Level III, retrospective comparative series.

Objective-The aim of the study was to evaluate the role of purinergic receptor P2Y, G protein-coupled 12 (P2Y12), an ADP receptor, in the development of atherosclerotic lesions. Methods and Results-Apolipoprotein E-null mice were crossed with P2y12 −/− mice to generate double knockout mice. The double knockout mice and the control apolipoprotein E-null mice were fed a high-fat diet for 20 weeks. Assessment of the atherosclerotic lesions in the control and double knockout mice demonstrated that P2Y12 deficiency caused a diminished lesion area, an increased fibrous content at the plaque site, and decreased monocyte/macrophage infiltration of the lesions. Polymerase chain reaction studies revealed that white blood cells do not express significant levels of P2Y12. Bone marrow transplantation experiments confirmed that P2Y12 expressed on platelets is a key factor responsible for atherosclerosis, but do not exclude a role of smooth muscle cell P2Y12. Supernatant fluid from activated P2y12 +/+ but not P2y12 −/− platelets was capable of causing monocyte migration. In vitro studies showed that platelet P2Y12 deficiency suppressed platelet factor 4 secretion and P-selectin expression. Further work demonstrated that platelet P2Y12, through inhibition of the cAMP/protein kinase A pathway, critically regulates the release of platelet factor 4, and thereby affects monocyte recruitment and infiltration. Key Words: atherosclerosis n platelets n purinergic receptor P2Y, G protein-coupled 12

Phosphatidylinositol 3-kinase (PI3K) has been shown to play an important role in collagen-induced platelet activation, but the role(s) of PTEN, a major regulator of the PI3K/Akt signaling pathway, has not been examined in platelets. Here, we report that Pten ؊/؊ mouse blood contains 25% more platelets than Pten ؉/؉ blood and that PTEN deficiency significantly shortened the bleeding time, increased the sensitivity of platelets to collagen-induced activation and aggregation, and enhanced phosphorylation of Akt at Ser473 in response to collagen. Furthermore, we found that PP2, and the combination of apyrase, indomethacin ؉ 1B5, respectively, inhibited collagen-induced aggregation in both PTEN ؉/؉ and PTEN ؊/؊ platelets. In contrast, LY294002 (a PI3K inhibitor) prevented the aggregation of PTEN ؉/؉ , but not PTEN ؊/؊ , platelets. Therefore, PTEN apparently regulates collagen-induced platelet activation through PI3K/Akt-dependent and -independent signaling pathways. IntroductionThe role of collagen/platelet interactions in hemostasis has been studied extensively. Collagen, acting on the glycoprotein VI (GPVI)/Fc receptor ␥ chain (FcR-␥ chain) complex, sequentially activates Src and Syk family tyrosine kinases that propagate potent signaling via phosphatidylinositol 3-kinase (PI3K) that culminates in ␣IIb␤3 activation, and platelet aggregation. [1][2][3] PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a dual-specificity protein phosphatase and an inositol phospholipid phosphatase. The role of PTEN as a tumor suppressor is well established. 4 PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) producing phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), thereby negatively regulating oncogenic and nononcogenic PI3K/Akt signaling. 5 PTEN/PI3K/ Akt constitutes an important pathway regulating the signaling of multiple biologic processes, including apoptosis, cell growth, and proliferation. PI3K plays an important role in GPVI-mediated platelet activation, yet the role of PTEN, the major regulator of PI3K/Akt signaling, has not been characterized in GPVI-mediated platelet activation. Here, using inducible and hematopoietic tissuespecific deletion of Pten in mice, we demonstrate that PTEN negatively regulates PI3K-dependent and -independent collageninduced platelet activation. Methods MaterialsCollagen was from Nycomed Arzneimittel. PP2 and LY294002 were from Calbiochem. Apyrase and prostaglandin E 1 were from Sigma-Aldrich. Hamster anti-mouse ␣IIb␤3 antibody (IB5) was a generous gift from Dr Barry Coller (Rockefeller University). Anti-phospho-Akt (Ser473), anti-PTEN, and anti-␤-actin antibodies were from Cell Signaling Technology. Secondary antibodies were from Santa Cruz Biotechnology. AnimalsMx1-Cre ϩ C57BL/6J mice were from Model Animal Research Center of Nanjing University (Nanjing, China). Pten loxp-loxp mice from The Jackson Laboratory were backcrossed onto the C57BL/6J background for 6 generations. The Pten loxp-loxp /Mx1-Cre ؉ mice were produced as described. 6 P...

Background The associations of different adiposity indicators and short-term adiposity change with diabetes risk are not fully elucidated. Objective We aimed to assess the independent and joint effects of different baseline adiposity indicators and short-term body adiposity change on the risk of type 2 diabetes. Methods We prospectively followed 10,419 Chinese adults aged 20–80 y in 2008–2012. Incident diabetes was diagnosed based on fasting glucose, 2-h glucose, or glycated hemoglobin (HbA1c) after an oral glucose tolerance test using the American Diabetes Association standard. Cox proportional hazard regression models were used to assess the associations of adiposity indicators and adiposity change with diabetes risk. Results During a mean follow-up of 2.8 y, we identified 805 type 2 diabetes cases. Baseline BMI, waist circumference, and waist-height ratio (WHtR) were all positively associated with diabetes risk. The area under the curve was significantly greater for waist circumference (0.624) and WHtR (0.627) than for BMI (0.608) (P <0.05). Compared with subjects with stable adiposity levels (±2 kg or ± 3 cm in changes in body weight or waist circumference) from baseline to Year 1, those subjects with the most weight gain or the most waist circumference gain had a 1.53-fold or 1.37-fold greater risk of diabetes; those with the most weight loss had a 46% lower risk of diabetes. Furthermore, regardless of baseline weight status, weight or waist circumference change in the first year was associated with diabetes risk. Conclusion Abdominal adiposity indicators, waist circumference and its change, are more strongly associated with the risk of type 2 diabetes than general adiposity indicators, BMI, and changes in body weight among Chinese adults.

Background To evaluate the effect of intramedullary nail and locking plate in the treatment of proximal humerus fracture (PHF). Methods China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wan-fang database, Chinese Biomedicine Database (CBM), PubMed, EMBASE, Web of Science, and Cochrane Library were searched until July 2018. The eligible references all show that the control group uses locking plates to treat PHF, while the experimental group uses intramedullary nails to do that. Two reviewers independently retrieved and extracted the data. Reviewer Manager 5.3 was used for statistical analysis. Results Thirty-eight retrospective studies were referred in this study which involves 2699 patients. Meta-analysis results show that the intramedullary nails in the treatment of proximal humeral fractures are superior to locking plates in terms of intraoperative blood loss, operative time, fracture healing time, postoperative complications, and postoperative infection. But there is no significance in constant, neck angle, VAS, external rotation, antexion, intorsion pronation, abduction, NEER, osteonecrosis, additional surgery, impingement syndrome, delayed union, screw penetration, and screw back-out. Conclusions The intramedullary nail is superior to locking plate in reducing the total complication, intraoperative blood loss, operative time, postoperative fracture healing time and postoperative humeral head necrosis rate of PHF. Due to the limitations in this meta-analysis, more large-scale, multicenter, and rigorous designed RCTs should be conducted to confirm our findings. Trial registration PROSPERO CRD42019120508

Brief description of insulin mRNA quantity and qualityMany factors may contribute to the control of insulin mRNA levels (1, 2), including transcriptional networks that control β cell function (3) as well as mRNA stability (4). While a detailed analysis of the transcriptional regulation of β cell development, differentiation, and dedifferentiation is beyond the scope of this Review, it is certainly clear that PDX1 and NEUROD1 can act together to directly stimulate transcription from the INS promoter (5). Moreover, PDX1, in combination with NKX2.2 (downstream of NEUROG3; ref. 6) and FOXA2, stimulates the expression of the β cell-specific activator MafA (7); in turn, MafA homodimers (or MafA/MafB heterodimers) help support β cell INS gene transcription (8) (two alleles in humans, four alleles in mice and rats), along with additional upstream factors (9). A number of human diabetes-related genes associated with INS mRNA expression are summarized in Table 1.Classic studies of the islets of insulin-resistant C57BL/KsJ db/db mice, a genetic model of type 2 diabetes (T2D), have shown that at 5 weeks of age (when glycemia is not yet significantly perturbed and pancreatic insulin content is still similar to that in +/db controls), there is an elevation of Ins mRNA that is likely

OBJECTIVES:Pilon fracture is a complex injury that is often associated with severe soft tissue damage and high rates of surgical site infection. The goal of this study was to analyze and identify independent risk factors for surgical site infection among patients undergoing surgical fixation of a pilon fracture.METHODS:The medical records of all pilon fracture patients who underwent surgical fixation from January 2010 to October 2012 were reviewed to identify those who developed a surgical site infection. Then, we constructed univariate and multivariate logistic regressions to evaluate the independent associations of potential risk factors with surgical site infection in patients undergoing surgical fixation of a pilon fracture.RESULTS:A total of 519 patients were enrolled in the study from January 2010 to October 2012. A total of 12 of the 519 patients developed a surgical site infection, for an incidence of 2.3%. These patients were followed for 12 to 29 months, with an average follow-up period of 19.1 months. In the final regression model, open fracture, elevated postoperative glucose levels (≥125 mg/dL), and a surgery duration of more than 150 minutes were significant risk factors for surgical site infection following surgical fixation of a pilon fracture.CONCLUSIONS:Open fractures, elevated postoperative glucose levels (≥125 mg/dL), and a surgery duration of more than 150 minutes were related to an increased risk for surgical site infection following surgical fixation of a pilon fracture. Patients exhibiting the risk factors identified in this study should be counseled regarding the possible surgical site infection that may develop after surgical fixation.

Trace elements, such as iodine and selenium, are closely related to autoimmune thyroiditis and thyroid function. Low serum magnesium is associated with several chronic diseases; however, its associations with autoimmune thyroiditis and thyroid function are unclear. We investigated the relationships between low serum magnesium, autoimmune thyroiditis, and thyroid function in 1,257 Chinese participants. Demographic data were collected via questionnaires, and levels of serum thyroid stimulating hormone, anti-thyroid peroxidase antibody, anti-thyroglobulin antibody (TGAb), free thyroxine, serum magnesium, serum iodine, and urinary iodine concentration were measured. Participants were divided into serum magnesium level quartiles (≤0.55, 0.551–0.85, 0.851–1.15, and >1.15 mmol/L). The median serum magnesium level was 0.89 (0.73–1.06) mmol/L; levels ≤0.55 mmol/L were considered severely low (5.9% of participants). The risks of TGAb positivity and Hashimoto thyroiditis (HT) diagnosed using ultrasonography in the lowest quartile group were higher than those in the adequate magnesium group (0.851–1.15 mmol/L) (p < 0.01, odds ratios [ORs] = 2.748–3.236). The risks of total and subclinical-only hypothyroidism in the lowest quartile group were higher than those in the adequate magnesium group (0.851–1.15 mmol/L) (p < 0.01, ORs = 4.482–4.971). Severely low serum magnesium levels are associated with an increased rate of TGAb positivity, HT, and hypothyroidism.