Delta-Globin Gene Expression Is Enhanced in vivo by Interferon Type I

Beta hemoglobinopathies are widely spread monogenic lethal diseases. Delta-globin gene activation has been proposed as a possible approach for curing these pathologies. The therapeutic potential of delta-globin, the non-alpha component of Hemoglobin A2 (α2δ2; HbA2), has been demonstrated in a mouse model of beta thalassemia, while its anti-sickling effect, comparable to that of gamma globin, was established some time ago. Here we show that the delta-globin mRNA level is considerably increased in a Deoxyribonuclease II-alpha knockout mouse model in which type 1 interferon (interferon beta, IFNb) is activated. IFNb activation in the fetal liver improves the delta-globin mRNA level, while the beta-globin mRNA level is significantly reduced. In addition, we show that HbA2 is significantly increased in patients with multiple sclerosis under type 1 interferon treatment. Our results represent a proof of principle that delta-globin expression can be enhanced through the use of molecules. This observation is potentially interesting in view of a pharmacological approach able to increase the HbA2 level

Reversible Disruption of Pre-Pulse Inhibition in Hypomorphic-Inducible and Reversible CB1-/- Mice

Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout (-/-) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1-/- mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1-/-) only in absence of doxycycline (Dox). In such mice, under Dox+ or vehicle, as well as in wild-type (WT) and CB1-/-, two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1-/- and IRh-CB1-/- showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1-/- animals, was on the contrary highly and significantly disrupted only in Dox+ IRh-CB1-/- mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1-/- mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1-/- mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders

Overexpression of the Cytokine BAFF and Autoimmunity Risk

$\textbf{BACKGROUND}$: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. $\textbf{METHODS}$: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. $\textbf{RESULTS}$: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. $\textbf{CONCLUSIONS}$: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).Supported by grants (2011/R/13 and 2015/R/09, to Dr. Cucca) from the Italian Foundation for Multiple Sclerosis; contracts (N01-AG-1-2109 and HHSN271201100005C, to Dr. Cucca) from the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH); a grant (FaReBio2011 “Farmaci e Reti Biotecnologiche di Qualità,” to Dr. Cucca) from the Italian Ministry of Economy and Finance; a grant (633964, to Dr. Cucca) from the Horizon 2020 Research and Innovation Program of the European Union; a grant (U1301.2015/AI.1157.BE Prat. 2015-1651, to Dr. Cucca) from Fondazione di Sardegna; grants (“Centro per la ricerca di nuovi farmaci per malattie rare, trascurate e della povertà” and “Progetto collezione di composti chimici ed attività di screening,” to Dr. Cucca) from Ministero dell’Istruzione, dell’Università e della Ricerca; grants (HG005581, HG005552, HG006513, and HG007022, to Dr. Abecasis) from the National Human Genome Research Institute; a grant (9-2011-253, to Dr. Todd) from JDRF; a grant (091157, to Dr. Todd) from the Wellcome Trust; a grant (to Dr. Todd) from the National Institute for Health Research (NIHR); and the NIHR Cambridge Biomedical Research Centre. Dr. Idda was a recipient of a Master and Back fellowship from the Autonomous Region of Sardinia

Mesenterite retrattile: presentazione di un caso

Gli Autori riportano un caso di mesenterite retrattile, processo infiammatorio cronico del meso evolvente verso la fibrosi. La mesenterite è una patologia istologicamente benigna che tuttora si associa, in una certa percentuale di casi, a neoplasie prevalentemente dell’apparato urogenitale. Le manifestazioni cliniche sono caratterizzate dalla comparsa di masse addominali e di crisi subocclusive intestinali che possono esitare in occlusioni franche. La diagnostica per immagini è aspecifica e spesso la diagnosi è possibile solo con la biopsia del meso. Il trattamento nei casi non complicati da occlusione è basato sull’uso di farmaci steroide

Colangiocarcinoma associato a malattia di Caroli monolobare sinistra

Caroli’s disease is a cystic expansion of hepatic biliary duct ,frequently shown with not specific pain symptomatology to the right abdominal quadrant, icterus and recurrent cholangitis, these ones hardly controllable with antibiotics therapy only. Cholangio-RM is the most appropriate investigational methodical to diagnose the disease and to show the continuity of cystic expansion with biliary three. Authors report a cases of Caroli’s associated to cholangiocarcinoma. When the disease is banished to one hepatic lobe only, the surgery resection is the most indicated election’s therapy to solve an eventual intrahepatic biliary lithiasis, potentials cholangitis, and the possible neoplastic risk. In the event of spreaded disease, the treatment includes endoscopic treatment, pharmacologic therapy and, at last, hepatic transplant

Chemio-radioterapia neoadiuvante nel carcinoma del retto. Studio clinico a lungo termine in un singolo centro

The standard therapy for patients with clinically resectable rectal cancer is generally surgery. Tumor regression can be obtained by preoperative radio-chemotherapy that allows radical tumor resection with an increase in sphincter-saving procedures. The aim of this study was to evaluate the safety and efficacy of preoperative combined radiotherapy (RT) and chemotherapy (CT) in patients with T2 and T3 rectal cancer. Between September 1999 and December 2008, 58 patients with palpable rectal adenocarcinoma received preoperative radiotherapy by the 3-field technique to a total of 50.5 Gy (5 x 1.8 Gy/die for a total of 28 sessions) and chemotherapy with 5-fluorouracil by continuous intravenous infusion. Surgery, 19 resections according to Miles (32%) and 39 anterior resections (67%) with total mesorectal excision, was performed 6 weeks later. Alive and free disease 33 (57%), Alive with metastases 3 (5%) deceased 15 (26%) Loose 7 (12%). The histopathological examination showed total tumor regression in 12 patients (20%). Local response to preoperative RT/CT was highly satisfactory, allowing anal sphincter preservation with a low local recurrence rate. Optimization of the combined therapy could yield even more optimal results.