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Enrico Torre,1 Sergio Di Matteo,2 Chiara Martinotti,2 Giacomo Matteo Bruno,3 Umberto Goglia,4 Gianni Testino,5 Alberto Rebora,1 Luigi Carlo Bottaro,6 Giorgio Lorenzo Colombo3 1Diabetology and Metabolic Diseases Unit - ASL3, Genoa, Italy; 2Center of Research, SAVE Studi - Health Economics and Outcomes Research, Milan, Italy; 3Department of Drug Sciences, University of Pavia, Pavia, Italy; 4Territorial Diabetology Unit, ASLCN1, Cuneo, Italy; 5Units of Addiction and Hepatology, ASL3, Genoa, Italy; 6General Direction, ASL3, Genoa, ItalyCorrespondence: Giorgio Lorenzo Colombo, Email giorgio.colombo@unipv.itBackground: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem condition destined to become pandemic in the coming decades. This study aimed at evaluating the economic impact of MASLD in the Italian population from the Italian National Healthcare Service (NHS) perspective.Methods: The economic impact of the MASLD was assessed by developing a calculation model in Microsoft Excel® from the Italian NHS perspective, considering healthcare resources and direct costs. The target population was based on the prevalence data. Through a literature search, complications of MASLD were identified, including MASH, with relative risk of evolution into CC, DCC, HCC, T2DM, cardiovascular diseases, in particular AMI and stroke, CKD, and CRC. The differential impact between complication development in the population with MASLD and the same sample size population without-MASLD was evaluated. Differential risk data, mortality rates, and event unit costs were drawn from the published international literature. Frequency and cost data were applied to the total target population, the total annual costs and mortality data, referring to the two arms, were then calculated, and the differential value was obtained.Results: Based on an estimated 11,546,370 MASLD target population, an annual illness impact of € 12,251,631,822 was calculated, corresponding to a difference of € 7,731,674,054 compared with the same sample size without MASLD. Moreover, the MASLD population is expected to experience 13,438 additional deaths annually.Conclusion: The growing epidemiological impact of MASLD and its complications represent a huge economic burden for healthcare services worldwide. An integrated approach, including changes in lifestyle behaviors, will be the first step. Specific drugs for MASLD are not yet available; however, studies are underway, and combined pharmaceutical therapies may be an inevitable choice to achieve adequate control of MASLD and its complications.Keywords: metabolic associated fatty liver disease MASLD, complications, MASLD burden in Italy, healthcare costs, treatment and perspectives

The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua , which means door . How many new doors will this old drug be able to open?, Competing Interests: The authors declare no conflicts of interest.

Objective: To report a case of an azoospermic subject with mild androgen insensitivity syndrome (MAIS) and review the relevant literature., Design: Case report., Setting: Academic research hospital., Patient(s): A 49-year-old man with undermasculinized features and a history of cryptorchidism and azoospermia., Intervention(s): Hormonal evaluation and genetic testing of the androgen receptor gene (AR)., Main Outcome Measure(s): Hormonal levels and sequence chromatogram of the proband and his mother., Result(s): We found total T in the normal range and high levels of gonadotropins. Karyotype was 46,XY. Genetic testing identified a novel mutation of exon 1 of AR, which resulted in an alanine to serine substitution in the transactivation domain at codon 240 (A240S). Fourteen other mutations of exon 1 of AR have been associated with MAIS to date., Conclusion(s): The novel mutation A240S of AR is involved in MAIS, a syndrome associated with azoospermia., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

293 kidney embryonic cells feature very low levels of the anti-apoptotic protein PED. In these cells, expression of PED to levels comparable with those occurring in normal adult cells inhibits apoptosis induced by growth factor deprivation and by exposure to H(2)O(2) or anisomycin. In PED-expressing 293 cells (293(PED)), inhibition of apoptosis upon growth factor deprivation was paralleled by decreased phosphorylation of JNK1/2. In 293(PED) cells, decreased apoptosis induced by anisomycin and H(2)O(2) was also accompanied by block of JNK1/2 and p38 phosphorylations, respectively. Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation. At variance with JNK1/2 and p38, PED expression increased basal and growth factor-stimulated Ras-Raf-1 co-precipitation and MAPK phosphorylation and activity. Treatment of 293(PED) cells with the MEK inhibitor PD98059 blocked ERK1/2 phosphorylations with no effect on inhibition of JNK1/2 and p38 activities. Complete rescue of JNK and p38 functions in 293(PED) cells by overexpressing JNK1 or p38, respectively, enabled only partial recovery of apoptotic response to growth factor deprivation and anisomycin. However, simultaneous rescue of JNK and p38 activities accompanied by block of ERK1/2 fully restored these responses. Thus, PED controls activity of the ERK, JNK, and p38 subfamilies of MAPKs. PED anti-apoptotic function in the 293 cells requires PED simultaneous activation of ERK1/2 and inhibition of the JNK/p38 signaling systems by PED.