Thyroid hormone resistance syndrome due to a novel heterozygous mutation and concomitant Hashimoto's Thyroiditis: A pedigree report.

Thyroid hormone resistance syndrome (THRS) is a rare disease characterized by reduced sensitivity to thyroid hormones. Mutations in the thyroid hormone receptor beta (THRB) gene are considered as contributing to the pathogenesis. This report describes a Chinese pedigree with THRS and Hashimoto's thyroiditis (HT) due to novel point mutation in the 11th exon of the THRB gene (c. 1378 G > A). The proband complained of goitre with increased thyroid hormone and normal thyroid stimulating hormone levels. Gene sequencing was performed to confirm the diagnosis. HT was also diagnosed based on positive thyroid autoantibodies and diffuse, grid-like changes in the thyroid on ultrasound examination. Additionally, a comprehensive examination of the proband's pedigree was conducted. The patient's father exhibited the same gene mutation site and was diagnosed with THRS and HT. No mutation site was detected in three patients with HT only and three healthy volunteers. Thus, gene sequencing should be considered the gold standard for diagnosing THRS. Furthermore, treatment should be individualized to control the patient's symptoms rather than normalizing thyroid hormone levels. Further studies that determine the relationship between THRS and TH are warranted.

The impact of perioperative glucose variability on outcomes after hip fracture.

ABSTRACT: Diabetes is considered an independent risk factor for hip fracture. In the present study, we evaluated whether perioperative glucose variability (GV) was a significant predictor of the outcomes of patients with diabetes after hip fracture.We analyzed the characteristics and outcomes of all patients with hip fractures admitted to our hospital between September 2008 and December 2012. Patients with diabetes were grouped into tertiles for GV, and multivariate survival analysis included age, sex, fracture type, mean fasting plasma glucose, and GV.Among the 1099 patients included in this study, 239 (21.7%) had diabetes. Patients with diabetes were more likely to develop infectious complications (5.4% vs 2.8%, P = .045), and experience mortality postoperatively (1 month: 5.5% vs 2.7%, P = .052; 12 months: 15.1% vs 8.7%, P = .006). The postoperative mortality rate was increased across the GV tertiles, and GV was an independent predictor of 1- and 12-month mortality after surgery.Patients with diabetes had poor prognoses after hip fracture. Perioperative GV is an independent predictor of mortality in patients with diabetes. Therefore, GV might be considered a valid additional parameter to consider in the management of these patients.

Anti-obesity effect and mechanism of mesenchymal stem cells influence on obese mice.

Mesenchymal stem cells (MSCs) can be obtained from almost all tissues and present promising therapeutic effects for metabolic diseases. Human adipose-derived MSCs (hASCs) have recently been widely studied due to their easy access and low immunity. Thus, we intended to figure out the effects and potential mechanism of hASCs on obesity in high-fat-diet (HFD)-induced obese mice. Following 16 weeks of being fed HFD, hASCs were intravenously injected. Two weeks later, body weight, body composition, and energy expenditure were evaluated. Additionally, the phenotypes of macrophages infiltrating adipose tissue were analyzed. The results revealed that hASCs administration significantly reduced adipose tissue weight, adipocyte size, and fat mass and exerted beneficial effects in serum lipid profile. This anti-obesity effect was mediated by the increased O2 consumption, CO2 production, and energy expenditure, which was further evidenced by the upregulation of uncoupling protein-1 (UCP-1) and metabolism-associated genes. Furthermore, hASCs infusion increased the amount of alternatively activated (M2) macrophages in adipose tissue, and the expression of pro-inflammatory cytokines-related genes was reduced. Taken together, these results indicated that hASCs suppressed obesity by increasing UCP-1 expression and enhancing energy expenditure, and this effect might be due to the increased M2 macrophages.

Decitabine assists umbilical cord-derived mesenchymal stem cells in improving glucose homeostasis by modulating macrophage polarization in type 2 diabetic mice.

BACKGROUND: Mesenchymal stem cells (MSCs) have emerged as a promising therapy for type 2 diabetes (T2D). Mechanistic researches demonstrate that the anti-diabetic effect of MSCs is partially mediated by eliciting macrophages into an anti-inflammatory phenotype thus alleviating insulin resistance. However, single MSC infusion is insufficient to ameliorate sustained hyperglycemia or normalize blood glucose levels. In this study, we used decitabine (DAC), which is involved in the regulation of macrophage polarization, to test whether MSCs combined with decitabine can prolong and enhance the anti-diabetic effect in T2D mice. METHODS: High-fat diet (HFD) and streptozocin (STZ) were given to induce T2D mouse model. Successfully induced T2D mice were randomly divided into four groups: T2D group, MSC group, DAC group, and MSC + DAC group. Blood glucose was monitored, and glucose tolerance and insulin sensitivity were evaluated during the entire analysis period. Epididymal fat was extracted for analysis of macrophage phenotype and inflammation in adipose tissue. In vitro, we examined the effect of MSC + DAC on macrophage polarization in bone marrow-derived macrophages (BMDMs) and explore the possible mechanism. RESULTS: MSC infusion effectively improved insulin sensitivity and glucose homeostasis in T2D mice within 1 week, whereas combination therapy of MSCs + DAC extended the anti-diabetic effects of MSCs from 1 to 4 weeks (the end of the observation). Correspondingly, more M2 macrophages in adipose tissue were observed in the combination therapy group over the entire study period. In vitro, compared with the MSC group, MSCs combined with decitabine more effectively polarized M1 macrophages to M2 macrophages. Further analysis showed that the effect of MSC + DAC on macrophage polarization was largely abrogated by the peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662. CONCLUSIONS: Our data suggest that MSCs combined with decitabine can more effectively alleviate insulin resistance and prolong and enhance the anti-diabetic effect of MSCs in T2D mice in part by prompting M2 polarization in a PPARγ-dependent manner. Thus, decitabine may be an applicable addition to MSCs for diabetes therapy. UC-MSCs combined with decitabine activate the IL4R/STAT6/STAT3/PPARγ axis to further promote M2 macrophage polarization in adipose tissue, reduce inflammation, improve insulin sensitivity, and lead to better glucose metabolism and long-term hypoglycemic effects.

Human umbilical cord-derived mesenchymal stem cells direct macrophage polarization to alleviate pancreatic islets dysfunction in type 2 diabetic mice.

Progressive pancreatic ß-cell dysfunction is recognized as a fundamental pathology of type 2 diabetes (T2D). Recently, mesenchymal stem cells (MSCs) have been identified in protection of islets function in T2D individuals. However, the underlying mechanisms remain elusive. It is widely accepted that ß-cell dysfunction is closely related to improper accumulation of macrophages in the islets, and a series of reports suggest that MSCs possess great immunomodulatory properties by which they could elicit macrophages into an anti-inflammatory M2 state. In this study, we induced a T2D mouse model with a combination of high-fat diet (HFD) and low-dose streptozotocin (STZ), and then performed human umbilical cord-derived MSCs (hUC-MSCs) infusion to investigate whether the effect of MSCs on islets protection was related to regulation on macrophages in pancreatic islets. hUC-MSCs infusion exerted anti-diabetic effects and significantly promoted islets recovery in T2D mice. Interestingly, pancreatic inflammation was remarkably suppressed, and local M1 macrophages were directed toward an anti-inflammatory M2-like state after hUC-MSC infusion. In vitro study also proved that hUC-MSCs inhibited the activation of the M1 phenotype and induced the generation of the M2 phenotype in isolated mouse bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs) and in THP-1 cells. Further analysis showed that M1-stimulated hUC-MSCs increased the secretion of interleukin (IL)-6, blocking which by small interfering RNA (siRNA) largely abrogated the hUC-MSCs effects on macrophages both in vitro and in vivo, resulting in dampened restoration of ß-cell function and glucose homeostasis in T2D mice. In addition, MCP-1 was found to work in accordance with IL-6 in directing macrophage polarization from M1 to M2 state. These data may provide new clues for searching for the target of ß-cell protection. Furthermore, hUC-MSCs may be a superior alternative in treating T2D for their macrophage polarization effects.

The homing of human umbilical cord-derived mesenchymal stem cells and the subsequent modulation of macrophage polarization in type 2 diabetic mice.

Umbilical cord-derived mesenchymal stem cells (UC-MSCs), with both immunomodulatory and pro-regenerative properties, are promising for the treatment of type 2 diabetes mellitus (T2DM). As efficient cell therapy largely relies on appropriate homing to target tissues, knowing where and to what extent injected UC-MSCs have homed is critically important. However, bio-distribution data for UC-MSCs in T2DM subjects are extremely limited. Beneficial effects of UC-MSCs on T2DM subjects are associated with increased M2 macrophages, but no systemic evaluation of M2 macrophages has been performed in T2DM individuals. In this study, we treated T2DM mice with CM-Dil-labelled UC-MSCs. UC-MSC infusion not only exerted anti-diabetic effects but also alleviated dyslipidemia and improved liver function in T2DM mice. To compare UC-MSC migration between T2DM and normal subjects, a collection of normal mice also received UC-MSC transplantation. UC-MSCs homed to the lung, liver and spleen in both normal and T2DM recipients. Specifically, the spleen harbored the largest number of UC-MSCs. Unlike normal mice, a certain number of UC-MSCs also homed to pancreatic islets in T2DM mice, which suggested that UC-MSC homing may be closely related to tissue damage. Moreover, the number of M2 macrophages in the islets, liver, fat and muscle significantly increased after UC-MSC infusion, which implied a strong link between the increased M2 macrophages and the improved condition in T2DM mice. Additionally, an M2 macrophage increase was also observed in the spleen, suggesting that UC-MSCs might exert systemic effects in T2DM individuals by modulating macrophages in immune organs.

M2 macrophages infusion ameliorates obesity and insulin resistance by remodeling inflammatory/macrophages' homeostasis in obese mice.

OBJECTIVE: The role of M2 macrophages infusion in dealing with obesity is still little known. In this study, the therapeutic effects of M2 macrophages infusion were investigated. METHODS: High fat diet (HFD) was used to induce obesity in C57BL/6N mice. 5 × 105 M2 macrophages, derived from the bone marrow, were injected into obese mice through the tail vein twice with an interval of one week. RESULTS: One week after the second injection, weight of inguinal adipose pad was significantly decreased. Accordingly, the adipocyte size of epididymal and inguinal adipose tissue (EAT and INAT) shrank. To our interest, we found that the infused M2 macrophages were homed to EAT, reversing the disturbed homeostasis of high M1 to low M2 in obese mice. Meanwhile, EAT with remodeled macrophages' homeostasis expressed less MCP-1, accompanying with decreased recruitment of inflammatory CCR2+CX3CR1lowLy6C+ monocytes from the blood in M2 infusion group. Further, increased M2 in EAT contribute to enhanced expression of UCP1 expression in EAT, which helped to ameliorate insulin resistance and, subsequently, improve the serum level of triglycerides (TG) and low density lipoprotein cholesterol (LDL-c). CONCLUSIONS: These findings highlighted that M2 macrophages infusion could ameliorate obesity as well as obesity-related insulin resistance, suggesting an effective and healthy weight loss strategy.

Mild hyperglycemia triggered islet function recovery in streptozotocin-induced insulin-deficient diabetic rats.

AIMS/INTRODUCTION: Moderate elevation of glucose level has been shown to effectively promote ß-cell replication in various models in vitro and in normal rodents. Here, we aimed to test the effect of moderately elevated glucose on ß-cell mass expansion and islet function recovery in diabetic animal models. MATERIALS AND METHODS: A single high dose of streptozotocin was given to induce insulin-deficient diabetes in adult male Sprague-Dawley rats. Then, 48 h after streptozotocin injection, newly diabetic rats were randomly divided into three groups: (i) no treatment to maintain hyperglycemia; (ii) daily exogenous long-acting human insulin analog injection that maintained mild hyperglycemia (15 mmol/L < blood glucose < 18 mmol/L); (iii) daily exogenous long-acting human insulin analog injection to restore normoglycemia (blood glucose <8 mmol/L) as a control. Islet function, ß-cell regeneration and ß-cell replication were monitored during the entire analysis period. RESULTS: A single high dose of streptozotocin induced massive loss of ß-cells, resulting in irreversible hyperglycemia. Mild hyperglycemia markedly promoted ß-cell proliferation, leading to robust ß-cell regeneration. Importantly, rats that maintained mild hyperglycemia showed nearly normal glucose-stimulated insulin secretion, glucose disposal and random blood glucose levels, suggesting almost full restoration of the islet function. Normalization of blood glucose levels profoundly blunted ß-cell replication, regeneration and islet function recovery observed in mild hyperglycemia. CONCLUSIONS: Our research provides a feasible approach to stimulate in situ ß-cell regeneration in diabetic rats, offering new perspectives for diabetes therapy.

The compliance of thromboprophylaxis affects the risk of venous thromboembolism in patients undergoing hip fracture surgery.

OBJECTIVE: Venous thromboembolism (VTE) is major problem after hip fracture surgery with substantial morbidity and mortality. This study aimed to assess the postoperative compliance of thromboprophylaxis in elderly patients undergoing hip fracture surgery and to confirm the correlation between compliance and VTE risk. METHODS: This retrospective cohort study included consecutive elderly hip fracture patients who undergoing surgery. According to the thromboprophylaxis regimens, patients were divided into non-compliant group (<14days), poor compliant group (14-27days) and good compliant group (≥28days). The primary outcome was the incidence of symptomatic DVT, PE within 6weeks postoperatively. RESULTS: Between 2008 and 2012, 1214 eligible patients were included in this study. 761 (64.7%) patients were non-compliant, 224 (19.0%) patients were poor compliant, and 192 (16.3%) patients were good compliant. The overall VTE rate was 7.9% (73/1177), PE rate was 0.3% (4/1177). The VTE rate in good compliant group was lowest among three groups (4.2 vs. 5.4 vs. 9.6%, P=0.013), but the PE rates showed no significant differences (0 vs. 0.9 vs. 0.3%, P=0.241). The multivariate analysis showed that non-compliance was an independent risk factor of suffering VTE undergoing hip fracture surgery. CONCLUSIONS: In this study we found fewer than 1 in 5 patients maintained compliant with thromboprophylaxis guidelines after discharge following hip surgery. This is particularly concerning because those who were non-compliant had a higher risk of VTE postoperatively compared with those who were good compliant.

Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats.

Insulin resistance, a major characteristic of type 2 diabetes (T2D), is closely associated with adipose tissue macrophages (ATMs) that induce chronic low-grade inflammation. Recently, mesenchymal stem cells (MSCs) have been identified in alleviation of insulin resistance. However, the underlying mechanism still remains elusive. Thus, we aimed to investigate whether the effect of MSCs on insulin resistance was related to macrophages phenotypes in adipose tissues of T2D rats. In this study, human umbilical cord-derived MSCs (UC-MSCs) infusion produced significantly anti-diabetic effects and promoted insulin sensitivity in T2D rats that were induced by a high-fat diet combined with streptozotocin and directed ATMs into an alternatively activated phenotype (M2, anti-inflammatory). In vitro, MSC-induced M2 macrophages alleviated insulin resistance caused by classically activated macrophages (M1, pro-inflammatory). Further analysis showed that M1 stimulated UC-MSCs to increase expression of interleukin (IL)-6, a molecule which upregulated IL4R expression, promoted phosphorylation of STAT6 in macrophages, and eventually polarized macrophages into M2 phenotype. Moreover, the UC-MSCs effect on macrophages was largely abrogated by small interfering RNA (siRNA) knockdown of IL-6. Together, our results indicate that UC-MSCs can alleviate insulin resistance in part via production of IL-6 that elicits M2 polarization. Additionally, human obesity and insulin resistance were associated with increased pro-inflammatory ATMs infiltration. Thus, MSCs may be a new treatment for obesity-related insulin resistance and T2D concerning macrophage polarized effects.

The association between serum uric acid levels, metabolic syndrome and cardiovascular disease in middle aged and elderly Chinese: results from the DYSlipidemia International Study.

BACKGROUND: To explore the association between serum uric acid (SUA) levels, metabolic syndrome (MetS) and cardiovascular disease (CVD) in patients treated with lipid-lowering agents from multiple centers in China. METHOD: We investigated 15,478 participants who had been documented with recorded SUA in the DYSlipidemia International Study which included 25,697 patients, aged 45 years old or older, who were treated with lipid-lowering agents from 122 centers between April 2012 and October 2012. Logistic regression analysis was performed to examine the association between SUA levels, MetS and CVD. RESULT: After adjusting for multi-variables, hyperuricemia (the highest category of SUA level) showed a significantly higher risk of MetS compared to the lowest category[according to NCEP-ATPIII criteria, odds ratio (OR) 1.51, 95 % confidence interval (CI) (1.30,1.74) in men, OR 2.35 95 % CI (2.00,2.75) in women; and according to IDF criteria, OR 1.40 95 % CI (1.20,1.63) in men, OR 1.65 95 % CI (1.41,1.94) in women]. In addition, elevated SUA concentration was shown to be associated with coronary heart disease (CHD) (OR 1.26 95 % CI (1.09, 1.45) in men, and OR 1.27, 95 % CI (1.07, 1.50) in women) and heart failure (HF) (OR 1.61 95 % CI (1.15, 2.24) in men, and OR 1.91, 95 % CI (1.29, 2.82) in women). CONCLUSION: Our research suggested a positive association between SUA levels and MetS in Chinese patients receiving lipid-lowering therapy. Elevated SU levels were positively associated independently of measured confounders to CHD and HF.

Efficacy and safety of rivaroxaban versus low-molecular-weight heparin therapy in patients with lower limb fractures.

Thromboprophylaxis with rivaroxaban has proved effective and safe in patients undergoing hip and knee replacement surgery. As it is unclear whether it is also effective and safe in fracture patients, the aim of the present study was to evaluate the efficacy and safety of rivaroxaban in patients with lower limb fractures. We performed a retrospective cohort study of 2,050 consecutive patients treated for lower limb fractures at our trauma center, comparing rates of venous thromboembolism (VTE), bleeding and surgical complications, and the length of hospital stay for 608 patients who received rivaroxaban and 717 who received a low-molecular-weight heparin (LMWH). Rates of symptomatic VTE were 4.9 and 8.6% in the rivaroxaban and LMWH groups, respectively (p = 0.008), and distal VTE rates were 1.8 and 5.7%, respectively (p = 0.036). The incidence of major bleeding events in the rivaroxaban group was also lower than in the LMWH group (0.2 vs 0.6%), but the difference between the groups was not statistically significant. The mean length of hospital stay was significantly shorter in the rivaroxaban group (12.2 vs 13.1 days, respectively; p = 0.016). This retrospective cohort study is the first report documenting the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE by 45% without increasing the risk of bleeding. However, prospective, randomized controlled trials comparing rivaroxaban and LMWH are needed to confirm our findings.