Search

Comprehensive evidence‐based guidelines for the practice of pancreas transplantation are yet to be established. The First World Consensus Conference on Pancreas Transplantation was convened for this purpose. A steering committee selected the participants and defined the questions to be addressed. A group of literature reviewers identified 597 studies to be included in summaries for guidelines production. Expert groups formulated the first draft of recommendations. Two rounds of discussion and voting occurred online, using the Delphi method (agreement rate ≥85%). After each round, critical responses of experts were reviewed, and recommendations were amended accordingly. Recommendations were finalized after live discussions. Each session was preceded by expert presentations and a summary of results of systematic literature review. Up to three voting rounds were allowed for each recommendation. To avoid potential conflicts of interest, deliberations on issues regarding the impact of pancreas transplantation on the management of diabetes were conducted by an independent jury. Recommendations on technical issues were determined by experts and validated using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Quality of evidence was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology. Each recommendation received a GRADE rating (Grading of Recommendations, Assessment, Development and Evaluations)., This article presents the results of literature search and the methods used to provide evidence‐based guidelines for the practice of pancreas transplantation at the First World Consensus Conference on Pancreas Transplantation.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10−9). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism. © 2021 UICC

The authors regret that the affiliation for Gian Luca Grazi was incorrect and should appear as above. The authors would like to apologise for any inconvenience caused.

Biliary cystadenoma (BCA) is a rare tumor which is difficult to diagnose before surgery. We present a case of 73 years old woman with a previous histological diagnosis of biliary cystadenoma occurred in 2009, surgically removed. In January 2018, abdomen Computerized Tomography scan (CTs) showed a 65 mm diameter cystic mass in the fifth hepatic segment. Even if the patient refused to undergo surgical resection due to her several comorbilities, imaging features and clinical history are suggestive for BCA recurrence.

Effects of glycated insulin on adipogenic differentiation. A. Piccoli1, T. Bisogno1,2, M. Maccarrone1,3, P. Pozzilli1,4, N. Napoli1,5, R. Strollo1. 1Universita Campus Bio-Medico di Roma, Rome, Italy; 2National Research Council, Pozzuoli, Italy; 3European Center for Brain Research (CERC)/Santa Lucia Foundation IRCCS, Rome, Italy; 4Queen Mary, University of London, London, UK; 5Washington University in St Louis, St Louis, MO, USA Hyperglycaemia and chronic low-grade inflammation associated with obesity and diabetes are a main source of reactive oxidants (ROS). High levels of ROS may generate oxidative post-translational modification (oxPTMs) that may impair proteins biological functions. We have shown that insulin could also be a target of these modifications that include glycation, oxidation and chlorination. Adipose tissue is a primary target of this hormone and a key player in insulin resistance (IR): evidence from animal studies show that the glycation of insulin or other proteins result in a significant impairment of biological function of adipose tissue, affecting adipokines expression and insulin sensitivity. However, how oxPTMs such as glycation interfere with insulin function and their involvement in IR and type 2 diabetes (T2D) is still unknown. We hypothesize that insulin glycation may be involved in insulin resistance and in the pathogenesis of T2D. Therefore, the aim of this study was to assess the possible effects of glycated vs. native insulin on adipocyte differentiation. Human recombinant insulin was glycated in vitro following our established protocol. Insulin glycation was monitored through PAGE. Human preadipocytes (HPAd), a primary cell line from subcutaneous adipose tissue, and adipose-derived stem cells (ASCs), isolated from tissues of lean and obese subjects (BMI30), were differentiated with standard adipogenic medium in presence of native or glycated insulin. Cellular differentiation was assessed by gene and protein expression analyses of adipogenic markers (adiponectin, peroxisome proliferator-activated receptor gamma -Ppar?-, fatty acid binding protein 4 -Fabp4-, glucose transporter 4 -Glut4-) and of receptors for adiponectin (AdipoR1) and for insulin (InsR), through real time RT-PCR and immunoblot respectively. Our preliminary results showed that preadipocytes (both HPAd and ASCs) exposed to glycated insulin had impaired differentiation capacities: Oil Red O-staining showed that these cells had lower number of lipid droplets compared to those exposed to native insulin, suggesting an impaired adipocyte differentiation. Considering gene expression, we observed an overall downregulation of adipogenic markers, with a significant decrease of adiponectin both in leans- and in obese-derived cells (p=0.007 and p=0.017 respectively), lower levels of Glut4 and a significant lower expression of Fabp4 (p=0.002) in cells from leans differentiated with glycated insulin. Immunoblotting showed a similar pattern to that observed with gene expression analysis but, regarding insulin receptor, protein levels of the receptor presented a significant down regulation in cells treated with glycated insulin, with a p value of 0.0266 in leans and p=0.011 in obese subjects. Conversely, gene expression of insulin receptor did not present any difference between the native and glycated insulin. In conclusion, our data suggest that glycated insulin could affect adipocytes differentiation and impair insulin receptor expression, acting at translational/post-translational level or increasing its degradation. Its role and mechanisms that lead to these effects should be investigated as a possible mediator in the pathogenesis of T2D.

The central role of vitamin D in bone health is well recognized. However, controversies regarding its clinical application remain. We therefore aimed to review the definition of hypovitaminosis D, the skeletal and extra-skeletal effects of vitamin D and the available therapeutic modalities.

Kikuchi–Fujimoto disease (KFD) is a rare, benign, generally self-limiting disease that has higher prevalence in Asian people with a few cases reported in European countries. It generally affects young subjects under 40 years of age and is characterized by regional lymphadenopathy. Here, we present a case of a 66-year-old Italian woman who was extensively examined for right unilateral laterocervical lymph nodes associated with fever, night sweats, fatigue, and weight loss. She was diagnosed as having the KFD only after an excision biopsy of the largest laterocervical lymph node and was then managed symptomatically with NSAIDs. We also made a review of the literature for better awareness of the disease among physicians especially in those countries, like Italy, where the disease is not prevalent and may be frequently misdiagnosed. In fact, to our best knowledge, only seven Italian cases of KFD have been published in the last 15 years with patients being younger than 40 years. We finally highlight that it is noteworthy to consider KFD as differential diagnosis of lymphadenopathy even in old patients, and, since a misdiagnosis of lymphoma is actually feasible, an early biopsy has to be taken into account for confirming diagnosis and helping in the timely and appropriate management.

Contains fulltext : 125353.pdf (Publisher’s version ) (Open Access) BACKGROUND: Vitamin D supplementation in childhood improves the achievement of peak bone mass. We investigated the effect of supplementation with calcitriol on bone turnover in recent-onset type 1 diabetes (T1D). Moreover, the association between osteocalcin and parameters of beta-cell function and metabolic control was examined. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a post-hoc analysis of a double-blind, placebo-controlled study of calcitriol supplementation to preserve beta-cell function. 27 recent-onset T1D subjects, mean age 22 years, were randomized to 0.25 microg calcitriol per day or placebo (1:1) and followed up for one year. Changes in bone formation (osteoclacin) and resorption (beta-CrossLaps) markers, and differences between placebo and calcitriol-treated group were evaluated. At baseline, osteocalcin levels were significantly lower in female than in male patients (P

International audience; SummaryThis article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes.IntroductionRare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients.MethodsIOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis.ResultsThis taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity.ConclusionsThis article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

Arabidopsis abcb1 abcb19 double mutants defective in the auxin transporters ABCB1/PGP1 and ABCB19/PGP19 are altered in stamen elongation, anther dehiscence and pollen maturation. To assess the contribution of these transporters to stamen development we performed phenotypic, histological analyses, and in situ hybridizations on abcb1 and abcb19 single mutant flowers. We found that pollen maturation and anther dehiscence are precocious in the abcb1 but not in the abcb19 mutant. Accordingly, endothecium lignification is altered only in abcb1 anthers. Both abcb1 and abcb1 abcb19 stamens also show altered early development, with asynchronous anther locules and a multilayer tapetum. DAPI staining showed that the timing of meiosis is asynchronous in abcb1 abcb19 anther locules, while only a small percentage of pollen grains are nonviable according to Alexander's staining. In agreement, TAM (TARDY ASYNCHRONOUS MEIOSIS), as well as BAM2 (BARELY ANY MERISTEM)--involved in tapetal cell development--are overexpressed in abcb1 abcb19 young flower buds. Correspondingly, ABCB1 and ABCB19 mRNA localization supports the observed phenotypes of abcb1 and abcb1 abcb19 mutant anthers. In conclusion, we provide evidence that auxin transport plays a significant role both in early and late stamen development: ABCB1 plays a major role during anther development, while ABCB19 has a synergistic role.

Arabidopsis abcb1 abcb19 double mutants defective in the auxin transporters ABCB1/PGP1 and ABCB19/PGP19 are altered in stamen elongation, anther dehiscence and pollen maturation. To assess the contribution of these transporters to stamen development we performed phenotypic, histological analyses, and in situ hybridizations on abcb1 and abcb19 single mutant flowers. We found that pollen maturation and anther dehiscence are precocious in the abcb1 but not in the abcb19 mutant. Accordingly, endothecium lignification is altered only in abcb1 anthers. Both abcb1 and abcb1 abcb19 stamens also show altered early development, with asynchronous anther locules and a multilayer tapetum. DAPI staining showed that the timing of meiosis is asynchronous in abcb1 abcb19 anther locules, while only a small percentage of pollen grains are non-viable according to Alexander's staining. In agreement, TAM (TARDY ASYNCHRONOUS MEIOSIS), as well as BAM2 (BARELY ANY MERISTEM)-involved in tapetal cell development-are overexpressed in abcb1 abcb19 young flower buds. Correspondingly, ABCB1 and ABCB19 mRNA localization supports the observed phenotypes of abcb1 and abcb1 abcb19 mutant anthers. In conclusion, we provide evidence that auxin transport plays a significant role both in early and late stamen development: ABCB1 plays a major role during anther development, while ABCB19 has a synergistic role.

Polymorphisms of the CYP450 genes that encode for the enzymes that metabolize estrogen are linked to hormone-related cancers. We investigated the impact of two polymorphisms of the CYP1B1 gene previously reported to be associated with hormone-related disorders on estrogen metabolism and bone mineral density (BMD), another hormone-dependent condition, in women from different ethnic backgrounds. Four hundred sixty-eight postmenopausal Caucasian women, 220 from St. Louis, MO, USA (mean age=63.5±0.53 years) and 248 from Palermo, Italy (mean age=72.9±0.44 years) participated in the study. Measurements of urinary estrogen metabolites by enzyme-linked immunoassay, serum estradiol by ultrasensitive radioimmnunoassay, and serum sex hormone-binding globulin by immunoradiometric assay were performed only in the American women, while BMD by dual energy X-ray absorptiometry and genotyping by pyrosequencing were performed in both American and Italian women. Differences in the levels of metabolites, free estradiol index and BMD were analyzed by analysis of covariance. Analysis among the American participants for the Valine432Leucine polymorphism showed that, compared to women with the Val/Val genotype, women with the Leu allele (Val/Leu and Leu/Leu) had significantly higher log-transformed values of total urinary estrogen metabolite (ng/mg-creatinine) levels (1.23±0.04, 1.35±0.02, and 1.34±0.03; p=0.03), and significantly lower BMD (gm/cm2) in the lumbar spine (1.009±0.02, 0.955±0.01 and 0.931±0.02; p=0.03) and the femoral neck (0.748± 0.02, 0.717±0.01 and 0.693±001, p =0.03) for the Val/Val, Val/Leu and Leu/Leu genotypes respectively. There were no significant differences in the urinary metabolites and BMD in the different genotypes for the Alanine119Serine polymorphism among the American women. Meanwhile, a separate analysis among the Italian women revealed no significant differences in BMD among the different genotypes for the two polymorphisms investigated. In conclusion, women with the Leu allele for the CYP1B1 Val432polymorphism have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites, compared to those with Val/Val genotype. This may lead to relative hypoestrogenism and lower BMD in the lumbar spine and femoral neck in these women. Our data suggest that through its effect on the rate of estrogen catabolism, the Val432Leu polymorphism of the CYP1B1 gene may represent as a possible genetic risk factor for osteoporosis in American women.

AimsTo investigate whether 25-hydroxyvitamin D concentration was associated with incident diabetes in a large cohort of older women.MethodsData were analysed from women included in the Study of Osteoporotic Fractures, a cohort of community-dwelling women aged ≥65 years at enrolment. Serum 25-hydroxyvitamin D concentration was assessed at the year 6 visit, as were BMI and other factors associated with vitamin D and/or diabetes. Diabetes status was determined at each subsequent visit by self-report and medication use. Only those without prevalent diabetes at the year 6 visit were included in the present analysis (N = 5463, mean age 76.5 years).ResultsDuring a mean ±sd follow-up of 8.6 ± 4.4 years, incident diabetes was reported in 320 participants. The mean BMI was higher in those with a 25-hydroxyvitamin D concentration

Studies carried out on individuals being treated long term with bisphosphonates have provoked considerable interest and perplexity about the effect that these drugs have on bone turnover in the long run. In fact the experiences reported by numerous researchers tend to highlight how treatment with high doses of bisphosphonates over many years, of individuals with osteoporosis complicated by or secondary to neoplastic pathologies, causes a suppression of bone turnover that over time predisposes the bone to the accumulation of micro damage that can then result in complicated fractures, as in the case described here.

Background: Recurrent chronic idiopathic urticaria (RCIU) is a common skin condition that affects 0.1–3% of the population in the USA and Europe and accounts for nearly 75% of all ‘ordinary’ chronic urticaria (CU) cases. Methods: We studied 838 consecutive patients with RCIU referred to hospital between 1998 and 2003. Patients with known causes of CU were excluded. Clinical history, physical examination, and symptom diaries were evaluated during two periods, a diet-free period (1 week) and a food-additive-free diet (FAFD) period (4 weeks), respectively, and two double-blind placebo-controlled (DBPC) challenges of six food additives were administered. The first DBPC challenge included a mixture of the six food additives (DBPCmixed) given to all patients. The second DBPC challenge comprised the single food additives, administered at increasing doses (DBPCsingle) to patients with a positive DBPCmixed test and 105 patients with a negative DBPCmixed test, as a control. Results: The DBPCmixed challenge was positive in 116 patients. None of the 105 control patients had a positive DBPCsingle test. Only 31 DBPCsingle tests were positive in patients with positive DBPCmixed challenge. Twenty-four of the 116 patients showing a positive DBPCmixed challenge also had a positive DBPCsingle result. Conclusions: Our results confirmed that food additive hypersensitivity reactions occurred in few RCIU patients using DBPCsingle challenge. The combination of the results of FAFD and DBPCmixed challenge seems to be of considerable practical interest for allergists, internists and dermatologists, rather than the data of clinical history and the results of DBPCsingle challenge, in patients with RCIU.

a b s t r a c t Background: Data on the efficacy of Peg-interferon/ribavirin therapy for chronic hepatitis C are mostly derived from treatment of selected patients enrolled in clinical trials. This study aimed to assess the effectiveness of Peg-interferon/ribavirin therapy in “real world” chronic hepatitis C patients in Italy. Methods: Independent observational multicentre study including consecutive patients receiving Peginterferon/ribavirin in the 18 months before (retrospective phase) and after (prospective phase) the start of the study. Results: 4176 patients were eligible. The final study population consisted of 2051 patients in the retrospective and 2073 in the prospective phase. Sustained virological response was achieved by 1036 patients (50.5%) during the retrospective phase: 325 were genotypes 1/4 (34.1%) and 684 were genotypes 2/3 (67.2%) and by 800 patients (38.6%) during the prospective phase: 300 were genotypes 1/4 (28.4%) and 473 were genotypes 2/3 (51.5%). During multivariate analysis genotypes 2/3 were significantly associated with higher sustained virological response rates; cirrhosis and -glutamil-transpeptidase >2 times the normal limit were associated with poorer response. Conclusions: The response to Peg-interferon/ribavirin therapy in “real world” clinical practice is distinctly lower than in registration trials. The difference in response rates was more pronounced among easy-totreat than among difficult-to-treat hepatitis C virus genotypes.

Knotted1-like homeobox (KNOX) transcription factors belong to the three amino acid loop extension (TALE) superclass of homeodomain proteins in higher plants (Hay and Tsiantis, 2010; Hamant and Pautot, 2010; Wu and Smith 2012; Di Giacomo et al., 2013). KNOX1 proteins play a key role in several developmental processes by maintaining a proper balance between undifferentiated and differentiated cell state through the modulation of multiple hormonal pathways Besides the homeodomain, KNOX proteins are characterized by the presence of a consensus region called MEINOX that defines this subclass of the TALE family. MEINOX domain is important for protein-protein interactions with a second group of TALE proteins, the BEL-like homeodomain (BLH) family. This interaction modulates KNOX nuclear localization and, likely, target selection . Mutations in KNAT1/BREVIPEDICELLUS (KNAT1/BP), one of the four Arabidopsis KNOX1 genes, result in plants with shorter internodes, downward pointing siliques, altered intra-bundle cell identity and altered lignin deposition (Mele et al., 2004). Recently, KNATM, a novel Arabidopsis KNOX1 gene that encodes a MEINOX domain but lacks the homeodomain was identified and shown to regulate KNAT1/BP (Magnani and Hake, 2008). We identified and characterized a novel isoform of KNAT1/BP transcription factor that arises from an event of alternative splicing and may encode a novel protein (BPhox) that contains the homeodomain but lacks the MEINOX domain. Phenotype and molecular analysis of Arabidopsis lines that overexpress each isoforms under the control of constitutive/inducible promoters and complementation analyses were carried out to unravel the function of BPhox in inflorescence architecture, vascular development and lignin deposition.