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Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (beta-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage-and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear beta-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat beta-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.

Ethical problems related to intensive care of extremely preterm newborns of ≤ 25 weeks' gestational age and at risk of disability have been extensively debated. The Bioethical Committee of the Department of Paediatrics of the University Hospital of Padua organized and started a multidisciplinary group to release guidelines to help staff facing problems related to prematurity. The vitality limit, survival, outcome, and ethical aspects were analyzed. Consequently, we suggest the following: at 22 weeks' gestational age, the deliverance of comfort care only; at 23 weeks, in the presence of detectable vital signs, the practice of immediate intubation, respiratory support, and a reassessment of the neonatal conditions; and at 24 weeks, the provision of intubation, ventilatory support, and cardiovascular resuscitation. If the clinical age and anamnestic gestational age are different, we proceed according to the more advanced one. The importance of providing parents with correct information and the role of comfort care are outlined. ( J Child Neurol 2004;19:31—34).

Background Routine testing of baseline EGFR T790M mutation may have important clinical impact but many discordant data have been reported regarding the diagnostic, prognostic and predictive role of this marker. In this study we aimed to assess T790M frequency in 164 untreated EGFR-mutated NSCLCs using methods with different sensitivity as well as to analyze the relationship between baseline T790M mutation status, patient's clinicopathologic features and tyrosine kinase inhibitors (TKI) treatment outcomes. Methods We compared the diagnostic performance, sensitivity and specificity of three methods, namely MALDI-TOF mass spectrometry (MS), Allele-Specific Real Time PCR (AS-PCR), droplet digital PCR (ddPCR). Ultra-deep next generation sequencing (NGS) validation of T790M-mutant NSCLCs was performed using SiRe® panel. Results Baseline T790M occurred in 17% of the tumors. Intermediately sensitive techniques such as MALDI-TOF MS (detection limit of T790M ≥5%) allow to detect T790M in 2% of cases exhibiting mutant-allele fractions ranging from 11.5% to 17%. Median overall survival (OS) in these patients was poor (7.3 months) and progression free survival (PFS) was of 3.3 months in patients treated with a 1st generation EGFR TKI. The remaining T790M-positive cases showed very low mutant-allele fractions ranging from 0.07% to 0.38% and required highly sensitive methods such as ddPCR and NGS to be identified. All these cases showed a concurrent sensitizing EGFR mutation (mainly exon 19 deletion), and clinicopathological features similar to those observed in EGFR mutant cancers. Median OS of these patients was 27 months while median PFS after TKI treatment was 20 months. Conclusions Routine test of baseline EGFR T790M may have an important role in the prediction to EGFR TKI therapy response and should be performed using highly sensitive and quantitative methods, such as ddPCR and NGS, in order to reliably distinguish NSCLCs with high or very low T790M mutant-allele fraction.

Background and aims An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. Methods A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. Results CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. Conclusions In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.

The literature shows that homesickness can have a negative impact on different areas of psychological functioning such as cognitive, emotional, behavioral, physical and social ones. The study, conducted on a sample of first-year university students, aimed to test a model hypothesizing that two distinct dimensions of homesickness, attachment to home and disliking university, could have both direct and indirect effects on their psychological distress and sleep difficulties. Two hundred and seventy-seven first-year students (70.4% Female) living away from home (mean age= 21.3, SD= 2.7) were included in the study and filled out questionnaires assessing homesickness, psychological distress and sleep difficulties. Structural Equation Model (SEM) analysis confirmed that the two homesickness dimensions worked differently since only the one relating to new place adjustment difficulties (i.e. disliking the university) resulted having both direct and indirect effects on students’ sleep difficulties. Although female students reported higher levels of psychological distress compared to males, the multi-group SEM analysis showed that the pattern of multivariate relationships linking the two dimensions of homesickness, psychological distress and sleep difficulties, was invariant across gender. The results of the present study suggest that university counselling and guidance services should quickly screen students experiencing homesickness and offer effective counselling programs focusing on enhancing their capacities to deal with the new academic environment.

Background: University students confront psychological difficulties that can negatively influence their academic performance. The present study aimed to assess several areas of adaptive and maladaptive psychological functioning among university students who request counseling services. Method: One hundred eighty-four young female students seeking professional psychological help (Counseling seekers) and 185 young female students who have never asked for psychological help (Non-counseling seekers) were asked to complete the Adult Self-Report (ASR) to evaluate both their internalizing and externalizing problems through DSM-oriented scales as well as their adaptive functioning. Results: ANOVA results indicated worse psychological functioning for the students who sought counseling. They reported lower score in ASR Adaptive Functioning Scales (i.e., friends, jobs, family, education), and higher scores in DSM-oriented scales (i.e., Depressive, Anxiety, Somatic, Avoidant Personality, Attention Deficit/Hyperactivity symptoms) than the students who never asked psychological help. Furthermore, discriminant analysis successfully discriminated between the two groups of students on the basis of the ASR’s adaptive and DSM-oriented scales. Conclusion: The study findings could be useful to guide university counseling services in their screening activities as well as useful for clinical practice.

Summary Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD+-dependent protein deacetylase. As NAD+ boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD+ play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD+ precursor, or reduction of NAD+ consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans., Graphical Abstract, Highlights • NAD+ is a substrate activator of Sirtuin 1, a key player of mitochondrial biogenesis • Parp1 inhibitors and nicotinamide riboside increase the NAD+ content in tissues • These compounds improve the phenotype of a mitochondrial disease mouse model • These are potential therapies for human mitochondrial disorders, Human mitochondrial disorders are heterogenous in nature and are crippling. Cerutti et al. correct the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin model through pharmacological activation of Sirt1-dependent mitochondrial biogenesis. Their results highlight the concept of a potential general therapeutic strategy in genetically diverse mitochondrial disorders.

Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1α-dependent homeostatic pathways has been proposed as a treatment for mitochondrial disease. We tested this hypothesis on three recombinant mouse models characterized by defective cytochrome c-oxidase (COX) activity: a knockout (KO) mouse for Surf1, a knockout/knockin mouse for Sco2, and a muscle-restricted KO mouse for Cox15. First, we demonstrated that double-recombinant animals overexpressing PGC-1α in skeletal muscle on a Surf1 KO background showed robust induction of mitochondrial biogenesis and increase of mitochondrial respiratory chain activities, including COX. No such effect was obtained by treating both Surf1-/- and Cox15-/- mice with the pan-PPAR agonist bezafibrate, which instead showed adverse effects in either model. Contrariwise, treatment with the AMPK agonist AICAR led to partial correction of COX deficiency in all three models, and, importantly, significant motor improvement up to normal in the Sco2KO/KI mouse. These results open new perspectives for therapy of mitochondrial disease. © 2011 Elsevier Inc.