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.

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.

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.

Toxic PCB congeners and organochlorine pesticides in Italian human milk.

Human milk from four major Italian cities was analyzed for individual congeners of polychlorinated biphenyls (PCB), DDT, DDE, hexachlorobenzene, and beta-hexachlorocyclohexane. Minimum and maximum concentrations in milk from individual mothers for most compounds ranged between one order of magnitude below and above the mean value of all mothers. Good agreements were found between results from pooled samples and mean values of individual samples. No statistically significant difference between cities was found and the levels in milk from Italian mothers did not differ significantly from published levels from other parts of the world. Principal component analyses revealed that the PCB congener distribution pattern was very similar in all mothers, independent of location. Average concentrations in milk from the four cities were 19(+/- 5) micrograms liter-1 total PCB or 3.2(+/- 0.8) ng liter-1 toxicity equivalents according to the most conservative TCDD toxicity equivalent factors of PCBs proposed in the literature, 70(+/- 18) micrograms liter-1 DDE, 4.5(+/- 1.2) micrograms liter-1 DDT, 5.6(+/- 1.9) micrograms liter-1 HCB, and 4.4(+/- 1.7) micrograms liter-1 beta-hexachlorocyclohexane.

Reliability assessment of a gas chromatographic method for polycyclic aromatic hydrocarbons in olive oil.

A quality control test was developed for a gas chromatographic method to determine polycyclic aromatic hydrocarbons in olive oil. Fifteen oil specimens were fortified with eight three- to six-ring polycyclic aromatic hydrocarbons at levels of between 3.0 (approximate detection limit) and 360 micrograms/kg. Three sets of five equally fortified specimens were obtained and assayed at random by three operators. For each fortification level, the means of recovery yield were in the range 56-107%, and were independent of the polycyclic aromatic hydrocarbon congener specificity and the operator's capability. Excluding subsets of data associated with both the fortification level at the detection limit and a deviant polycyclic aromatic hydrocarbon term (benzo[ghi]perylene), an overall mean accuracy of 96% and a precision of 7% were achieved.

Assisted circulation for myocardial recovery after repair of congenital heart disease.

Between January 1987 and May 1990, six children underwent ventricular assisted circulation for recovery of myocardial function after cardiac surgery. Their ages ranged from 9 months to 12 years. Three patients had tetralogy of Fallot and one had atrioventricular discordance with ventriculoarterial concordance, ventricular septal defect, and under-over ventricles. Double outlet left ventricle and a large ventricular septal defect with pulmonary hypertension was present in the remaining two. The duration of circulatory support averaged 126 +/- 57 h. An extracorporeal membrane oxygenator (ECMO) was used in four patients, biventricular assistance with centrifugal pumps in one, and left ventricular assistance followed by ECMO in the last patient. Circulatory support was begun in the operating room in two patients who could not be weaned from cardiopulmonary bypass. Both these patients are long-term survivors. Assisted circulation was implanted in four patients in the intensive care unit because of low cardiac output refractory to any pharmacological treatment. Only one of these patients could be weaned from circulatory support but he died 20 days later because of multiorgan failure due to persistent poor myocardial function. The causes of death in the remaining three patients were intracranial hemorrhage, untreatable bleeding, and failure of myocardial recovery, respectively. We believe that early postoperative use of circulatory support can be a major determinant for recovery of myocardial function in patients who have severe low cardiac output following repair of congenital cardiac lesions. Our initial experience with the use of biventricular assistance in small children is encouraging. Nevertheless, further observations are clearly necessary to establish the role of postoperative circulatory support in children with congenital cardiac lesions.

[Circulatory assistance in high-risk coronary angioplasty]. / Assistenza circolatoria nell'angioplastica coronarica ad alto rischio.

Femoral vein to artery cardiopulmonary by-pass was used during coronary angioplasty in five high risk patients. In four patients the target vessel supplied more than half of the viable myocardium; in one of these, the ejection fraction of the left ventricle was less than 20%. In one patient the relative contraindications for surgery were the patient's age and the presence of concomitant renal failure. Cardiopulmonary support was established by using cut-down cannulae insertion in three patients and by using the percutaneous system in two. In the latter, the support was stand-by, but the abrupt closure of the artery ten minutes after the end of the successful procedure, required the prompt activation of the support and the patient was treated with emergency saphenous graft. The use of the cardiopulmonary support either as a prophylactic or as a stand-by, enabled coronary angioplasty to be performed on these high-risk patients. The clinical and anatomical data relative to the five patients as well as the possible use of the cardiopulmonary support system either as a prophylactic or standby application during high-risk PTCA are discussed.

Primary vaginal squamous cell carcinoma in the young patient.

This report, prompted by the recent observation of three cases of primary squamous cell carcinoma in relatively young patients, reviews the English-language literature in search of information on age-related incidence for this tumor in the below-40 age group. From those series providing data, it was found that only 10% of these tumors occur in patients less than 40 years old. No authentic squamous cell vaginal cancer could be found in patients less than 10 years of age, and only five such well-documented cases were found in the age group 11-20. The incidence of this tumor then rises abruptly to 60 patients in the age group 21-30 and to 160 patients in the age group 31-40. The rarity of the tumor, particularly with regard to the anatomical location, is impressive as well as enigmatic.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in the environment: human health risk estimation and its application to the Seveso case as an example.

Findings from selected dose-response experimental studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) carcinogenic action in rodents were utilized for low-dose lifetime cancer risk estimation in man. The Weibull, Armitage-Doll, and linearized Armitage-Doll mathematical models were employed in this work. Conversion factors, based on body surface, of 1/5 and 1/11 were also employed for rat- and mouse-to-man extrapolation. Conservative estimates from the linearized Armitage-Doll upper 99% confidence limit associate a 10(-5) risk probability level to TCDD daily doses of 0.15-2.4 pg/kg body wt., while levels of 10(-6) and 10(-7) are associated with uptakes 10- and 100-fold lower, respectively. Based on environmental microanalytical records, exposure to TCDD of Seveso (Milan, Italy) Zone B and R inhabitants was calculated from 0.5 year after the accident onward. Exposure through food produced locally was assumed to be zero. The lifetime cancer risk for the considered cohort at the highest exposure does not appear to exceed 10(-5).

Ecotoxicological profile of xylenes. Working Party on Ecotoxicological Profiles of Chemicals.

The xylenes (o, m, p), which are produced in large amounts and widely used, must be considered as environmental contaminants, as they have been identified in the atmosphere of many countries. Their acute and chronic toxicity in mammals is moderate. Mutagenic and teratogenic properties can be excluded. Carcinogenic potential has been at present inadequately studied. In man some disturbances are evident at the concentration of 45 ppm. Hepatic metabolism is a valid process of detoxification and its high rate limits the risk of accumulation of the xylenes in adipose tissue. Ecotoxicological data refer almost exclusively to water. No long-term tests have been made. However, the high volatility, elevated elimination, and the low factor of accumulation suggest the impact on aquatic environment should be limited. Xylenes are easily biodegraded by many microorganisms. Photoxydation is one of the main degradation processes, responsible for the disappearance of the xylenes from the atmosphere.