Preserving and Restoring Bone with Continuous Insulin Infusion Therapy in a Mouse Model of Type 1 Diabetes

Those with type 1 diabetes (T1D) are more likely to suffer a fracture than age- and sex-matched individuals without diabetes, despite daily insulin therapy. In rodent studies examining the effect of bone- or glucose-targeting therapies on preventing the T1D-related decrease in bone strength, insulin co-therapy is often not included, despite the known importance of insulin signaling to bone mass accrual. Therefore, working toward a relevant pre-clinical model of diabetic bone disease, we assessed the effect of continuous subcutaneous insulin infusion (CSII) therapy at escalating doses on preserving bone and the effect of delayed CSII on rescuing the T1D-related bone deterioration in an established murine model of T1D. Osmotic minipumps were implanted in male DBA/2 J mice 2 weeks (prevention study) and 6 weeks (rescue study) after the first injection of streptozotocin (STZ) to deliver insulin at 0, 0.0625, 0.125, or 0.25 IU/day (prevention study; n = 4–5 per dose) and 0 or 0.25 IU/day (rescue study; n = 10 per group). CSII lasted 4 weeks in both studies, which also included age-matched, non-diabetic DBA/2 J mice (n = 8–12 per study). As the insulin dose increased, blood glucose decreased, body weight increased, a serum maker of bone resorption decreased, and a serum marker of bone formation increased such that each end-point characteristic was linearly correlated with dose. There were insulin dose-dependent relationships (femur diaphysis) with cross-sectional area of cortical bone and cortical thickness (micro-computed tomography) as well as structural strength (peak force endured by the mid-shaft during three-point bending). Likewise, trabecular bone volume fraction (BV/TV), thickness, and number (distal femur metaphysis) increased as the insulin dose increased. Delayed CSII improved glycated hemoglobin (HbA1c), but blood glucose levels remained relatively high (well above non-diabetic levels). Interestingly, it returned the resorption and formation markers to similar levels as those seen in non-T1D control mice. This apparent return after 4 weeks of CSII translated to a partial rescue of the structural strength of the femur mid-shaft. Delayed CSII also increased Tb.Th to levels seen in non-T1D controls but did not fully restore BV/TV. The use of exogenous insulin should be considered in pre-clinical studies investigating the effect of T1D on bone as insulin therapy maintains bone structure without necessarily lowering glucose below diabetic levels

Postnatal Loss of the Insulin Receptor in Osteoprogenitor Cells Does Not Impart a Metabolic Phenotype

The relationship between osteoblast-specific insulin signaling, osteocalcin activation and gluco-metabolic homeostasis has proven to be complex and potentially inconsistent across animal-model systems and in humans. Moreover, the impact of postnatally acquired, osteoblast-specific insulin deficiency on the pancreas-to-skeleton-to-pancreas circuit has not been studied. To explore this relationship, we created a model of postnatal elimination of insulin signaling in osteoprogenitors. Osteoprogenitor-selective ablation of the insulin receptor was induced after ~10 weeks of age in IRl°x/lox/Osx-Cre+/− genotypic male and female mice (designated postnatal-OIRKO). At ~21 weeks of age, mice were then phenotypically and metabolically characterized. Postnatal-OIRKO mice demonstrated a significant reduction in circulating concentrations of undercarboxylated osteocalcin (ucOC), in both males and females compared with control littermates. However, no differences were observed between postnatal-OIRKO and control mice in: body composition (lean or fat mass); fasting serum insulin; HbA1c; glucose dynamics during glucose tolerance testing; or in pancreatic islet area or islet morphology, demonstrating that while ucOC is impacted by insulin signaling in osteoprogenitors, there appears to be little to no relationship between osteocalcin, or its derivative (ucOC), and glucose homeostasis in this model

Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

Background: Synovial tissue fibrosis is common in advanced OA with features including the presence of stress fiber-positive myofibroblasts and deposition of cross-linked collagen type-I. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. PRG4 is a ligand of the CD44 receptor. Our objective was to examine the role of PRG4-CD44 interaction in regulating synovial tissue fibrosis in vitro and in vivo. Methods: OA synoviocytes were treated with TGF-β ± PRG4 for 24h and α-SMA content was determined using immunofluorescence. Rhodamine-labeled rhPRG4 was incubated with OA synoviocytes ± anti-CD44 or isotype control antibodies and cellular uptake of rhPRG4 was determined following a 30-min incubation and α-SMA expression following a 24-h incubation. HEK-TGF-β cells were treated with TGF-β ± rhPRG4 and Smad3 phosphorylation was determined using immunofluorescence and TGF-β/Smad pathway activation was determined colorimetrically. We probed for stress fibers and focal adhesions (FAs) in TGF-β-treated murine fibroblasts and fibroblast migration was quantified ± rhPRG4. Synovial expression of fibrotic markers: α-SMA, collagen type-I, and PLOD2 in Prg4 gene-trap (Prg4GT) and recombined Prg4GTR animals were studied at 2 and 9 months of age. Synovial expression of α-SMA and PLOD2 was determined in 2-month-old Prg4GT/GT&Cd44−/− and Prg4GTR/GTR&Cd44−/− animals. Results: PRG4 reduced α-SMA content in OA synoviocytes (p \u3c 0.001). rhPRG4 was internalized by OA synoviocytes via CD44 and CD44 neutralization attenuated rhPRG4’s antifibrotic effect (p \u3c 0.05). rhPRG4 reduced pSmad3 signal in HEKTGF- β cells (p \u3c 0.001) and TGF-β/Smad pathway activation (p \u3c 0.001). rhPRG4 reduced the number of stress fiberpositive myofibroblasts, FAs mean size, and cell migration in TGF-β-treated NIH3T3 fibroblasts (p \u3c 0.05). rhPRG4 inhibited fibroblast migration in a macrophage and fibroblast co-culture model without altering active or total TGF-β levels. Synovial tissues of 9-month-old Prg4GT/GT animals had higher α-SMA, collagen type-I, and PLOD2 (p \u3c 0.001) content and Prg4 re-expression reduced these markers (p \u3c 0.01). Prg4 re-expression also reduced α-SMA and PLOD2 staining in CD44-deficient mice. Conclusion: PRG4 is an endogenous antifibrotic modulator in the joint and its effect on myofibroblast formation is partially mediated by CD44, but CD44 is not required to demonstrate an antifibrotic effect in vivo

Frequency of root fenestration in a Greek subpopulation: A cone beam computed tomography clinical study

This cone beam computed tomography (CBCT) study aimed to assess the root fenestration (RF) frequency in healthy, intact teeth and analyse their features in a Greek subpopulation. 432 CBCT scans were examined. 5486 teeth were evaluated for RF prevalence. RF prevalence and distribution were recorded for each jaw, tooth group, as well as patient age and sex. RF symmetry, distribution to the affected root surface and the effects of age and sex were evaluated. The prevalence of RF ranged from 0.57% (central incisors) to 7.18% (first premolars) and from 0.48% (second premolars) to 10.79% (lateral incisors) for the maxilla and the mandible, respectively. No symmetrical occurrence of RF was detected. Most RF patients presented one or two defects in both jaws. Types I and IV were the most prevalent in the maxilla, while Types III, II and V were the most prevalent in the mandible. No statistical difference was detected between different sexes and age groups (P > 0.05). © 2021 Australian Society of Endodontology In

Multilingual Global E-Learning Pediatric Endocrinology and Diabetes Curriculum for Front Line Health Care Providers in Resource-Limited Countries: Development Study.

BACKGROUND: Electronic learning (e-learning) is a widely accessible, low-cost option for learning remotely in various settings that allows interaction between an instructor and a learner. OBJECTIVE: We describe the development of a free and globally accessible multilingual e-learning module that provides education material on topics in pediatric endocrinology and diabetes and that is intended for first-line physicians and health workers but also trainees or medical specialists in resource-limited countries. METHODS: As complements to concise chapters, interactive vignettes were constructed, exemplifying clinical issues and pitfalls, with specific attention to the 3 levels of medical health care in resource-limited countries. The module is part of a large e-learning portal, ESPE e-learning, which is based on ILIAS (Integriertes Lern-, Informations- und Arbeitskooperations-System), an open-source web-based learning management system. Following a review by global experts, the content was translated by native French, Spanish, Swahili, and Chinese-speaking colleagues into their respective languages using a commercial web-based translation tool (SDL Trados Studio). RESULTS: Preliminary data suggest that the module is well received, particularly in targeted parts of the world and that active promotion to inform target users is warranted. CONCLUSIONS: The e-learning module is a free globally accessible multilingual up-to-date tool for use in resource-limited countries that has been utilized thus far with success. Widespread use will require dissemination of the tool on a global scale

Overview of challenges of residential nearly Zero Energy Buildings (nZEB) in Southern Europe

In times of great transition of the European construction sector to energy efficient and nearly zero energy buildings (nZEBs), a market observation containing qualitative and quantitative indications should help to fill out the enormous information gaps concerning the EU 2020 carbon targets. Next to the economic challenges, there are equally important factors that hinder renovating the existing residential building stock and adding newly constructed high performance buildings. Under these circumstances this paper summarizes the findings of a cross-comparative study of the societal and technical barriers of nZEBs implementation in 7 Southern European countries. The aim of the study was to enhance the understanding and provide and overview on future challenges of residential nZEBs in Southern Europe. The result presents an overview of challenges and provides recommendations based on available empirical evidence to further lower those barriers in the European construction sector. The paper finds that the most Southern European countries are poorly prepared for nZEBs implementation and especially for existing buildings. It is essential creating a common approach to further develop nZEBs concepts and definitions in adaptation with the climatic, societal and technical state of progress in Southern Europe. The paper provides suggestions for minimum energy efficiency and renewable energy thresholds to shift the identified gaps into opportunities for future development in deep renovation of buildings.2n

Atrial fibrillation and cognitive function in patients with heart failure: a systematic review and meta-analysis

Cognitive impairment and dementia are established complications of heart failure (HF) in adult patients and impair medication adherence and self-care. Atrial fibrillation (AF) is suggested to play an independent role in the cognitive decline in patients with HF. The objective of this systematic review was to assess the effect of AF on cognitive function in these patients. Medline (PubMed), Scopus, and the CENTRAL databases were queried from their inception up to April 30, 2016. The search included primary research articles evaluating the effect of AF on cognition in HF patients. There were five eligible studies, including a total of 1670 patients with HF; of these, 449 (26.9%) had AF. Different AF types were studied, including persistent, paroxysmal, or permanent. Four cognitive tests were used to assess cognitive function (Mini-Mental State Examination, Short Portable Mental Status Questionnaire, Modified Mini-Mental Examination, and Montreal cognitive assessment tool). Using the inverse variance method and a random effects model, we observed that presence of AF was significantly associated with increased risk of cognitive impairment in HF patients (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.30–2.87), although with significant heterogeneity (I2 = 39%). This heterogeneity can be attributed to the different populations and types of AF studied as well as to varying cognitive assessment methods. Concomitant AF may exacerbate cognitive dysfunction in HF patients. However, data are sparse and heterogeneous. Well-designed, prospective studies are needed to (a) establish a causative link and (b) identify the underlying mechanism in order to design appropriate interventions to attenuate risk of cognitive impairment in patients with HF. © 2016, Springer Science+Business Media New York

Atrial fibrillation and cognitive function in patients with heart failure: a systematic review and meta-analysis

Cognitive impairment and dementia are established complications of heart failure (HF) in adult patients and impair medication adherence and self-care. Atrial fibrillation (AF) is suggested to play an independent role in the cognitive decline in patients with HF. The objective of this systematic review was to assess the effect of AF on cognitive function in these patients. Medline (PubMed), Scopus, and the CENTRAL databases were queried from their inception up to April 30, 2016. The search included primary research articles evaluating the effect of AF on cognition in HF patients. There were five eligible studies, including a total of 1670 patients with HF; of these, 449 (26.9%) had AF. Different AF types were studied, including persistent, paroxysmal, or permanent. Four cognitive tests were used to assess cognitive function (Mini-Mental State Examination, Short Portable Mental Status Questionnaire, Modified Mini-Mental Examination, and Montreal cognitive assessment tool). Using the inverse variance method and a random effects model, we observed that presence of AF was significantly associated with increased risk of cognitive impairment in HF patients (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.30–2.87), although with significant heterogeneity (I2 = 39%). This heterogeneity can be attributed to the different populations and types of AF studied as well as to varying cognitive assessment methods. Concomitant AF may exacerbate cognitive dysfunction in HF patients. However, data are sparse and heterogeneous. Well-designed, prospective studies are needed to (a) establish a causative link and (b) identify the underlying mechanism in order to design appropriate interventions to attenuate risk of cognitive impairment in patients with HF. © 2016, Springer Science+Business Media New York