsatile LH secretion in response to senktide in rats pretreated with nor-binaltorphimine, a selective KOR antagonist. We show that nor-binaltorphimine blocks the senktide-induced suppression of pulsatile LH secretion but does not affect LH pulse frequency per se. In order to address the effects of acute activation of ARC NK3R, we quantified (using quantitative RT-PCR) changes in mRNA levels of KNDy-associated genes in hypothalamic micropunches following intra-ARC administration of senktide. Senktide down-regulated expression of genes encoding GnRH and GPR54 (GNRH1 and Kiss1r, respectively), but did not affect the expression of Kiss1 (which encodes kisspeptin). We conclude that NKB suppresses the GnRH pulse generator in a KOR-dependent fashion and regulates gene expression in GnRH neurons.

[Endometrial ablation versus hysterectomy in women treated with tamoxifen]. / Ablazione endometriale versus isterectomia in pazienti in trattamento con tamoxifene.

AIM: The aim of our study is the assessment of the importance of the endometrial ablation versus hysterectomy in patients treated with tamoxifen for previous breast cancer. METHODS: Fifty-eight outpatients in therapy with tamoxifen for 1 year were controlled in the Department of Gynaecology of the University of Naples. We have selected these patients in two groups: group A, with 28 women with abnormal uterine bleeding and endometrial thickness >8 mm and group B, with 30 normal endometrium asymptomatic women. All patient of group A and 18 of group B were treated with endometrial ablation. RESULTS: Next follow-up showed normal hysteroscopy figures in 89% of cases and 5% of cases needed a hysterectomy for new abnormal uterine bleeding and cytology. CONCLUSION: Our results show the utility of endometrial ablation especially in selected cases in therapy with tamoxifen for previous breast cancer.

[Fetal and maternal amniocentesis complications]. / Complicanze materno fetali dell'amniocentesi.

AIM: The aim of this study was to estimate the incidence of complications due to the prenatal invasive diagnosis performed by amniocentesis at the Department of Prenatal Diagnosis of the Second University of Naples. METHODS: A total of 1.580 patients who underwent amniocentesis from January 2001 to December 2003, were submitted to a telephone interview concerning the complications that occurred after the invasive diagnosis. RESULTS: Only 1.416 patients out of the total patients interviewed answered correctly to the questionnaire. The complications that occurred in the first 24 h from amniocentesis (early complications) included light contractions and lipothymia respectively in 8.3% and 6.7% of cases; losses of amniotic fluid took place in 1.06% while bleedings were observed in 0.85% of cases. The incidence of abortions occurred in the week following amniocentesis was 0.78%. Preterm labor occurred in only 6% of the patients submitted to amniocentesis, spontaneous labor at term in 43% and cesarean section in 51%. The Apgar index at birth was normal in 95.7% of cases. In the remaining 4.3% pathologies like hypoglycemia or respiratory distress, which promptly regressed, were observed. Early complications and the incidence of abortions were significantly and independently associated with the double needle puncture but not with maternal age or the placenta specimen obtained during amniocentesis. CONCLUSIONS: A careful observation of the technique and the protocol, as well as a careful selection of patients are necessary presuppositions in order to further decrease the occurrence of complications due to amniocentesis.

[Haemocoagulative modifications correlated with pregnancy]. / Modificazioni emocoagulative correlate allo stato gravidico.

AIM: The aim of this paper was to establish the physiologic changes in the coagulation and fibrinolytic systems during normal pregnancy. METHODS: One-hundred and twenty normal pregnant women were investigated in a longitudinal study involving 3 measurements: blood samples were collected at 12, 24 and 36 weeks of gestation and were assayed for prothrombin time, antithrombin III (ATIII) activity, protein C activity, protein S (PS) activity, prothrombin fragments 1+2, type 1 plasminogen activator inhibitor activity, tissue plasminogen activator antigen, plasminogen, activated protein C resistance, factors VII and VIII levels and D dimer. Student t-test, one way analysis of variance (ANOVA) and Fisher test were used for statistical analysis. RESULTS: Factor VII and factor VIII were always increased with respect to controls. Variance analysis showed a statistically significant reduction for anticoagulants (PS) and a rise for F1+2 and D dimer. With regard to fibrinolysis, there was an increase both for t-PA and PA1-1 during pregnancy. Moreover, the increased activity of factors of haemostasis was accompanied by an increase of activity and concentration of ATIII and acquired activated protein C resistance. CONCLUSIONS: These findings suggest that normal pregnancy is associated with an hypercoagulable state, resulting into a moderate risk for thrombosis during the different trimesters of pregnancy. Also broad spectrum assays which measure a range of trombin/fibrin formation in serum have become an established mean to identify activation of blood coagulation and/or fibrinolysis. There is a considerable interest in the application of these assays to the diagnosis of other acquired hypercoagulable states; such as thrombophilia during pregnancy. From the viewpoint of coagulation/fibrinolysis changes, the follow-up of thrombophilia markers could be recommended when levels of coagulation parameters exceed the normal values during pregnancy.

The importance of Doppler ultrasonography in the management of fetal growth restriction.

AIM: To evaluate the importance of Doppler ultrasonography in fetuses in the management of fetal growth restriction (FGR). METHODS: Sixty-five pregnant women, aged between 23 to 39 years and from 27 to 37 weeks of pregnancy were selected; they all carried a single fetus showing a diminished growth curve in respect to the previous echographic examinations. Women affected with diabetes types I and II, renal pathologies and/or past endocrinopathies were excluded. All the patients with fetal growth restriction underwent accurate flussimetric mapping of some fetal districts such as umbilical artery and ductus venosus. Modalities of birth and the neonatal outcome were also considered. RESULTS: The patients selected were divided into 4 groups according to the velocimetrical data. The neonatal outcome was positive when the end diastolic flow was present in the umbilical artery associated with a normal flow in the ductus venosus. In cases where the end diastolic flow was absent in the umbilical artery, the management and neonatal outcome varied in relation to the morphology of the flow in the ductus venosus: the absence or reverse A phase of the mentioned flow is often indicative of acute fetal distress and unfavourable prognosis. Reverse end diastolic flow in the umbilical artery was always associated with the intrauterine death of the fetus. CONCLUSIONS: Our results confirm the validity of Doppler ultrasonography in the management and in the choice of timing for birth in cases of fetal growth restriction.

The incidence of chromosomal anomalies in fetuses affected by mild renal pyelectasis.

AIM: The aim of this study was to evaluate the clinical significance of borderline fetal pyelectasis, whether it is associated with chromosomal aberration or is the expression of a structural defect of the urinary tracts. METHODS: We carried out echographies on 2900 pregnant women in the 2nd trimester of their pregnancies between January 1998 and March 2002 at the Department of Obstetrics, Gynaecology and Neonatology. Any patient with fetuses affected by borderline pyelectasis in association with other echographic markers of aneuploidy and in women 35 years of age and older with fetuses presenting isolated pyelectasis underwent amniocentesis for karyotyping. RESULTS: We discovered 2.1% (62 cases) of borderline pyelectasis in the general population. The karyotype was normal in all cases of isolated pyelectasis; 3/5 of the fetuses with borderline renal pyelectasts associated with other risk factors showed a chromosomal aberration. CONCLUSION: In accordance with existing documentation, the results of our research confirmed that isolated borderline pyelectasis does not increase the risk of chromosomopathies; this latter is significantly more frequent when pyelectasis is present in older pregnant women (>35 years of age) or is associated with other sonographic markers of chromosomal anomalies (choroids plexus cysts, cystic hygroma etc.). Prenatal cytogenetic tests of the fetal karyotype are to be recommended in older mothers and/or in presence of associated echographic anomalies. In this study we propose an early diagnosis of mild forms of pyelectasis which are misdiagnosed by superficial echographies, but which can be associated with chromosomopathy.

[Risk of chromosomal pathology in fetus with abnormal umbilical artery flowmetry]. / Rischio di cromosomopatie in feti con alterazioni flussimetriche dell'arteria ombelicale.

BACKGROUND: Goal of this study is to consider the incidence of chromosomal abnormalities in fetuses by velocimetry abnormalities. METHODS: The author select 64 pregnancies by velocimetry abnormalities of umbilical artery diastolic flow (ARED: Absent or Reverse end Diastolic Flow). RESULTS: The fetal cariotype from amniociti or from umbilical blood at delivery moment is resulted abnormal in 5 cases. Fetal-maternal risk factors of chromosomopaties are: malformations; fetal growth retardation; maternal age > or = 35. CONCLUSIONS: Other studies and other results are necessary for this discussion.

[Usefulness of ultrasonography of the cervical canal in the screening of pregnant women at risk of premature labor]. / Utilità dello studio ecografico del canale cervicale nello screening delle gestanti a rischio di parto pretermine.

BACKGROUND: Goal of the study is to evaluate the utility of cervical sonography in the second quarter as screening of pregnancies with risk of preterm labor. METHODS: A.A. evaluate, by transvaginal sonography (TVS) of the uterine cervix, 75 pregnancies with history of preterm labor and 25 with risk of preterm labor between XXIV and XXXIII week of pregnancy. The uterine cervix length < 40 mm and width > 5 mm, funneling were pathological and predictive factors of preterm labor. RESULTS: Eighty-five percent of pregnancies that have, at sonography TVG, abnormal values of length and width of uterine cervix, delivered before XXXVI week. CONCLUSIONS: These results confirm the importance of the high frequency ultrasonography transvaginal, TVS, for its predictive value and for treatment in pregnancies with risk of preterm labor.

[Prevention of gestational hypertension with calcium, linoleic acid, mono and polyunsaturated fatty acid supplements]. / Calcio, acido linoleico e acidi grassi mono e polinsaturi nella prevenzione della ipertensione gestazionale.

BACKGROUND: The aim of this study was to evaluate the benefits of calcium, linoleic acid and mono- and polyunsaturated fatty acids in the prevention of gestational hypertension. METHODS: Between January 1999 and June 2000, 65 primagravidas with a risk of gestational hypertension between the 20th and 24th week of pregnancy were recruited using Doppler velocimetry of the uterine arteries and Holter 24-h pressure monitoring. Patients with diabetes, hypertensive gestosis and previous renal pathologies were excluded. The patients were divided into 2 unequal groups: Group A (40 patients) was treated with calcium, linoleic acid, and mono and polyunsaturated fatty acid supplements; Group B (25 patients) received no treatment. The patients in both groups underwent Doppler velocimetry of the uterine arteries and Holter pressure monitoring at 28-30-32-35 weeks of gestation. RESULTS: Calcium linoleic acid and mono and polyunsaturated fatty acid supplements were effective in significantly reducing the incidence of gestational hypertension (p>0.05); in fact 90% of patients in Group A underwent a physiological evolution of pregnancy compared to only 10% affected by gestational hypertension. In the control group the incidence of this pathology was much higher (32%). CONCLUSIONS: The authors conclude that calcium linoleic acid and mono and polyunsaturated fatty acid supplements are useful and effective in the prevention of gestational hypertension in women at risk for this pathology.

PCDDs, PCDFs, PCBs and DDE in edible marine species from the Adriatic Sea.

Edible marine species from several areas of the Adriatic sea were analyzed for their content in persistent organic pollutants (POPs), such as polychlorinated dibenzodioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), and pp'-DDE (dichlorodiphenyldichloroethylene), a metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT). On the whole, PCDD/F contamination levels were low. In general, I-TEQ findings were greater for those species at higher levels in the trophic web (mackerel > red mullet > anchovy). Contamination levels were within 0.23 and 1.07 pg TEQ/g fw (fresh weight) in the aforesaid species, while all remaining species exhibited contamination levels ranging from approximately 0.07 to 0.25 pg TEQ/g fw. Besides, TEQ cumulative findings in species from the northern area were in general greater than those from the central and southern areas. PCB cumulative findings in the samples also revealed a detectable difference in contamination levels in species obtained from the northern, central, and southern sampling sites, between 7.6 and 177, 2.3 and 157, and 4.5 and 94 ng/g fw, respectively. The greatest PCB concentrations were found in mackerel (94-177 ng/g fw). Finally, DDE concentration levels varied from 0.7 to 32.4 ng/g fw. The highest levels of contamination were found in mackerel, red mullet and anchovy (17.7-32.4 ng/g fw, 8.1-9.8 ng/g fw, and 6.4-11.9 ng/g fw, respectively).

An overview of TCDD half-life in mammals and its correlation to body weight.

Major determinants of TCDD half-life in organisms are lipophilicity, metabolism, and hepatic binding sites. In addition, half-life seems to be empirically correlated to organism body weight. In this paper, this correlation is evaluated by a regression analysis of half-life measures and body weight data selected from the literature. Single exposure studies on laboratory mammals and human half-life data were specifically taken in consideration. The analysis outcome appears to be highly significant probably owing to the stability and generally slow metabolism of the substance in the organisms considered. The effect on half-life of factors other than body weight does not seem to influence significantly data dispersion around the regression line. The potential effects of a dose-dependent excretion cannot be excluded as toxicokinetic studies have been usually carried out at high exposure doses.