Human umbilical cord mesenchymal stem cells alleviate the imbalance of CD4+ T cells via protein tyrosine phosphatase non-receptor type 2/signal transducer and activator of transcription 3 signaling in ameliorating experimental autoimmune thyroiditis in rats.

This study aimed to investigate the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on experimental autoimmune thyroiditis (EAT) and the underlying mechanisms by utilizing a porcine thyroglobulin-induced EAT rat model. The rats received four tail vein injections of vehicle or hUCMSCs at an interval of 7 days and were sacrificed on day 28 after the first injection. Hematoxylin and eosin staining and enzyme-linked immunosorbent assays (ELISAs) were used to assess the therapeutic effects of hUCMSCs on EAT. Splenic lymphocytes were isolated from rats, and the proportions of CD4+ T cell subsets were analyzed by flow cytometry. Splenic CD4+ T cells from EAT rats were cocultured with hUCMSCs. A loss-of-function assay for protein tyrosine phosphatase non-receptor type 2 (PTPN2) was performed to explore the involvement of PTPN2/signal transducer and activator of transcription 3 (STAT3) signaling on the therapeutic benefit of hUCMSCs in EAT. hUCMSC treatment significantly alleviated inflammation, reduced serum thyroid antibody levels, and decreased the ratios of IL-17α+/CD25+FOXP3+ cells and serum IFN-γ/IL-4 in EAT rats. Furthermore, hUCMSC treatment upregulated PTPN2 protein expression in splenic lymphocytes of EAT rats as well as enhanced the PTPN2 protein level and attenuated phosphorylation of STAT3 in CD4+ T cells in vitro. Importantly, knockdown of Ptpn2 significantly reversed hUCMSC-mediated suppression of cell proliferation and hUCMSC-induced alterations in the expression of inflammatory cytokines in CD4+ T cells. Thus, hUCMSC treatment alleviates thyroid inflammation and the CD4+ T cell imbalance in EAT via PTPN2/STAT3 signaling, serving as a promising therapeutic approach for autoimmune thyroiditis.

The effects of adipose-derived mesenchymal stem cells combined with sodium selenite on Hashimoto's thyroiditis.

Recent research found that sodium selenite (Na2SeO3) could ameliorate oxidative damage in patients with Hashimoto's thyroiditis (HT). Additionally, the effects of adipose-derived mesenchymal stem cells (AMSCs) in an animal model of HT were also reported. However, the effects of AMSCs combined with Na2SeO3 on HT are unknown. We investigated the combined effects of AMSCs and Na2SeO3 in a rat model of HT and the in vitro effect of Na2SeO3 on AMSCs using gene microarray analyses. In the HT rat model, the combination of AMSCs and Na2SeO3 restored thyroid tissue structure to that of normal controls and increased the levels of most antioxidant and inflammatory cytokines examined, but decreased the levels of interleukin 10 (IL-10) in HT thyroid tissues. At 0.5-20 µM, Na2SeO3 promoted AMSC growth and increased the levels of reduced glutathione and total antioxidant capacity in AMSCs (P<0.05). Na2SeO3 increased the levels of hepatocyte growth factor (HGF), transforming growth factor beta (TGF-ß), and stem cell factor (SCF) in AMSC culture supernatants. The results of the gene microarray analyses showed that the expression levels of certain genes involved in mitosis, DNA replication and repair, ubiquitination, synthesis and metabolism, and mitochondrial transport changed in response to Na2SeO3 treatment. In conclusion, the combination of AMSCs and Na2SeO3 restored the function and structure of the thyroid in an HT model, and Na2SeO3 promoted the growth, improved the secretion, and the antioxidant capacity of AMSCs in vitro. This combination treatment may provide a new therapy for patients with HT.

Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis.

Thyroid dysgenesis (TD) accounts for most cases of congenital hypothyroidism. Although mutations in thyroid hormone receptor ß (THRB) have been identified in TD, the mutational spectrum of THRB and phenotype-genotype correlations have not been fully elucidated. In this study, we aimed to find mutations of THRB, examine the functions of these mutations, and attempt to elucidate the relationship between THRB and TD. Thus, we screened the exons of THRB in 280 patients with TD and 200 normal subjects in samples collected from China. We performed cell morphology assays, MTT assays, flow cytometric analyses, and a quantitative reverse-transcription polymerase chain reaction in human thyroid follicular epithelial cells (Nthy-ori cell line) to examine the impact of THRB mutations. In two unrelated patients, two novel missense mutations, c.76G>A (p.D26N) and c.107G>A (p.C36Y), were identified in THRB. Functional studies suggested that the C36Y mutant caused changes in morphology, inhibiting cell proliferation and promoting apoptosis in a human thyroid cell line. In addition, we found that messenger RNA expressions of thyroglobulin (TG) and the Na+ /I- symporter (NIS) were decreased in a time-dependent manner in mutant THRB compared with the wild type. To our knowledge, this is the first study to document the prevalence of THRB mutations and the genotype-phenotype spectrum of TD in a Chinese population. We characterized the function of a C36Y mutation, which reduced cell proliferation and increased cell death in thyroid epithelial cells. This study provides further evidence for genetic THRB defects and disease mechanisms in TD.

Genetic and functional analysis of two missense DUOX2 mutations in congenital hypothyroidism and goiter.

Mutations in the dual oxidase 2 gene (DUOX2) impair hydrogen peroxide (H2O2) production and cause dyshormonogenesis. In addition, these mutations have been implicated in autosomal recessive congenital hypothyroidism (CH) with goiter. In this study, we identified DUOX2 mutations that were causative for CH and explored the effects of these mutations on DUOX2 function. Blood samples were collected from 10 infants born with CH and goiter to unrelated parents. We extracted genomic DNA and sequenced all exons by polymerase chain reaction direct sequencing. The effects of DUOX2 mutations were characterized by H2O2 production assays and cycloheximide (CHX) chase experiments. Sequence analysis revealed one novel DUOX2 mutation and one known DUOX2 mutation in unrelated families: c.1060C>T (p.R354W) and c.3616 G>A (p.A1206T). Both mutations impaired H2O2 production. CHX chase experiments demonstrated the DUOX2 mutants had shorter half-lives and degraded more rapidly than wild-type DUOX2. Our study identified two novel DUOX2 mutations in Chinese patients with CH and goiter, which were responsible for the deficit in the organification process.

Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis.

BACKGROUND: The abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population. METHODS: The exons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next-generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined. RESULTS: Seven variants were detected in TSHR-p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c.-26G>A) were detected in PAX8. CONCLUSIONS: Our study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.

Identification and characterization of novel PAX8 mutations in Congenital Hypothyroidism(CH) in a Chinese population.

OBJECTIVE: Based on mutations in PAX8 is associated with thyroid dysgenesis. We aim to identify and characterize PAX8 mutations in a large cohort of congenital hypothyroidism(CH) from thyroid dysgenesis in Chinese population. METHODS: We screened 453 unrelated Chinese patients with CH from thyroid dysgenesis for PAX8 mutations by sequencing the whole coding regions of PAX8 on genomic DNA isolated from blood. Cell transfection assays using various vector constructs and induced mutagenesis as well as electrophoretic mobility shift assays were used to investigate the effects of selected mutations on the transcribing and binding activities of PAX8 at the promoters of target genes for thyroglobulin (TG) and thyroperoxidase (TPO). RESULTS: Five PAX8 mutations were found, yielding a mutation prevalence of 5/453 (1.1%). We selected two mutations in the critical paired domain of PAX8 and generated mutants D94N and G41V. We demonstrated G41V was unable to bind the specific sequence in the promoters of TG and TPO and activate them. D94N could bind to TG and TPO promoters and normally activate the TG promoter transcription but not the TPO promoter transcription. We also demonstrated a dominant negative role of the PAX8 mutants in impairing the function of the wild-type PAX8. CONCLUSION: We for the first time documented the prevalence and characterized the function of PAX8 mutations in CH in Chinese population. The study specifically demonstrated the role of novel mutations D94N and G41V in impairing the function of PAX8, providing further evidence for genetic PAX8 defects as a disease mechanism in CH.

Long term effect and safety of Wharton's jelly-derived mesenchymal stem cells on type 2 diabetes.

Cellular therapies offer novel opportunities for the treatment of type 2 diabetes mellitus (T2DM). The present study evaluated the long-term efficacy and safety of infusion of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) on T2DM. A total of 61 patients with T2DM were randomly divided into two groups on the basis of basal therapy; patients in group I were administered WJ-MSC intravenous infusion twice, with a four-week interval, and patients in group II were treated with normal saline as control. During the 36-month follow-up period, the occurrence of any adverse effects and the results of clinical and laboratory examinations were recorded and evaluated. The lack of acute or chronic adverse effects in group I was consistent with group II.. Blood glucose, glycosylated hemoglobin, C-peptide, homeostasis model assessment of pancreatic islet ß-cell function and incidence of diabetic complications in group I were significantly improved, as compared with group II during the 36-month follow-up. The results of the present study demonstrated that infusion of WJ-MSC improved the function of islet ß-cells and reduced the incidence of diabetic complications, although the precise mechanisms are yet to be elucidated. The infusion of WJ-MSC may be an effective option for the treatment of patients with type 2 diabetes.

Serum Uric Acid Levels and Diabetic Peripheral Neuropathy in Type 2 Diabetes: a Systematic Review and Meta-analysis.

Previous studies suggested a possible association between serum uric acid levels and peripheral neuropathy in patients with type 2 diabetes, but no definite evidence was available. A systematic review and meta-analysis of relevant studies were performed to comprehensively estimate the association. Pubmed, Web of Science, Embase, and China Biology Medicine (CBM) databases were searched for eligible studies. Study-specific data were combined using random-effect or fixed-effect models of meta-analysis according to between-study heterogeneity. Twelve studies were finally included into the meta-analysis, which involved a total of 1388 type 2 diabetic patients with peripheral neuropathy and 4746 patients without peripheral neuropathy. Meta-analysis showed that there were obvious increased serum uric acid levels in diabetic patients with peripheral neuropathy (weighted mean difference [WMD] = 50.03 µmol/L, 95% confidence interval [95%CI] 22.14-77.93, P = 0.0004). Hyperuricemia was also significantly associated with increased risk of peripheral neuropathy in patients with type 2 diabetes (risk ratio [RR] = 2.83, 95%CI 2.13-3.76, P < 0.00001). Meta-analysis of two studies with adjusted risk estimates showed that hyperuricemia was independently associated with increased risk of peripheral neuropathy in type 2 diabetic patients (RR = 1.95, 95%CI 1.23-3.11, P = 0.005). Type 2 diabetic patients with peripheral neuropathy have obvious increased serum uric acid levels, and hyperuricemia is associated with increased risk of peripheral neuropathy. Further prospective cohort studies are needed to validate the impact of serum uric acid levels on peripheral neuropathy risk.

Thyrotropin and Alzheimer's Disease Risk in the Elderly: a Systematic Review and Meta-Analysis.

Although several epidemiological studies assessed the relationship between thyrotropin and risk of Alzheimer's disease in the elderly, the results were inconsistent. A systematic review and meta-analysis of cohort studies was conducted to assess the impact of serum thyrotropin levels on Alzheimer's disease risk. PubMed, Embase, and Web of Science were searched through September 20, 2014 to identify cohort studies on the relationship between serum thyrotropin levels and risk of Alzheimer's disease in the elderly. Pooled relative risks (RR) and 95% confidence intervals (95% CI) were calculated to assess the risk of Alzheimer's disease according to serum thyrotropin levels. Eight prospective cohort studies were included, with a total of 9456 participants and 640 cases of Alzheimer's disease. Low thyrotropin level was significantly associated with an increased risk of Alzheimer's disease (fixed RR = 1.69, 95% CI 1.31-2.19, P < 0.001; I(2) = 38.0%). High thyrotropin level was also significantly associated with an increased risk of Alzheimer's disease (fixed RR = 1.70, 95% CI 1.18-2.45, P = 0.005; I(2) = 42.2%) when compared with normal thyrotropin level. When using random effect model, low thyrotropin level was still significantly associated with risk of Alzheimer's disease (random RR = 1.65, 95% CI 1.14-2.37, P = 0.007), but high thyrotropin level was not (random RR = 1.54, 95% CI 0.88-2.68, P = 0.129). When investigating thyrotropin levels continuously, an inverse but not significant association between serum thyrotropin levels and Alzheimer's disease risk was observed (per standard deviation increment of thyrotropin: RR = 0.89, 95% CI 0.78-1.01, P = 0.06; I(2) = 31.3%). This meta-analysis supports that low thyrotropin level is significantly associated with an increased risk of Alzheimer's disease in the elderly.

Serum Uric Acid Levels and Outcomes After Acute Ischemic Stroke.

Previous studies assessing the association between serum uric acid levels and neurological outcome after acute ischemic stroke reported conflicting results. A systematic review and meta-analysis were conducted to assess the impact of serum uric acid levels on outcome after acute ischemic stroke. Pubmed, Embase, Web of Science, and Google scholar were searched through September 26, 2014 to identify eligible published or unpublished studies on the association between serum uric acid levels and outcome after acute ischemic stroke. Hazard ratio (HR) for poor outcome or mean differences of serum uric acid levels with 95% confidence intervals (95% CIs) were pooled using meta-analysis. The primary outcome was occurrence of poor outcomes, while the secondary outcome was the mean differences of serum uric acid levels in patients with good or poor outcomes. Ten eligible studies with a total of 8131 acute ischemic stroke patients were included into the meta-analysis. Compared with low serum uric acid level, high serum uric acid level was associated better outcome after acute ischemic stroke (HR = 0.77, 95% CI 0.68-0.88, P = 0.0001). Sensitivity analysis further identified the prognostic role of serum uric acid levels on outcome after acute ischemic stroke. Patients with good outcomes had a higher serum uric acid level compared with those with poor outcome (mean difference = 30.61 µmol/L, 95% CI 20.13-41.08, P < 0.00001). There was no obvious risk of publication bias in the meta-analysis. This meta-analysis supports that serum uric acid level has a protective effect on neurological outcome after acute ischemic stroke. High uric acid level at the onset is a biomarker of better prognosis in patients with acute ischemic stroke.

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats.

The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytokines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet ß cells and concentration of vWF in islets in ASC group increased, while activity of caspase-3 in islets was reduced. Moreover, concentrations of TNF-α, IL-6 and IL-1ß in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet ß cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM.

Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis.

BACKGROUND: Results of several studies have shown a possible beneficial effect of renin-angiotensin system (RAS) inhibitors on diabetic retinopathy, but the findings were contradictory. We did a systematic review and meta-analysis to assess the effect of RAS inhibitors on diabetic retinopathy. METHODS: We identified relevant publications in PubMed, Embase, Cochrane Library Central Register of Controlled Trials, and abstracts from main annual meetings. Only randomised controlled trials comparing angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) monotherapy with other antihypertensive drugs or placebo in type 1 or type 2 diabetes were eligible for inclusion in the analysis. The primary outcomes were progression and regression of diabetic retinopathy in all patients and several subgroups. Risk ratios (RRs) with corresponding 95% CIs were pooled. We also did a network meta-analysis to assess the effect of different antihypertensive drugs on diabetic retinopathy by ranking order. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42013004548. FINDINGS: 21 randomised clinical trials with 13,823 participants were included in the meta-analysis. RAS inhibitors were associated with reduced risk of progression (absolute risk difference -3%, 95% CI -5 to -1; pooled RR 0.87, 95% CI 0.80-0.95; p=0.002) and increased possibility of regression of diabetic retinopathy (8%, 1-16; RR 1.39, 95% CI 1.19-1.61; p=0.00002). In normotensive patients, RAS inhibitors decreased risk of diabetic retinopathy progression (0.81, 0.69-0.94; p=0.007) and increased possibility of regression (1.43, 1.14-1.79; p=0.002). In hypertensive patients, RAS inhibitors were not associated with difference in risk of progression of diabetic retinopathy (0.93, 0.79-1.10; p=0.42) or possibility of diabetic retinopathy regression (2.21, 0.92-5.31; p=0.08). ACE inhibitors were associated with reduced risk of diabetic retinopathy progression (0.84, 0.75-0.94; p=0.002) and higher possibility of disease regression (1.50, 1.20-1.86; p=0.0003). ARBs were associated with a higher possibility of diabetic retinopathy regression (1.32, 1.07-1.61; p=0.008), but had no effect on disease progression (0.92, 0.80-1.06; p=0.25). Network meta-analysis showed the association of antihypertensive drugs with risk of diabetic retinopathy progression was lowest for ACE inhibitors, followed by ARBs, ß blockers, calcium channel blockers, and placebo in rank order. The association of antihypertensive drugs with possibility of diabetic retinopathy regression was highest for ACE inhibitors, followed by ARBs, placebo, and calcium channel blockers in rank order. INTERPRETATION: In patients with diabetes, RAS inhibitors reduce the risk of diabetic retinopathy, and increase the possibility of diabetic retinopathy regression. ACE inhibitors might be better than ARBs for treating diabetic retinopathy, and might exert the most beneficial effect on diabetic retinopathy of all widely used antihypertensive drug classes.

A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression.

CONTEXT: Dual-oxidase maturation factor 2 (DUOXA2) is a component of the thyroid hydrogen peroxidase (H2O2) generator, which is crucial for hormone synthesis. Genetic defects in DUOXA2 lead to an impairment of the H2O2-generating system, in turn causing congenital hypothyroidism (CH) with goiter. CASE DESCRIPTION: Our study aimed to identify DUOXA2 mutations associated with Chinese congenital goiter hypothyroidism patients and to examine the molecular mechanism underlying the genotype-phenotype relationship. All exons and flanking sequences of DUOXA2 in 75 unrelated CH with goiter patients were amplified by PCR and directly sequenced. DUOXA2 and DUOX2 protein expression levels were detected by Western blotting, and nicotinamide adenine dinucleotide phosphate oxidase activity was determined by measuring H2O2 generation in HeLa cells. A novel heterozygous missense mutation, c.C78G (p.I26M), and a homozygous nonsense mutation, c.C738G (p.Y246X), in DUOXA2 were identified in CH patients with mild transient and mild permanent goiter, respectively. In vitro experiments showed that the mutant I26M protein expression levels did not differ from those of wild-type DUOXA2 but that mutant I26M resulted in a complete deficiency of H2O2 generation. CONCLUSIONS: We identified a novel DUOXA2 mutation (I26M) causing CH with goiter, which affected H2O2 generation but did not alter the protein expression levels, further confirming the essential role of DUOXA2 in thyroid hormone synthesis.

Association between height and thyroid cancer risk: a meta-analysis of prospective cohort studies.

While several epidemiological studies have investigated the relationship between height and risk for thyroid cancer, the results were inconsistent. In the present study, a systematic review and meta-analysis of prospective cohort studies was conducted to assess the impact of height on thyroid cancer risk. Online databases were searched up to December 30, 2014, for prospective cohort studies on the association between height and thyroid cancer risk. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model of meta-analysis. In all, 11 articles were included in this meta-analysis, including 15 prospective cohort studies, containing 6,695,593 participants and 7,062 cases of thyroid cancer. By comparing the highest versus the lowest categories of height, we reported that risk of thyroid cancer was increased with height in both men (summary RR = 1.40, 95%CI 1.09-1.78, p = 0.008) and women (summary RR = 1.54, 95%CI 1.30-1.83, p < 0.001). The summary RR of thyroid cancer per 5-cm increase in height was 1.16 (95%CI 1.09-1.23, p < 0.001). The results were similar among men (per 5-cm increase RR = 1.13, 95%CI 1.03-1.23, p = 0.011) and women (per 5-cm increase RR = 1.18, 95%CI 1.10-1.27, p < 0.001). No obvious risk of publication bias was observed. Our meta-analysis provides strong evidence for a dose-response relationship between height and risk of thyroid cancer in both men and women.

Effect of intensive insulin therapy on first-phase insulin secretion in newly diagnosed type 2 diabetic patients with a family history of the disease.

Intensive insulin treatment is known to improve ß-cell function in the majority of patients with newly diagnosed type 2 diabetes mellitus (T2DM), and family history (FH) is known to be an important independent risk factor for T2DM. Thus, the aim of the present study was to investigate the difference in first-phase insulin secretion and the effect of intensive insulin therapy on the improvement of ß-cell function between T2DM patients with and without a FH of diabetes. Patients with newly diagnosed T2DM and healthy controls were divided into groups according to their FH of diabetes. Improvement in ß-cell function was evaluated with an arginine stimulation test after two weeks of continuous subcutaneous insulin infusion (CSII). Compared with the control group, the level of fasting insulin and the homeostasis model assessment of insulin resistance (HOMA2-IR) were higher in the DM group, while the homeostasis model assessment of ß-cell insulin secretion (HOMA2-%ß) and the first-phase peak ratio were lower (P<0.05). In addition, the first-phase peak ratio in the FH- control group was higher compared with that in the FH+ control group (P=0.023). Following CSII, all the patients achieved excellent blood glucose control in 6.2±3.6 days, without severe adverse effects. In the DM groups, the fasting insulin level and HOMA2-IR were lower, while the HOMA2-%ß and first-phase peak ratio were higher, when compared with the values prior to treatment, particularly in the FH- DM group. The HOMA2-%ß in the FH+ DM group was lower compared with the FH- DM group (P=0.027). Therefore, T2DM patients with and without a FH of the disease were shown to have a good response to CSII in the improvement of insulin resistance and ß-cell function; however, the improvements were less significant in patients with a FH compared with patients without a FH of diabetes.

[DUOX2 mutations in children with congenital hypothyroidism].

OBJECTIVE: To study the features of DUOX2 mutations and genotype-phenotype relationship in children with congenital hypothyroidism (CH), in order to provide evidence for gene diagnosis and gene treatment of CH. METHODS: Blood samples were collected from 10 CH children with thyromegaly. Genomic DNA was extracted from peripheral blood leukocytes. All exons of DUOX2 gene were analyzed using PCR and direct sequencing. RESULTS: G3632A mutation in the exon 28 of DUOX2 that may result in arginine to histidine substitution at codon 1211 was found in one patient. T2033C mutation in the exon 17 of DUOX2 that may result in histidine to arginine substitution at codon 678 was found in three patients. They were all heterozygous mutations. CONCLUSIONS: Heterozygous mutations in DUOX2 may affect protein function and cause CH. The relationship between DUOX2 genotypes and clinical phenotypes is unclear and needs further studies.

Effect and mechanisms of human Wharton's jelly-derived mesenchymal stem cells on type 1 diabetes in NOD model.

Type 1 diabetes is an autoimmune disease that results from an inflammatory destruction of ß-cells in islets. Mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs) own a peculiar immunomodulatory feature and might reverse the inflammatory destruction and repair the function of ß-cells. Sixty NOD mice were divided into four groups, including normal control group, WJ-MSCs prevention group (before onset), WJ-MSCs treatment group (after onset), and diabetic control group. After homologous therapy, onset time of diabetes, levels of fasting plasma glucose (FPG), fed blood glucose and C-peptide, regulation of cytokines, and islet cells were examined and evaluated. After WJ-MSCs infusion, FPG and fed blood glucose in WJ-MSCs treatment group decreased to normal level in 6-8 days and maintained for 6 weeks. Level of fasting C-peptide of these mice was higher compared to diabetic control mice (P=0.027). In WJ-MSCs prevention group, WJ-MSCs played a protective role for 8-week delayed onset of diabetes, and fasting C-peptide in this group was higher compared to the other two diabetic groups (P=0.013, 0.035). Compared with diabetic control group, frequencies of CD4+CD25+Foxp3+ Tregs in WJ-MSCs prevention group and treatment group were higher, while levels of IL-2, IFN-γ, and TNF-α were lower (P<0.001); the degree of insulitis was also depressed, especially for WJ-MSCs prevention group (P<0.05). Infusion of WJ-MSCs could aid in T1DM through regulation of the autoimmunity and recovery of islet ß-cells no matter before or after onset of T1DM. WJ-MSCs might be an effective method for T1DM.

Effect of long-term exposure to air pollution on type 2 diabetes mellitus risk: a systemic review and meta-analysis of cohort studies.

OBJECTIVE: To assess the effect of long-term exposure to air pollution on type 2 diabetes risk, a meta-analysis of prospective cohort studies was performed. METHODS: Literature search was conducted with Pubmed, Embase, and Web of Science for prospective cohort studies investigating the association of type 2 diabetes risk with increments in particulate matter (PM, diameter<2.5 µm (PM2.5) or <10 µm (PM10)) or nitrogen dioxide (NO2). We used a random-effects model to calculate the overall relative risk (RR) with 95% CI. RESULTS: Of 808 identified articles, ten cohort studies were finally included, which involved a total of 2 37,1 907 participants and 21,095 incident cases of type 2 diabetes. Elevated risk of type 2 diabetes was significantly associated with long-term exposures to high levels of PM2.5 (RR=1.28, 95% CI 1.06-1.55, P=0.009, I2=83.5%), PM10 (RR=1.15, 95% CI 1.02-1.30, P=0.022, I2=0%), and NO2 (RR=1.12, 95% CI 1.02-1.23, P=0.015, I2=63.5%). When using standardized risk estimates, the RRs of type 2 diabetes were significant for increments in concentrations of PM2.5 (1.39 per 10 µg/m3 increment, 95% CI 1.14-1.68, P=0.001), PM10 (1.34 per 10 µg/m3 increment, 95% CI 1.22-1.47, P<0.001), and NO2 (1.11 per 10 µg/m3 increment, 95% CI 1.07-1.16, P<0.001). No obvious evidence of publication bias was observed. CONCLUSION: Long-term exposure to high levels of main air pollutants is significantly associated with elevated risk of type 2 diabetes mellitus.

Main air pollutants and diabetes-associated mortality: a systematic review and meta-analysis.

OBJECTIVE: Exposure to high levels of air pollutants may be linked to diabetes-associated mortality, but the associations remain unclear. To assess the associations between main air pollutants and diabetes-associated mortality, a systematic review and meta-analysis was performed. METHODS: PubMed, Embase and Web of Science were searched for studies investigating the associations between increments in gaseous (nitrogen dioxide (NO2), sulphur dioxide, ozone (O3) and carbon monoxide) and particulate matter (PM; diameter<2.5 µm (PM2.5) or <10 µm (PM10)) air pollutants and diabetes-associated mortality. Using a random-effects model, relative risks (RRs) and 95% CIs were calculated per interquartile range (IQR) increment or per 10 µg/m3 increment in pollutant concentrations. RESULTS: Out of 925 identified articles, 36 were reviewed in depth and 12 studies from 13 articles satisfying the inclusion criteria (five time-series, five case-crossovers and two cohorts) were finally included. Increased risk of diabetes-associated mortality was associated with higher levels of PM2.5 (per 10 µg/m3: RR=1.123, 95% CI 1.036-1.217, P=0.005, I2=96.1%), PM10 (per 10 µg/m3: RR=1.008, 95% CI 1.004-1.013, P<0.001, I2=0%), NO2 (per 10 µg/m3: RR=1.024, 95% CI 1.007-1.041, P=0.006, I2=49.7%) and O3 (per IQR increment: RR=1.065, 95% CI 1.017-1.115, P=0.007, I2=0.0%). No obvious risk of publication bias was observed. CONCLUSIONS: Exposure to high levels of air pollutants is significantly associated with an increased risk of diabetes-associated mortality.

Significant association between MTHFR C677T polymorphism and thyroid cancer risk: evidence from a meta-analysis.

BACKGROUND: Many studies were published to assess the associations of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with thyroid diseases, including thyroid cancer, but the results were controversial. METHODS: A comprehensive search was performed in the Pubmed, Embase, and Chinese Biomedical Database (CBM) databases or published studies investigating the associations of MTHFR C677T polymorphism with thyroid diseases. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to assess the possible associations. RESULTS: Nine studies with a total of 2421 individuals were finally included into the meta-analysis. Meta-analysis of nine studies showed that there was no association between MTHFR C677T polymorphism and thyroid diseases (OR (T vs. C) =1.09, 95% CI 0.94-1.26, p=0.25; OR (TT vs. CC) =1.04, 95% CI 0.75-1.42, p=0.83; OR (TT vs. CC/CT) =1.13, 95% CI 0.86-1.50, p=0.37; OR (TT/CT vs. CC) =1.22, 95% CI 0.88-1.68, p=0.24). Meta-analysis of studies on thyroid cancer showed that there was an obvious association between MTHFR C677T polymorphism and increased risk of thyroid cancer in Caucasians (OR (T vs. C) =1.30, 95% CI 1.03-1.65, p=0.03; OR (TT vs. CC) =2.06, 95% CI 1.04-4.10, p=0.04; OR (TT vs. CC/CT) =2.02, 95% CI 1.02-3.92, p=0.04). There was no obvious risk of publication bias in the meta-analysis. CONCLUSION: This meta-analysis suggests that there is a significant association between MTHFR C677T polymorphism and thyroid cancer risk in Caucasians.