La prevenzione del diabete mellito di tipo 1

Il trattamento del diabete di tipo 1 (DM1) prevede la somministrazione di insulina che tuttavia non rappresenta, com’è noto, una vera e propria “cura” per questa malattia. Negli ultimi decenni stiamo assistendo allo sviluppo di strategie preventive per il DM1 articolate su tre livelli: una prevenzione primaria finalizzata a prevenire lo sviluppo del processo autoimmune responsabile della distruzione β-cellulare che caratterizza la malattia; una prevenzione secondaria per arrestare il processo autoimmunitario e impedire l’esordio clinico del diabete; una prevenzione terziaria per preservare la massa β-cellulare residua e per ridurre il rischio di sviluppo delle complicanze croniche. Fra i molteplici approcci terapeutici sviluppati per impedire, ritardare o arrestare la distruzione β-cellulare l’immunoterapia, in particolare, è stata ed è tutt’oggi oggetto di innumerevoli ricerche. I risultati sono tutt’altro che semplici da raggiungere, in quanto i meccanismi eziopatogenetici alla base del DM1 sono complessi e non ancora del tutto noti. Per il raggiungimento di un’efficacia preventiva è importante, inoltre, tenere in considerazione l’eterogeneità del DM1, la quale indubbiamente ha influenzato i risultati dei trattamenti finora sperimentati, così come validare nuovi biomarcatori che ci permettano di selezionare al meglio i pazienti da indirizzare a un determinato trattamento

Lack of germline A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) gene in familial papillary thyroid cancer

Thyroid cancer may have a familial predisposition but a specific germline alteration responsible for the disease has not been discovered yet. We have shown that familial papillary thyroid cancer (FPTC) patients have an imbalance in telomere-telomerase complex with short telomeres and increased telomerase activity. A germline mutation (A339V) in thyroid transcription factor-1 has been described in patients with multinodular goiter and papillary thyroid cancer. In this report, the presence of the A339V mutation and the telomere length has been studied in FPTC patients and unaffected family members. All samples analyzed displayed a pattern typical of the homozygous wild type revealing the absence of the A339V mutation. Shortening of telomeres was confirmed in all patients. We concluded that the A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) is not correlated with the familial form of PTC, even when the tumor was in the context of multinodular goiter

Circulating microRNA (miRNA) expression profiling in plasma of patients with gestational diabetes mellitus reveals upregulation of miRNA miR-330-3p

Gestational diabetes mellitus (GDM) is characterized by insulin resistance accompanied by low/absent beta-cell compensatory adaptation to the increased insulin demand. Although the molecular mechanisms and factors acting on beta-cell compensatory response during pregnancy have been partially elucidated and reported, those inducing an impaired beta-cell compensation and function, thus evolving in GDM, have yet to be fully addressed. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs, which negatively modulate gene expression through their sequence-specific binding to 3'UTR of mRNA target. They have been described as potent modulators of cell survival and proliferation and, furthermore, as orchestrating molecules of beta-cell compensatory response and function in diabetes. Moreover, it has been reported that miRNAs can be actively secreted by cells and found in many biological fluids (e.g., serum/plasma), thus representing both optimal candidate disease biomarkers and mediators of tissues crosstalk(s). Here, we analyzed the expression profiles of circulating miRNAs in plasma samples obtained from n = 21 GDM patients and from n = 10 non-diabetic control pregnant women (24-33 weeks of gestation) using TaqMan array microfluidics cards followed by RT-real-time PCR single assay validation. The results highlighted the upregulation of miR-330-3p in plasma of GDM vs non-diabetics. Furthermore, the analysis of miR-330-3p expression levels revealed a bimodally distributed GDM patients group characterized by high or low circulating miR-330 expression and identified as GDM-miR-330highand GDM-miR-330low. Interestingly, GDM-miR-330highsubgroup retained lower levels of insulinemia, inversely correlated to miR-330-3p expression levels, and a significant higher rate of primary cesarean sections. Finally, miR-330-3p target genes analysis revealed major modulators of beta-cell proliferation and of insulin secretion, such as the experimentally validated genes E2F1 and CDC42 as well as AGT2R2, a gene involved in the differentiation of mature beta-cells. In conclusion, we demonstrated that plasma miR-330-3p could be of help in identifying GDM patients with potential worse gestational diabetes outcome; in GDM, miR-330-3p may directly be transferred from plasma to beta-cells thus modulating key target genes involved in proliferation, differentiation, and insulin secretion

influence of mechanical parameters on non linear static analysis of masonry buildings a relevant case study

Abstract In seismic zones, suitable procedures to assess the seismic vulnerability of existing buildings are necessary also in view of optimal planning of interventions. Starting from the agreement between the Municipality of Florence and the Department of Civil and Industrial Engineering of the University of Pisa, a research program is ongoing, devoted to setup a simplified, fast but reliable procedure for the evaluation of seismic performance of masonry buildings. In this paper, a simplified non-linear pushover type method for the verification of unreinforced multi-story masonry buildings with both deformable and non-deformable slabs is presented, starting from some of the basic assumptions of the POR method. Various tests on the procedure show that the method is able to give results that are comparable with those obtained by the classical pushover analysis performed on equivalent frame models. The intuitiveness of the method and the low computational effort required by the new algorithm allow the evaluation of the sensitivity of non-linear static analysis regarding the definition of mechanical parameters. In particular, the relevant influence of the modulus of elasticity as well as the ultimate inter-story displacement assumed for masonry walls on the assessment of seismic performance are discussed in detail. The results are presented for a significant case study, the Primary School "G. Carducci" in Florence, a four-story masonry building, with a horseshoe layout where lateral appendixes detached from the central block

MicroRNA expression analysis of in vitro dedifferentiated human pancreatic islet cells reveals the activation of the pluripotency-related microRNA cluster miR-302s

β-cell dedifferentiation has been recently suggested as an additional mechanism contributing to type-1 and to type-2 diabetes pathogenesis. Moreover, several studies demonstrated that in vitro culture of native human pancreatic islets derived from non-diabetic donors resulted in the generation of an undifferentiated cell population. Additional evidence from in vitro human β-cell lineage tracing experiments, demonstrated that dedifferentiated cells derive from β-cells, thus representing a potential in vitro model of β-cell dedifferentiation. Here, we report the microRNA expression profiles analysis of in vitro dedifferentiated islet cells in comparison to mature human native pancreatic islets. We identified 13 microRNAs upregulated and 110 downregulated in islet cells upon in vitro dedifferentiation. Interestingly, among upregulated microRNAs, we observed the activation of microRNA miR-302s cluster, previously defined as pluripotency-associated. Bioinformatic analysis indicated that miR-302s are predicted to target several genes involved in the control of β-cell/epithelial phenotype maintenance; accordingly, such genes were downregulated upon human islet in vitro dedifferentiation. Moreover, we uncovered that cell-cell contacts are needed to maintain low/null expression levels of miR-302. In conclusion, we showed that miR-302 microRNA cluster genes are involved in in vitro dedifferentiation of human pancreatic islet cells and inhibits the expression of multiple genes involved in the maintenance of β-cell mature phenotype

shear modulus of masonry walls a critical review

Abstract In the assessment of seismic performance of masonry buildings, the proper definition of mechanical parameters of masonry, the shear modulus in particular, is a critical issue. Moreover, considering that existing buildings are characterized by several masonry types, depending on the material as well as on the texture, mechanical parameters can vary in a very wide range, also because they depend on many other parameters and in particular on the integrity of the walls and on the stress level. Although the in situ or laboratory experimental evaluation of the G modulus has been the subject of a wide literature concerning flat jacks, diagonal and single compression and shear-compression test results, its outcomes are often contradictory. In effect, values given by different studies often differ significantly, even for the same class of masonry. Since the intrinsic scattering of the parameter is not sufficient by itself to justify the huge variability of the results, a critical discussion of the results as well as of the individual test arrangements is necessary to make the background more reliable, also in view of better addressing further studies- A huge database has been setup combining masonry test results available in the relevant scientific literature with the test results obtained in the framework of the in situ experimental campaign carried out by the authors for the assessment of seismic vulnerability of masonry school buildings in the Municipality of Florence. The analysis of the database underlines that values of the shear modulus G, which is a fundamental parameter for the definition of capacity curve for walls commonly used in non-linear static analysis, are extremely scattered. Testing methodology and arrangement are discussed and a possible procedure is proposed to arrive to sounder estimations of relevant mechanical parameter of existing building masonry

Follow-up after bariatric surgery: is it time to tailor it? Analysis of early predictive factors of 3-year weight loss predictors of unsuccess in bariatric patients

Bariatric surgery (BS) is the most effective treatment strategy for obesity. Nevertheless, a subset of patients does not reach a successful weight loss or experience long-term weight regain. Conflicting evidence exists regarding predictors of BS outcomes. We aimed to define the early factors linked to 3 year unsuccessful weight loss in order to promote a tailored close follow-up. We enrolled 443 patients who underwent BS from January 2014 to December 2018 with a 3 year follow-up. An unsuccessful BS outcome was defined as a percentage of total weight loss (%TWL) <20. We compared the characteristics between successful and unsuccessful patients in order to identify predictor factors of unsuccess after surgery. We found that the proportion of patients with unsuccessful weight loss progressively increased from one to three years after BS. In a multiple regression model, only 1 month %TWL and sleeve gastrectomy (SG) were significantly associated with 3 year unsuccessful weight loss. We stratified our cohort in four groups according to the risk of BS unsuccess, in terms of 1 month %TWL and type of surgery (SG vs gastric bypass). Interestingly, groups showed a significant difference in terms of %TWL at each follow-up point. Patients submitted to SG with lower 1 month %TWL must be considered at higher risk of future weight regain; consequently, they require a tailored and closer follow-up.[GRAPHICS]. © 2022, The Author(s)

Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors

The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells

Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation

The loss of functional beta-cell mass in type 2 diabetes (T2D) is associated with molecular events that include beta-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several beta-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects beta-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in beta-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human beta-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the beta-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects beta-cells from apoptosis through a CRTC1-dependent mechanism

New advances in metabolic syndrome, from prevention to treatment. The role of diet and food

The definition of metabolic syndrome (MetS) has undergone several changes over the years due to the difficulty in establishing universal criteria for it. Underlying the disorders related to MetS is almost invariably a pro-inflammatory state related to altered glucose metabolism, which could lead to elevated cardiovascular risk. Indeed, the complications closely related to MetS are cardiovascular diseases (CVDs) and type 2 diabetes (T2D). It has been observed that the predisposition to metabolic syndrome is modulated by complex interactions between human microbiota, genetic factors, and diet. This review provides a summary of the last decade of literature related to three principal aspects of MetS: (i) the syndrome’s definition and classification, pathophysiology, and treatment approaches; (ii) prediction and diagnosis underlying the biomarkers identified by means of advanced methodologies (NMR, LC/GC-MS, and LC, LC-MS); and (iii) the role of foods and food components in prevention and/or treatment of MetS, demonstrating a possible role of specific foods intake in the development of MetS