Animal models of compulsive eating behavior

In industrialized nations, overeating is a significant problem leading to overweight, obesity, and a host of related disorders; the increase in these disorders has prompted a significant amount of research aimed at understanding their etiology. Eating disorders are multifactorial conditions involving genetic, metabolic, environmental, and behavioral factors. Considering that compulsive eating in the face of adverse consequences characterizes some eating disorders, similar to the way in which compulsive drug intake characterizes drug-addiction, it might be considered an addiction in its own right. Moreover, numerous review articles have recently drawn a connection between the neural circuits activated in the seeking/intake of palatable food and drugs of abuse. Based on this observation, “food addiction” has emerged as an area of intense scientific research and accumulating evidence suggests it is possible to model some aspects of food addiction in animals. The development of well-characterized animal models would advance our understanding of the etiologic neural factors involved in eating disorders, such as compulsive overeating, and it would permit to propose targeted pharmacological therapies. However, to date, little evidence has been reported of continued food seeking and intake despite its harmful consequences in rats and mice

N=1* model superpotential revisited (IR behaviour of N=4 limit)

The one-loop contribution to the superpotential, in particular the Veneziano-Yankielowicz potential in N=1 supersymmetric Yang-Mills model is discussed from an elementary field theory method and the matrix model point of view. Both approaches are based on the Renormalization Group variation of the superconformal N=4 supersymmetric Yang-Mills model.Comment: 31 page

Generation of the Becker muscular dystrophy patient derived induced pluripotent stem cell line carrying the DMD splicing mutation c.1705-8 T>C

Becker Muscular dystrophy (BMD) is an X-linked syndrome characterized by progressive muscle weakness. BMD is generally less severe than Duchenne Muscular Dystrophy. BMD is caused by mutations in the dystrophin gene that normally give rise to the production of a truncated but partially functional dystrophin protein. We generated an induced pluripotent cell line from dermal fibroblasts of a BMD patient carrying a splice mutation in the dystrophin gene (c.1705-8 T>C). The iPSC cell-line displayed the characteristic pluripotent-like morphology, expressed pluripotency markers, differentiated into cells of the three germ layers and had a normal karyotype

Generation of human induced pluripotent stem cells (EURACi001-A, EURACi002-A, EURACi003-A) from peripheral blood mononuclear cells of three patients carrying mutations in the CAV3 gene

Caveolinopathies are a heterogeneous family of genetic pathologies arising from alterations of the caveolin-3 gene (CAV3), encoding for the isoform specifically constituting muscle caveolae. Here, by reprogramming peripheral blood mononuclear cells, we report the generation of induced pluripotent stem cells (iPSCs) from three patients carrying the ΔYTT deletion, T78K and W101C missense mutations in caveolin-3. iPSCs displayed normal karyotypes and all the features of pluripotent stem cells in terms of morphology, specific marker expression and ability to differentiate in vitro into the three germ layers. These lines thus represent a human cellular model to study the molecular basis of caveolinopathies

Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer

Background:Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function.Methods:BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERα)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERα-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model.Results:Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.Conclusion:BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network

Depressione e solitudine in adolescenza: emergere della soggettività o emergenza psicopatologica?

L’adolescenza ha continuamente posto il problema della normalità e della patologia. Infatti, con le sue inevitabili, imponenti, modificazioni strutturali (cognitive, affettive e corporee), ha da sempre evocato i temi della discontinuità, della rottura, dell’incertezza esistenziale e della separazione, del bisogno di approdo ad un sentimento d’identità stabilmente definito. Tuttavia quest’incertezza sembra aver avuto una ricaduta e un eco anche sul pensiero intorno all’adolescenza e alla sua patologia, rilevabile nella storia della psichiatria infantile attraverso il continuo accostamento operato tra processo adolescenziale e diverse problematiche psicopatologiche ‒depressione e psicosi in particolare ‒ in un’operazione non innocua, in cui il continuo riverbero tra normalità e patologia sembrava poter fornire elementi di comprensione sia per l’una che per l’altra. Storicamente, la specificità del processo evolutivo in atto ha spinto alcuni autori (Blos, 1962; Freud, A. 1937; Erikson, 1968; Eissler, 1958; Jacobson, 1964) a considerare l’adolescenza come un tempo fisiologicamente depressivo, in cui integrare vissuti legati alla perdita, al lutto, al cambiamento. Questo punto di vista corrisponde al concetto di turmoil, che letteralmente significa agitazione, scompiglio, tumulto, e che corrisponde alla crisi normale ed universale dell’adolescenza. Tuttavia, questa impostazione è stata giustamente criticata (Chan, Rinsley e Masterson, Laufer, Baranes, Jeammet) per un eccesso di generalizzazione e trova il suo limite nel rischio che tale “omologazione” tra processo normale dell’adolescenza e patologia ‒ ben sapendo, ovviamente, che i limiti tra normalità e patologia sono spesso sfumati, soprattutto in questa fascia d’età ‒ possa andare più nella direzione dell’ambiguità e della confusione che facilitare il riconoscimento delle crisi più gravi, destinate ad abitare il territorio della patologia psichiatrica franca. Per questo motivo l’intento di queste riflessioni è di cercare un dialogo continuo tra elementi di contatto e necessità di distinzione tra normalità e patologia sul doppio registro della processualità adolescenza/depressione e della definizione di alcuni temi spesso associati allo spettro depressivo, che in altre pagine di questo libro sono stati definiti come la “marmellata depressiva”. Dopo aver dato voce agli interrogativi e alla confusione legati all’uso dei vari paradigmi diagnostici per inquadrare la depressione in adolescenza, cercheremo di mettere a confronto sia le modificazioni dell’apparato psichico operate dal processo adolescenziale con la psicodinamica della depressione, sia i concetti di “solitudine”, “lutto”, “depressione”, “separazione”, “dolore”, che così frequentemente sono stati accostati al lavoro dell’adolescenza