PPAR gamma pro12Ala polymorphism and type 2 diabetes: a study in a spanish cohort

Type 2 diabetes (T2D) is a disease whose occurrence is increasing prevalent in westernized civilizations and is responsible for the proliferation in the morbidity and total mortality of patients with cardiovascular diseases, worldwide. However, the complexity in the treatment and prevention of T2D arises from the intricacy of the many physical and biological factors involved in its etiology. Impaired pathways for insulin signaling have been implicated as one the many factors in the development of T2D Individual peroxisome proliferator-activated receptors (PPARs) have previously exhibited associations with alterations of lipid profiles, fat tissue and T2D and displayed complications derived from high levels of glucose. However, PPARgamma has not yet been associated with the development or developmental pathways of T2D. We performed an observational study a Spanish cohort in order to better understand the association between the SNP PPARgamma polymorphism Pro12Ala in our patients and the incidence of T2D and other cardiovascular complications. We study did not find a statistically significant relationship between the Pro12Ala and T2D development in our cohort, future observations will help us to know the association with vascular disease in patients with T2D

Targeted Inactivation of Rin3 Increases Trabecular Bone Mass by Reducing Bone Resorption and Favouring Bone Formation

AbstractCommon genetic variants at the RIN3 locus on chromosome 14q32 predispose to Paget’s disease of bone (PDB) but the mechanisms by which they do so are unknown. Here, we analysed the skeletal phenotype of female mice with targeted inactivation of the mouse Rin3 gene (Rin3−/−) as compared with wild-type littermates. The Rin3−/− mice had higher trabecular bone volume (BV/TV%) compared with wild type. Mean ± standard deviation values at the distal femur at 8 weeks were 9.0 ± 2.5 vs. 7.0 ± 1.5 (p = 0.002) and at 52 weeks were 15.8 ± 9.5 vs. 8.5 ± 4.2 (p = 0.002). No differences were observed in femoral cortical bone parameters with the exception of marrow diameter which was significantly smaller in 52-week-old Rin3−/− mice compared to wild type: (0.43 mm ± 0.1 vs. 0.57 mm ± 0.2 (p = 0.001). Bone histomorphometry showed a lower osteoclast surface / bone surface (Oc.S/BS%) at 8 weeks in Rin3−/− mice compared to wild type (24.1 ± 4.7 vs. 29.7 ± 6.6; p = 0.025) but there were no significant differences in markers of bone formation at this time. At 52 weeks, Oc.S/BS did not differ between genotypes but single labelled perimeter (SL.Pm/B.Pm (%)) was significantly higher in Rin3−/− mice (24.4 ± 6.4 vs. 16.5 ± 3.8, p = 0.003). We conclude that Rin3 negatively regulates trabecular bone mass in mice by inhibiting osteoclastic bone resorption and favouring bone formation. Our observations also suggest that the variants that predispose to PDB in humans probably do so by causing a gain-in-function of RIN3.</jats:p

Paget disease of bone-associated UBA domain mutations of SQSTM1 exerts distinct effects on protein structure and function

SQSTM1 mutations are common in patients with Paget disease of bone (PDB), with most affecting the C-terminal ubiquitin-associated (UBA) domain of the SQSTM1 protein. We performed structural and functional analyses of two UBA domain mutations, an I424S mutation relatively common in UK PDB patients, and an A427D mutation associated with a severe phenotype in Southern Italian patients. Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and resulted in activation of basal NF-kappa B signalling, compared to wild-type, in reporter assays. We found evidence for a relationship between the ability of different UBA domain mutants to activate NF-kappa B signalling in vitro and number of affected sites in vivo in 1152 PDB patients from the UK and Italy, with A427D-SQSTM1 producing the greatest level of activation (relative to wild-type) of all PDB mutants tested to date. NMR and isothermal titration calorimetry studies were able to demonstrate that I424S is associated with global structural changes in the UBA domain, resulting in 10-fold weaker UBA dimer stability than wild-type and reduced ubiquitin-binding affinity of the UBA monomer. Our observations provide insights into the role of SQSTM1-mediated NF-kappa B signalling in PDB aetiology, and demonstrate that different mutations in close proximity within loop 2/helix 3 of the SQSTM1 UBA domain exert distinct effects on protein structure and stability, including indirect effects at the UBA/ubiquitin-binding interfac

Evolution of the use of corticosteroids for the treatment of hospitalised COVID-19 patients in Spain between March and November 2020: SEMI-COVID national registry

Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID- 19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years; p < 0.001), with hypertension (57.0% vs. 47.7%; p < 0.001), obesity (26.4% vs. 19.3%; p < 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%; p < 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7-160) vs. 49.3 (16-109) mg/dL; p < 0.001), ferritin (791 (393-1534) vs. 470 (236- 996) µg/dL; p < 0.001), D dimer (750 (430-1400) vs. 617 (345-1180) µg/dL; p < 0.001), and lower Sp02/Fi02 (266 (91.1) vs. 301 (101); p < 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September; p < 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%

Letter to the Editor: The Endocrine Society Clinical Practice Guidelines on Paget's Disease: Many Recommendations Are Not Evidence Based

Dear Sir, We write with regard to the Endocrine Society Clinical Guideline on Paget's disease (1). Preparing guidelines that balance the available evidence with the need to give clinicians practical advice is a difficult task, especially in conditions like Paget's disease of bone (PDB) where high-quality evidence on patient-centered outcomes is lacking. Notwithstanding the challenge the authors faced, we have concerns that many recommendations seem to have been based on personal opinion rather than evidence and that some relevant evidence has been overlooked. In the background, the authors state that bone pain is only present in a minority of patients with PDB. Although it is true that many patients with PDB never come to medical attention (2), the guideline focused on the management of those that do present clinically. In this population, bone pain occurs in about 50% of cases (3). In view of this, we were surprised that treatment of bone pain did not figure more prominently in the guideline because the evidence base in support of this is strong (4). Recommendation 2.1 (moderate quality evidence) advises that most patients with active PDB who are at risk of complications should be treated with a bisphosphonate. This recommendation is impossible to implement because there is no validated method of identifying PDB patients who are at risk of complications. Recommendation 2.5 (low quality evidence) suggests that bisphosphonate treatment should be given with the aim of reducing the chosen biochemical marker to below the midpoint of the reference range. The implication from both of these recommendations is that bisphosphonate treatment in general and normalizing bone turnover in particular are beneficial in PDB in helping to prevent complications. However, the supporting evidence is that “it seems reasonable to suppose despite the lack of objective evidence that long-term complications might be reduced by normalization of bone turnover.” With all due respect to the authors, this is an opinion and not evidence. A randomized trial has been performed to investigate whether it is beneficial to try and normalize bone turnover in PDB, but no difference was found in the rate of complications between groups of patients treated with the aim of normalizing alkaline phosphatase concentrations, as opposed to those who were treated symptomatically (5). Recommendation 2.6 (moderate quality evidence) similarly suggests that biochemical markers of bone turnover should be used as a more objective indication of relapse than symptoms. Implicit in this recommendation is that “biochemical relapse” predicts clinical relapse. We are aware of no evidence to suggest that this is the case. Recommendation 3.1 (low quality evidence) suggests that a potent bisphosphonate should be given to prevent worsening of a hearing deficit, with supporting evidence from an observational study with calcitonin (6). The effects of bisphosphonates on hearing loss in PDB have been studied, and no benefit has been observed (5, 7). Recommendation 3.2b (low quality evidence) suggests that bisphosphonates should be given to prevent cartilage degeneration in patients with osteoarthritis adjacent to an affected bone. The supporting evidence is that “it is conceivable that drug treatment of Paget's disease may slow the arthritis process.” This recommendation is based on the authors' opinion, rather than evidence. We have great respect for the authors of the guideline, many of whom have extensive personal experience in the treatment of PDB. It is crucially important, however, that clinical guidelines accurately portray the level of supporting evidence, and if no evidence exists, this should be highlighted as a gap in knowledge. These guidelines have not done that adequately