Selenoproteins Are Essential for Proper Keratinocyte Function and Skin Development

Dietary selenium is known to protect skin against UV-induced damage and cancer and its topical application improves skin surface parameters in humans, while selenium deficiency compromises protective antioxidant enzymes in skin. Furthermore, skin and hair abnormalities in humans and rodents may be caused by selenium deficiency, which are overcome by dietary selenium supplementation. Most important biological functions of selenium are attributed to selenoproteins, proteins containing selenium in the form of the amino acid, selenocysteine (Sec). Sec insertion into proteins depends on Sec tRNA; thus, knocking out the Sec tRNA gene (Trsp) ablates selenoprotein expression. We generated mice with targeted removal of selenoproteins in keratin 14 (K14) expressing cells and their differentiated descendents. The knockout progeny had a runt phenotype, developed skin abnormalities and experienced premature death. Lack of selenoproteins in epidermal cells led to the development of hyperplastic epidermis and aberrant hair follicle morphogenesis, accompanied by progressive alopecia after birth. Further analyses revealed that selenoproteins are essential antioxidants in skin and unveiled their role in keratinocyte growth and viability. This study links severe selenoprotein deficiency to abnormalities in skin and hair and provides genetic evidence for the role of these proteins in keratinocyte function and cutaneous development

Sonographic evaluation of the shoulder in asymptomatic elderly subjects with diabetes

<p>Abstract</p> <p>Background</p> <p>The prevalence of rotator cuff tears increases with age and several studies have shown that diabetes is associated with symptomatic shoulder pathologies. Aim of our research was to evaluate the prevalence of shoulder lesions in a population of asymptomatic elderly subjects, normal and with non insulin - dependent diabetes mellitus.</p> <p>Methods</p> <p>The study was performed on 48 subjects with diabetes and 32 controls (mean age: 71.5 ± 4.8 and 70.7 ± 4.5, respectively), who did not complain shoulder pain or dysfunction. An ultrasound examination was performed on both shoulders according to a standard protocol, utilizing multiplanar scans.</p> <p>Results</p> <p>Tendons thickness was greater in diabetics than in controls (Supraspinatus Tendon: 6.2 ± 0.09 mm <it>vs </it>5.2 ± 0.7 mm, p < 0.001; Biceps Tendon: 4 ± 0.8 mm <it>vs </it>3.2 ± 0.4 mm, p < 0.001). Sonographic appearances of degenerative features in the rotator cuff and biceps were more frequently observed in diabetics (Supraspinatus Tendon: 42.7% <it>vs </it>20.3%, p < 0.003; Biceps Tendon: 27% <it>vs </it>7.8%, p < 0.002).</p> <p>Subjects with diabetes exhibited more tears in the Supraspinatus Tendon (Minor tears: 15 (15.8%) <it>vs </it>2 (3.1%), p < 0.03; Major tears: 15 (15.8%) <it>vs </it>5 (7.8%), p = ns), but not in the long head of Biceps. More effusions in subacromial bursa were observed in diabetics (23.9% <it>vs </it>10.9%, p < 0.03) as well as tenosynovitis in biceps tendon (33.3% <it>vs </it>10.9%, p < 0.001).</p> <p>In both groups, pathological findings were prevalent on the dominant side, but no difference related to duration of diabetes was found.</p> <p>Conclusions</p> <p>Our results suggest that age - related rotator cuff tendon degenerative changes are more common in diabetics.</p> <p>Ultrasound is an useful tool for discovering in pre - symptomatic stages the subjects that may undergo shoulder symptomatic pathologies.</p

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

Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN): results from a meta-analysis and survey study

Objective: The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, inc luding care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pi tuitary adenoma within Endo-ERN. Design and Methods: Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by refere nce centers on their current surgical practice. Results: A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6- represented countries published 48 articles. Remission rates we re 50% (95% CI: 42–59) for patients with acromegaly, 68% (95% CI: 60–75) for Cushing’s disease, and 53% (95% CI: 39–66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37–61%) of patients and visual improvement in 78% (95% CI: 68–87). Mort ality, hemorrhage, and carotid injury occurred in less than 1% of patients. New-onset hypopituitarism occurred in 16% (95% CI: 11–23), transient diabetes insipidus in 12% (95 % CI: 6–21), permanent diabetes insipidus in 4% (95% CI: 3–6), syndrome of inappropria te secretion of antidiuretic hormone (SIADH) in 9% (95% CI: 5–14), severe epist axis in 2% (95% CI: 0–4), and cerebrospinal fluid leak in 4% (95% CI: 2–6). Thirty-five (81 %) centers completed the survey: 54% were operated endoscopically and 57% were together with an ENT surgeon. Conclusion: The results of this study could be used as a first benchmark for the outcomes of pituitary adenoma surgery within Endo-ERN. However, the hete rogeneity between studies in the reporting of outcomes hampers comparability and warrants outcome collection through registries