The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling.

AIMS: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. METHODS: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. RESULTS: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. CONCLUSIONS: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.

[Obesity and Eating Disorders. Indications for the different levels of care. An Italian Expert Consensus Document]. / Documento di Consensus. Obesità e Disturbi dell'Alimentazione Indicazioni per i diversi livelli di trattamento.

This paper is an Italian Expert Consensus Document on multidimensional treatment of obesity and eating disorders. The Document is based on a wide survey of expert opinion. It presents, in particular, considerations regarding how clinicians go about choosing the most appropriate site of treatment for a given patient suffering from obesity and/or eating disorders: outpatient, partial hospitalization, residential rehabilitation centre, inpatient hospitalization. In a majority of instances obesity and eating disorders are long-term diseases and require a multiprofessional team-approach. In determining an initial level of care or a change to a different level of care, it is essential to consider together the overall physical condition, medical complications, disabilities, psychiatric comorbidity, psychology, behaviour, family, social resources, environment, and available services. We first created a review manuscript, a skeleton algorithm and two rating scales, based on the published guidelines and the existing research literature. As the second point we highlighted a number of clinical questions that had to be addressed in the specific context of our National Health Service and available specialized care units. Then we submitted eleven progressive revisions of the Document to the experts up to the final synthesis that was approved by the group. Of course, from point to point, some of the individual experts would differ with the consensus view. The document can be viewed as an expert consultation and the clinical judgement must always be tailored to the particular needs of each clinical situation. We will continue to revise the Document periodically based on new research information and on reassessment of expert opinion to keep it up-to-date. The Document was not financially sponsored.

Metabolic or bariatric surgery? Long-term effects of malabsorptive vs restrictive bariatric techniques on body composition and cardiometabolic risk factors.

BACKGROUND: Obesity is an increasing health problem and surgery seems to be the only treatment effective in achieving weight loss without relapse. Among bariatric techniques, many differences exist in terms of weight loss and resolution of comorbidities. Up to now, there are no prospective studies comparing long-term effects of malabsorptive vs restrictive techniques. OBJECTIVE: In this study, cardiometabolic risk factors and body composition changes after malabsorptive biliointestinal bypass (BIBP) and restrictive laparoscopic adjustable gastric banding (LAGB) were compared during a 4-year follow-up. DESIGN: Prospective, case-control and cohort study. PATIENTS: In all, 80 obese subjects, matched for weight and age. Altogether, 40 patients underwent BIBP and 40 underwent LAGB. MEASUREMENTS: Weight, body composition, fasting and post-loading plasma glucose and insulin, homeostatic model assessment index (HOMA-I), lipid profile, blood pressure (BP), erythrocyte sedimentation rate and fibrinogen were monitored at baseline, 12 and 48 months. RESULTS: At 12 months after surgery, a significant reduction in body mass index, total fat mass (FM), trunk FM (trFM), trFM/legs FM (lFM) ratio (trFM/lFM), triglycerides, BP and inflammation markers was observed in both groups. BIBP patients showed a significant reduction in total cholesterol (Tot-C), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), whereas the LAGB group showed a significant increase of HDL-C. A further improvement of all the parameters evaluated was seen in the BIBP group at 48 months after surgery. CONCLUSIONS: Both bariatric procedures exerted positive effects on cardiometabolic risk factors and on weight loss in the population studied, but on the long-term period, HOMA-I, Tot-C/HDL-C ratio and body composition improvements were more evident after BIBP. We conclude that malabsorptive BIBP seems to be more effective than LAGB in treating visceral obesity and its metabolic complications.

Reduction of risk factors for cardiovascular diseases in morbid-obese patients following biliary-intestinal bypass: 3 years' follow-up.

BACKGROUND: Obese patients are often affected by hypertension, dyslipidaemia, impaired glucose metabolism, and suffer from cardiovascular disease (CVD), related to the characteristic metabolic alterations. AIM OF THE STUDY: To evaluate reduction of risk factors for CVDs in morbid-obese patients (body mass index (BMI)>40 kg/m2) after weight loss upon bariatric surgery intervention of biliary-intestinal bypass. SUBJECTS: 45 (17 men, 28 women) morbid-obese patients (age: 19-49 y, BMI>40 kg/m2). All patients were selected on the basis of medical history, physical and biochemical evaluation and of psychiatric tests, which were performed on all individuals admitted to our Day Hospital to verify the safety of surgical intervention. MEASUREMENTS: Body weight, body composition (by dual X-ray absorptiometry, DXA), blood pressure, lipid profile, fibrinogen and glucose metabolism were monitored at baseline and 1, 3, 6, 9, 12, 24 and 36 months after surgery. RESULTS: A significant and persistent weight loss was present in all patients at the end of the 3 y follow-up period (P<0.001), with a progressive reduction of total and trunk fat mass as evaluated by means of DXA. Additionally, a parallel significant reduction in systolic (P<0.001) and diastolic (P<0.001) blood pressure was observed. Total and LDL cholesterol were significantly reduced (P<0.001), while HDL showed no modifications; triglycerides declined progressively during the 3 y follow-up (P<0.001). Fibrinogen decreased from 364.5+/-82.4 to 266.4+/-45.7 mg/dl at the end of the period (P<0.001). Fasting glucose levels and glucose levels 120 min after an oral glucose tolerance test were reduced from 95.1+/-20.3 to 78.6+/-9.1 mg/dl (P<0.001) and from 116.9+/-34.7 to 77.6+/-15.5 mg/dl (P<0.001), respectively, at baseline and at the end of the study. Moreover, fasting insulin decreased from 30.0+/-20.4 to 8.6+/-2.9 microUI/ml (P<0.001) after 3 y, while insulin levels after (120 min) oral glucose load decreased from 105.5+/-61.5 to 12.0+/-6.0 microUI/ml (P<0.001). CONCLUSION: Our results show that biliary-intestinal bypass may represent a valid and alternative therapeutic approach in patients with morbid obesity since it induces a significant and stable reduction of body weight and obesity-related risk factors for CVD.

The orexigram in patients affected by morbid obesity: a preliminary report on daily hunger sensation before bariatric surgery.

OBJECTIVE: The present study investigated the orexigram, the time-qualified self-rated estimate of hunger sensation (HS), in patients affected by morbid obesity (MO) with the aim of detecting how daily HS behaves before morbidly obese patients (MOP) undergo bariatric surgery (BS). This article is therefore a preliminary report as it is necessary to make subsequent comparisons with post-BS orexigrams. Preoperative orexigrams may be helpful in selecting the MOPs who are candidates for surgical treatment. MATERIALS AND METHODS: Ten MOPs (five males and five females, with a mean age of 34 +/- 11 yr and a mean BMI of 49.32 +/- 7.26 kg/m2), and 19 clinically healthy control subjects (CHS: nine males and ten females, with a mean age of 24 +/- 2 yr and a mean BMI of 21.00 +/- 1.70 kg/m2) gave their informed consent to participate in the study. All of the study participants were asked to compile a 24-h orexigram, which was then biometrically analysed by means of: 1) conventional methods for parametric statistics; 2) rhythm analysis for their circadian rhythms; and 3) spectral analysis for their harmonic structure. RESULTS: The orexigrams of the MOPs had significantly increased mean daily levels (daily hyperorexia), retained their circadian periodicity despite an increase in mesor, and were consistently modified in their ultradian spectral harmonic components. CONCLUSIONS: The results show that the studied MOPs complain of a daily hyperorexia that is still perceived circadically. This perception is a structured abnormality, as demonstrated by the consistent changes in the spectral analysis, and so MOPs can be diagnosed as being affected by so-called "hyperorectic obesity". It will be interesting to see whether or not presurgical hyperorexia in MOPs is corrected by BS: if so, hyperorexia may become an additional indication, and presurgery orexigrams could be suggested as an additional means of selecting the hyperorectic MOPs who are candidates for surgical treatment.

[Radiological examination of the Lap-Band for the treatment of severe obesity]. / L'esame radiologico del Lap-Band nel trattamento della grave obesità.

The aim of this study is to determine the role of radiographic assessment in patient who underwent an adjustable laparoscopic (or laparotomic) banding for the treatment of morbid obesity, and to evaluate the different type of postoperative complications. Forty-three consecutive patients with morbid obesity were examined before and after surgical treatment with positioning of Lap-Band. In all patients radiological examination permitted to evaluate the bend position, the dimensions of the gastric pouch and of the stoma. In such cases it was possible to modify the stoma dimensions under fluoroscopy. 74.4% of patients obtained satisfactory weight loss without complications. In 16.2% of patients the treatment was unsatisfactory and the radiological examination demonstrated the presence and the type of complications. In 9.3% of patients the radiological exam was negative for complications but they didn't obtain satisfactory weight loss. Radiographic assessments are crucial in the management of weight loss and detection of postoperative complications in this surgical treatment.

Patency of anastomoses after bilio-intestinal bypass: radioisotope demonstration.

BACKGROUND: Bilio-intestinal bypass (BIB) is effective for the treatment of refractory obesity. BIB permits bile flow into the non-functional jejunum, whereas food transit occurs via the remaining intestine. We used the radioisotope method of 99mTc-Hida cholescintigraphy (HC) in the follow-up of patients. METHODS: 21 patients were studied 3 months to 3 years after BIB with HC. After 3 hours acquisition, images were reviewed by two independent observers. Regions of interest (ROIs) were drawn on images: liver parenchyma, cholecysto-jejunal anastomosis (CC), choledochus (COL). Radioactivity taken up by liver was compared with radioactivity of CC and COL. % radioactivity passing through CC (%CC) and through COL (%COL) were determined. The final parameter, -COL, indicates the radioactive bile which does not pass through the choledochus. RESULTS: Anastomoses were found patent a few months to 3 years after operation. -COL showed linear correlation with the decrease in cholesterolemia and in body weight in the 1st year after BIB. CONCLUSIONS: HC shows passage of radioactive bile through anastomoses and provides semiquantitative evaluation of bile flux diversion. Bile flux towards the gallbladder and non-functional jejunal limb far exceeds flux directed towards the duodenum via the choledochus.

[Biliary-intestinal bypass in the treatment of severe obesity: personal experience with 23 patients]. / I1 bypass biolio-intestinale nel trattamento dell'osesità grave: nostra esperienza su 23 pazienti.

BACKGROUND: The aim of this study was to determine the efficacy and safety of biliary-intestinal bypass in severely obese subjects (Body Mass Index > 35). METHODS: From January to December 1999, 23 patients (8 men and 15 women, mean age 36.6 years: range 20-51) affected with primary morbid obesity (BMI >40: range 40.1-64.7), in whom different attempt using conservative medicine have proved non-resolutive, underwent biliary-intestinal bypass. After the operation all the patients have been followed- up for 12 months. RESULTS: The mean Body Mass Index was reduced to 36.9 (range 27.7-44.1) after 6 months and to 33 (range 24.9-40.1) after 12 months. Peri and postoperative mortality was zero. Excessive malabsorption was efficaciously controlled by adequate replacement therapy. Diarrhoea, common compliance of every operation inducin malabsorbition, was reduced to 2-3 evacuation a day after 2-3 months. CONCLUSIONS: On the basis of personal experience it is underlined that biliary-intestinal bypass, as surgical treatment of morbid obesity refractory to medical therapy, is today a safe and effective operation (up to 80% of excess body weight lose); the presence of biliary-intestinal anastomosis reduces the post-operative loss of bile acids, choleretic diarrhoea and electrolytic disorders.

Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region.

IgA deficiency (IgA-D) has been associated with the HLA region, in particular with the North European haplotype HLA-A1, -B8, -DR3, but the exact location of the susceptibility gene(s) is unknown. Some reports suggest that a susceptibility gene is encoded in the class II region, while others implicate the class III region. We exploited differences between the common Sardinian and North European HLA-DR3 haplotypes to help localize the IgA-D susceptibility gene(s). With the knowledge that approximately 13% of HLA-DR3 homozygous individuals of North European origin are IgA-D, we examined 43 HLA-DR3 homozygous Sardinians to find that all had normal serum IgA, IgG and IgM levels. A detailed analysis of their MHC haplotypes indicated a common Sardinian HLA-DR3 haplotype TAP1A, TAP2A, HLA-DQB1*0201, -DQA1*0501, -DRB1*0301, LH1-(Z + 2), D3A-(Z + 2), C4B-0, C4A-L, G11-15, Bf-0-4, C2-a, HSP70-7.5, 9N3-(Z + 10), 82I-(Z - 2), TNFalpha-9, 62-(Z - 20), HLA-B18, -Cw5, -A30 which diverges from the common North European HLA-DR3 haplotype telomeric to the HLA-DR region. In parallel studies of five Sardinians with IgA-D, two of the 10 HLA haplotypes (20%) contained HLA-DR3, a frequency similar to that observed in the background population. One of these was the HLA-DR3- B8 North European haplotype, which occurs rarely in Sardinia. Our data favour the hypothesis that a class III region allele, present on the common North European but not on the Sardinian HLA-DR3 haplotype, confers susceptibility to IgA-D.

[Endoscopic palliative treatment of a neoplastic esophageal fistula: report of a case]. / Palliazione endoscopica di una fistola neoplastica esofagea: caso clinico.

Oesophago-respiratory neoplastic fistulas present serious problems of management, because of the severe status of the patient. Therefore, a palliative treatment, to allow for a gradual respiratory and digestive function recovery with clinical improvements is needed. Surgical palliation has a mortality rate of 40% and a long post-operative hospitalization. Endoscopic palliation, on the other hand, has the same percentage of success of surgical palliation, but has the advantage to be performed in those patients with severe health conditions immediately improving the symptomatology and not excluding a subsequent surgical approach. The Authors present the case of a 70-year-old patient with a neoplastic relapse on the oesophago-gastric anastomosis, associated to an oesophago-respiratory fistula manifesting as severe dysphagia and dyspnoea. An endoscopic palliative treatment of the fistula was performed introducing a metallic coated prosthesis into the oesophagus. Severe clinical conditions regressed immediately and after 3 months they are unchanged. The Authors suggest endoscopic palliation with oesophageal prosthesis as the best therapeutic choice in those cases not amenable to surgery.

Seismic telescope for astrophysical research from space (STARS) triply reflecting telescope: a space instrument for astrophysics.

We describe the characteristics of the wide-field, triply reflecting telescope adopted for the European Space Agency project STARS (seismic telescope for astrophysical research from space), operating in the visible and UV range.

[Persistent varicocele: experience with prophilaxis and microsurgical treatment]. / Il varicocele persistente: nostra esperienza di profilassi e trattamento microchirurgico.

Persisting varicocele is still a rather hard clinical and therapeutical problem requiring a good level of surgical and microsurgical capability. In order to prevent and to treat postsurgical persistence, our trend is to resort to a correct and rational etiopathogenetical framing allowing us to choose the most appropriate surgical treatment. Relying on such procedure we perform all sorts of traditional and microsurgical interventions. We can say that the microsurgical techniques are the most appropriate ones to solve the problems of the second surgical intervention.

[Abdominal aortic aneurysm and rectal cancer: what surgical strategy?]. / Aneurisma dell'aorta addominale e cancro del retto: quale strategia operatoria?

The incidence of abdominal aortic aneurysm and colorectal cancer association is 0.5-1%. This concomitance of two potentially lethal diseases creates a decision making problem regarding priority of treatment. The Authors report a case in which colorectal cancer and abdominal aortic aneurysm were present. This patient first underwent surgery for colorectal cancer, then for aortic aneurysm. Moreover, the Authors review the Literature and discuss their decisional principles about treatment priorities.

[Anomalies of the inferior vena cava: observations on the anterior approach to the vertebral column]. / Anomalie della vena cava inferiore: osservazioni nell'approccio anteriore alla colonna vertebrale.

The inferior vena cava is formed through a complex process of embryogenesis from the sixth to the tenth week of gestation. Improper completion of the process of embryogenesis may result in four anatomic anomalies: 1) duplication of the inferior vena cava; 2) left-sided inferior vena cava; 3) retroartic left renal vein and 4) circumaortic left renal vein. The Authors report the cases of two patients in which duplication of the inferior vena cava and retroartic left renal vein were respectively observed. The importance to avoid injuries and subsequent bleeding from these anomalous structures during surgical operations is stressed. Moreover, a correct preoperative diagnosis may reduce these complications.

p53 gene mutations in medulloblastoma. Immunohistochemistry, gel shift analysis, and sequencing.

Medulloblastoma (MB), the most common malignant tumor of the CNS in children, bears a loss of the short arm of chromosome 17 in almost half of the cases. The tumor suppressor gene p53 is located on this chromosome and its role in the pathogenesis of this primitive tumor is controversial. Twenty-two MBs were analyzed by single-strand conformation polymorphism (SSCP) of polymerase chain reaction-amplified conserved exons. Fragments displaying a gel mobility shift were subsequently analyzed by direct sequencing. Immunohistochemistry for p53 was performed in all cases; three had cytogenetic analysis. Two cases (9%) were found to harbor a mutation: one homozygous and one heterozygous. The latter showed focal p53 immunostaining. None of the cases with chromosome 17p abnormality by cytogenetic analysis were found to have a mutation in the remaining allele. Loss of heterozygosity (LOH) of 17p, however, was found in four cases (one by SSCP and three by cytogenetic analysis). Together with the homozygous deletion in one case, the overall incidence of p53 allelic involvement in MB is 23%. Although LOH for the p53 gene may confer a selective advantage to tumor cells harboring mutations with dominant negative oncogenic effect, the infrequent occurrence of p53 mutations in face of frequent LOH for this gene supports the previously formulated hypothesis of a novel tumor-related locus distal to p53 on chromosome 17p.

Rare frequencey of point mutations for codon 12, 13 and 61 of ras gene in italian neuroblastoma.

Single point mutations of ras oncogenes are found in many tumors and contribute to the pathogenesis of the cancer. The product of the ras gene, p21 protein, was found expressed in several neuroblastoma tissues. However, the role of ras gene in this tumor has yet to be clarified. To contribute to the understanding of the ras activation, 79 fresh biopsies of neuroblastoma were studied to investigate the possibility that ras would be activated by point mutation. Analysis of H-ras and N-ras was performed by means of PCR and SSO, while K-ras mutations were detected by multiplex-ASPCR. None of the neuroblastomas examined showed H- or K-ras activation, while N-ras mutations were demonstrated in only three patients (3,7%). N-myc oncogene is amplified in a substantial number of patients with neuroblastoma. N-myc amplification was studied by Southern blot technique. N-myc amplification was demonstrated in 13.2% of patients less than 1 year of age at diagnosis and 23% of older children. Two of the patients (one stage I and one stage IVs) with N-ras mutation and without N-myc amplification had a good outcome, while the third (stage IVs) with N-myc amplification had a poor prognosis. These results suggest that ras activation is a rare event in both amplified and non-amplified neuroblastoma tumors and that N-ras activation was not involved in the clinical outcome of these patients. Moreover, our data suggest that p21 expression is induced by a post-transcriptional activation.

Large-cell medulloblastomas. A distinct variant with highly aggressive behavior.

We present four cases of infantile cerebellar neoplasms composed of cells with large vesicular nuclei with prominent nucleoli. All four cases were strongly immunoreactive for synaptophysin, and one case showed immunoreactivity for neurofilaments. Filter hybridization for N-myc and c-myc oncogenes showed a 27-fold c-myc amplification in one case. The cytogenetic analysis in this case showed Double-Minutes and isochromosome 17q. An intracerebral xenograft in nude mice obtained from one such tumor showed a similar morphology to that of the original tumor as well as strong immunoreactivity for synaptophysin and neurofilaments. All the neoplasms were characterized by highly aggressive behavior leading to early cerebrospinal fluid dissemination despite radiotherapy and chemotherapy. We conclude that large-cell medulloblastoma represents a distinct and more aggressive variant of medulloblastoma that requires more aggressive therapy.

p53 gene expression in medulloblastoma by quantitative polymerase chain reaction.

The frequent cytogenetic abnormality--isochromosome 17q [i(17)q]--observed in medulloblastomas (MB) may result in altered expression of the oncosuppressor gene p53 that is located on 17p. p53 expression was therefore evaluated in five MBs and in one MB cell line derived from one of these tumors. Expression levels of p53 utilizing serially diluted unfractionated RNA from tumors and the cell line were assessed both by dot-blot and by reverse transcription (RT) followed by the polymerase chain reaction (PCR). The quality of RNA, efficiency of reaction, and transcript quantitation were determined by simultaneous transcription and amplification of a similarly sized fragment of the alpha-tubulin gene. All MBs showed low levels of expression of p53 compared to those found in normal tissues. p53 messenger RNA (mRNA) was significantly increased (two- to threefold) in the MB cell line compared to its tumor of origin and to the other MBs. Immunoperoxidase studies performed with monoclonal antibodies to the p53 protein product showed focal nuclear expression in one of five of the original tumors while most cells grown in vitro and in the xenograft were positive.(ABSTRACT TRUNCATED AT 250 WORDS)