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.

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.

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.

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.

[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.

Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes.

OBJECTIVE: The aim of this study was to screen for DUOX2, TPO and TG mutations in Chinese patients with congenital hypothyroidism (CH) and goitre and to define the relationships between DUOX2 genotypes and clinical phenotypes. METHODS: Blood samples were collected from 67 patients with CH and goitre in Shandong Province, China. Genomic DNA was extracted from peripheral blood leucocytes. PCR and direct sequencing were used to analyse all exons of DUOX2, TPO and TG. Detailed medical records were then collected, and the relationship between DUOX2 genotype and the clinical phenotype of CH and goitre caused by DUOX2 mutations was investigated. RESULTS: Analysis of DUOX2 revealed nine mutations, including one novel nonsense mutation (p.W734X), six novel missense mutations (p.N100D, p.S660L, p.A1131S, p.W1181G, p.A1206T and p.R1267W) and two recurrent mutations (p.R701X and p.R1110Q) in 10 patients from 10 unrelated families. Monoallelic and compound heterozygous mutations in DUOX2 were associated with permanent or transient CH. No mutation was found after screening all exons of TPO and TG. CONCLUSION: Our study identified DUOX2 mutations in 14·9% of Chinese patients investigated with CH and goitre. Because the relationships between DUOX2 genotypes and clinical phenotypes are extremely complex, however, further studies are needed to identify more mutations in known genes which are involved in CH and goitre.

Significant associations between X-ray repair cross-complementing group 3 genetic polymorphisms and thyroid cancer risk.

Polymorphisms in X-ray cross-complementing group 3 (XRCC3) are proposed to be associated with cancer susceptibility, but previous studies on the associations between XRCC3 polymorphisms and thyroid cancer are controversial. We performed a systemic review and meta-analysis to investigate the associations of XRCC3 polymorphisms with thyroid cancer risk. We used odds ratio (OR) with 95 % confidence interval (95%CI) to assess the associations. For XRCC3 C241T polymorphism, meta-analysis of total eligible studies showed that there was no association between XRCC3 C241T polymorphism and thyroid cancer risk, but subgroup analysis in Caucasians showed that there was a significant association between XRCC3 C241T polymorphism and thyroid cancer risk (T versus C: OR = 1.30, 95%CI 1.05-1.62, P = 0.01; TT versus CC: OR = 1.74, 95%CI 1.13-2.70, P = 0.01; TT versus CC/CT: OR = 1.74, 95%CI 1.16-2.60, P = 0.007). For XRCC3 A17893G polymorphism, meta-analysis of total eligible studies showed that there was an obvious association between XRCC3 A17893G polymorphism and thyroid cancer risk (GG versus AA/AG: OR = 0.57, 95%CI 0.35-0.93, P = 0.02), but subgroup analysis by ethnicity only identify the significant association in Asians. In summary, the meta-analysis suggests that there are significant associations of XRCC3 polymorphisms with thyroid cancer risk. Besides, more studies with large sample sizes are needed to further assess the associations above.

Association between TP53 Arg72Pro polymorphism and thyroid carcinoma risk.

TP53 Arg72Pro polymorphism has been proposed to have some effects on host's susceptibility to cancer. Several studies were published to assess the association between TP53 Arg72Pro polymorphism and thyroid carcinoma, but they reported controversial results. We performed a systemic review and meta-analysis to assess the association between TP53 Arg72Pro polymorphism and thyroid carcinoma. Odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the association. Fourteen individual studies with 3,483 subjects were finally included into the meta-analysis. Overall, there was an obvious association between TP53 Arg72Pro polymorphism and thyroid carcinoma under the recessive model (ProPro vs. ArgArg/ArgPro, OR = 2.02, 95% CI 1.13 to 3.62, P = 0.02). Subgroup analysis by race showed that TP53 Arg72Pro polymorphism was associated with thyroid carcinoma in Caucasians (ProPro vs. ArgArg/ArgPro, OR = 2.31, 95% CI 1.08 to 4.93, P = 0.03). Subgroup analysis by histological type showed that TP53 Arg72Pro polymorphism was not associated with a risk of different types of thyroid carcinoma. In summary, the meta-analysis suggests that TP53 Arg72Pro polymorphism is associated with thyroid carcinoma risk in Caucasians. Besides, more studies with large sample size are needed to further assess the associations above.

Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia).

BACKGROUND: This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin ± sulfonylurea. METHODS: In this 24-week, double-blind, placebo-controlled, multinational study, patients were randomized to lixisenatide 20 µg once daily or placebo. The primary endpoint was absolute change in glycated haemoglobin (HbA1c ) from baseline to week 24. RESULTS: A total of 391 patients were randomized. Lixisenatide significantly reduced HbA1c levels compared with placebo (LS mean difference: -0.36%, p = 0.0004). A significantly higher proportion of lixisenatide-treated patients achieved HbA1c targets of <7% (p = 0.003) and ≤6.5% (p = 0.001) versus placebo. Lixisenatide was associated with a statistically significant reduction in 2-h postprandial plasma glucose after a standardized breakfast versus placebo (LS mean difference: -4.28 mmol/L, p < 0.0001) and a significant reduction in fasting plasma glucose (p = 0.0109). There was no difference in weight loss versus placebo, with a modest reduction in body weight reported for both groups (lixisenatide: -1.50 kg, placebo: -1.24 kg; p = 0.296). The incidence of treatment-emergent adverse events (TEAEs) was 64.3% with lixisenatide versus 47.4% with placebo, with serious TEAEs reported in 1.5% versus 2.1% of patients, respectively. The most common TEAE in the lixisenatide group was nausea (16.3% vs 2.6% with placebo). The incidence of symptomatic hypoglycaemia was 5.6% with lixisenatide treatment and 2.6% with placebo (p = 0.1321), with no severe symptomatic hypoglycaemia events reported. CONCLUSIONS: In Asian patients with type 2 diabetes mellitus insufficiently controlled on metformin ± sulfonylurea, lixisenatide significantly improved glycaemic control and was well tolerated during the 24-week study.

Hypothermia induced by adenosine 5'-monophosphate attenuates injury in an L-arginine-induced acute pancreatitis rat model.

BACKGROUND AND AIM: This study sought to investigate the effects of hypothermia induced by adenosine 5'-monophosphate (5'-AMP) on L-arginine (L-Arg)-induced acute pancreatitis in rats. METHODS: The rats were divided into four groups: the control group, the acute pancreatitis group, the 5'-AMP pretreatment group, and the 5'-AMP posttreatment group. Rats in all groups, except for the control group, received two injections of 2.5 g/kg body weight (intraperitoneally) L-Arg, with an interval of 1 h between the injections. Subsequently, the rats were observed to assess whether hypothermia induced by 5'-AMP could effectively inhibit inflammation associated with L-Arg-induced acute pancreatitis in rats. RESULTS: Hypothermia induced by 5'-AMP produced protective effects in our acute pancreatitis model. These effects exhibited the following manifestations: (i) a significant reduction in rat mortality rates; (ii) a significant decrease in the occurrence of pancreatic edema; (iii) significant reductions in serum amylase (P < 0.001), interleukin-6 (P < 0.001), interleukin-1ß (P < 0.001) and tumor necrosis factor-α (P < 0.001); (iv) the significant inhibition of nuclear factor-κB (NF-κB) activation in rats that were pre- and posttreated with 5'-AMP compared with rats that were only injected with L-Arg; and (v) significant decreases in the occurrence of pancreatic interstitial edema, inflammatory cell infiltration, hemorrhage, and acinar cell necrosis. CONCLUSIONS: Hypothermia induced by 5'-AMP could inhibit the acute inflammatory reaction and NF-κB activation associated with acute pancreatitis.

Long term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulted from T cell-mediated destruction of pancreatic ß-cells, how to regenerate ß-cells and prevent the autoimmune destruction of remnant and neogenetic ß-cells is a tough problem. Immunomodulatory propertity of mesenchymal stem cell make it illuminated to overcome it. We assessed the long-term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord for Newly-onset T1DM. Twenty-nine patients with newly onset T1DM were randomly divided into two groups, patients in group I were treated with WJ-MSCs and patients in group II were treated with normal saline based on insulin intensive therapy. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 21 months, the occurrence of any side effects and results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I compared with group II, both the HbA1c and C peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of WJ-MSCs for the treatment of newly-onset T1DM is safe and effective. This therapy can restore the function of islet ß cells in a longer time, although precise mechanisms are unknown, the implantation of WJ-MSCs is expected to be an effective strategy for treatment of type1 diabetes.

Risk factors for gout developed from hyperuricemia in China: a five-year prospective cohort study.

The aim of the study was to investigate the factors that promote the development of gout in Chinese patients with hyperuricemia. Chinese cohort with 659 patients with hyperuricemia who had no history of gout at base line had been followed up for 5 years. The baseline data of the general states (gender, age, occupation and education level), lifestyle and behavior (smoking, drinking, and diet), the major chronic diseases (diabetes and hypertension), family history and gout attacks, physical examination (height, weight and blood pressure), and blood parameters (creatinine, urea nitrogen, triglycerides, total cholesterol and high-density lipoprotein cholesterol) were recorded before the follow-up. Over the five-year period, 75 hyperuricemia patients developed gout. In the logistic regression model, shrimp intake and shell intake were the risk factors (P = 0.038 and P < 0.001, respectively) and, combined with diabetes, also served as risk factor for gout developed from hyperuricemia, with relative risk (RR) of 2.571 (95 % confidence interval (95 % CI), 1.110-5.953), and females served as protective factors of gout, with RR of 0.113 (95 % CI, 0.041-0.312, referred to male). We identified that shrimp intake and shell intake, combined with diabetes, were the independent risk factors, and females served as protective factors of gout in those suffering from hyperuricemia in coast regions of Shandong province, China.

Hypothermia induced by adenosine 5'-monophosphate attenuates early stage injury in an acute gouty arthritis rat model.

To investigate whether the hypothermia induced by Adenosine 5'-Monophosphate (5'-AMP) could attenuate early stage injury in a rat acute gouty arthritis model. Ankle joint injection with monosodium urate monohydrate crystals (MSU crystals) in hypothermia rat model which was induced by 5'-AMP and then observe whether hypothermia induced by 5'-AMP could be effectively inhibit the inflammation on acute gouty arthritis in rats. AMP-induced hypothermia has protective effects on our acute gouty arthritis, which was demonstrated by the following criteria: (1) a significant reduction in the ankle swelling (p < 0.001); (2) a significant decrease in the occurrence of leukocyte infiltration and mild hemorrhage; (3) a significant reduction in the presence of serum Interleukin-1ß (IL-1ß, p < 0.001) and metalloproteinase-9 (MMP-9, p < 0.001); and (4) a significant inhibition in the Nuclear Factor -κappaB (NF-κB) activity (p < 0.001). AMP-induced hypothermia could inhibit acute inflammation reaction and protect the synovial tissue against acute injury in a rat acute gouty arthritis model.

Clinical and genetic analysis of a compound heterozygous mutation in the thyroglobulin gene in a Chinese twin family with congenital goiter and hypothyroidism.

Mutations in the thyroglobulin (TG) gene, which has an estimated incidence of approximately 1 in 100,000 new-borns, cause autosomal recessive congenital hypothyroidism. The mutational spectrum of the TG gene and the phenotype-genotype correlations have not yet fully been established. We report a compound heterozygous mutation in the TG gene in a Chinese twin family with congenital goiter and hypothyroidism. We also describe the gene mutation associated with the genotype-phenotype of these children with congenital goiter and hypothyroidism. The whole coding sequence of the TG gene was analyzed by direct sequence, and the identified changes in the sequence were tested for benign polymorphism by denaturing high-performance liquid chromatography screening of the mutation and sequencing 200 chromosomes from normal controls. Analysis of the TG gene of the affected twin revealed a compound heterozygous mutation, including a novel missense mutation G2687A, which is predicted to result in a glutamine to arginine substitution at codon 877, and a known nonsense mutation C7006T, predicted to result in an arginine to stop codon at codon 2317. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. This is the first report of a TG gene mutation in the Chinese Han population. Our study provides further evidence that mutations in the TG gene cause congenital goiter and hypothyroidism, demonstrates genetic heterogeneity of the mutation, and increases our understanding of phenotype-genotype correlations in congenital hypothyroidism.

Long term effects of the implantation of autologous bone marrow mononuclear cells for type 2 diabetes mellitus.

Previous studies have shown that several types of stem cells can differentiate into insulin-secreting islet beta-cells and that these cells can reduce blood glucose in some trials, but there has been no report of a long-term follow-up. We assessed the long-term effects of the use of autologous bone marrow mononuclear cells in the treatment of type 2 diabetes mellitus (T2DM). Based on the willingness to receive implantation of bone marrow mononuclear cells, One hundred and eighteen patients with T2DM were divided into two groups; the patients in group I were treated with autologous bone marrow mononuclear cells and patients in group II were treated with insulin intensification therapy. Mononuclear cells from bone marrow were injected back into the patient's pancreas via a catheter. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 33 months, the occurrence of any side effects and the results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I and both the HbA1c and C-peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of autologous bone marrow mononuclear cells for the treatment of T2DM is safe and effective. This therapy can partially restore the function of islet beta-cells and maintain blood glucose homeostasis in a longer time.

Multiple single nucleotide polymorphisms in the human urate transporter 1 (hURAT1) gene are associated with hyperuricaemia in Han Chinese.

OBJECTIVE: The present study investigated whether single nucleotide polymorphisms (SNPs) in the human urate transporter 1 (hURAT1) gene are associated with primary hyperuricaemia (HUA) in Han Chinese people. METHODS: A total of 538 subjects (215 cases and 323 control subjects) were recruited from Qingdao, China. SNPs in potentially functional regions of the gene were identified and genotypes determined by direct sequencing. Association analyses were conducted using Fisher's exact test and logistic regression assuming a genotype model. RESULTS: By sequencing the promoter, 10 exons, and the exon-intron junctions of the hURAT1 gene, 14 SNPs were identified. Two of the SNPs identified were associated with susceptibility to HUA. The first was a rare intron 3 (11 G-->A) SNP (p=0.0005), where carriers of the 'A' allele had a 3.4-fold (95% CI 1.67 to 6.93) increased risk of HUA. The second was a common exon 8 (T1309C) SNP (rs7932775), where carriers of one and two 'C' alleles had respective fold increased risks of 1.64 (95% CI 1.07 to 2.52) and 2.32 (95% CI 1.37 to 3.95). These SNPs had a joint additive effect of risk of HUA, with those individuals carrying at least one 'A' allele at the intron 3 SNP and two 'C' alleles at rs7932775 having a 5.88-fold (95% CI 1.25 to 15.57) increased risk of HUA in comparison to those with no risk alleles. CONCLUSION: In conjunction with other studies, our results suggest that there are multiple genetic variants within or near hURAT1 that are associated with susceptibility to HUA in Han Chinese, including a novel SNP located in intron 3.

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.

Insulin resistance acts as an independent risk factor exacerbating high-purine diet induced renal injury and knee joint gouty lesions.

OBJECTIVE AND DESIGN: Insulin resistant Otsuka-Long-Evans-Tokushima Fatty (OLETF) and its control Long-Evans Tokushima Ohtsuka (LETO) rats were used to generate a model for acute hyperuricemia. Upon the onset of insulin resistance OLETF rats were feed with high-purine diet, and the development of acute hyperuricemic renal injury and gouty-like lesions was monitored. Rosiglitazone was also administered to demonstrate whether improved insulin sensitivity would prevent high-purine diet induced renal injury and gouty-like lesions. RESULTS: Otsuka-Long-Evans-Tokushima Fatty rats showed significant higher incidence of hyperuricemia as compared to the control LETO rats (77 vs. 36.1%, P < 0.05), indicating that insulin resistance exacerbates the development of hyperuricemia following high-purine load. Consistent with this observation, improvement of insulin sensitivity by administration of rosiglitazone significantly reduced high-purine diet induced renal injury and gouty-like lesions. It was found that insulin resistance is associated with impaired capability for maintaining the homeostasis of renal uric acid excretion and reabsorption. Upon high-purine load, insulin resistance enhances urate reabsorption as manifested by up-regulated URAT1 expression and reduces urate excretion as characterized by down-regulated UAT expression. CONCLUSIONS: Our data demonstrated strong evidence indicating that insulin resistance acts as an independent risk factor predisposing OLETF rats more susceptible to the development of hyperuricemia and gouty arthritis following high-purine load.

[Effect of lipid-bound apoA-I cysteine mutants upon lipopolysaccharide-induced endotoxemia in mice].

OBJECTIVE: To determine the anti-inflammatory functions of different cysteine mutants of apolipoprotein A-I recombinant HDLs. METHODS: The authors reconstituted recombinant HDLs (namely rHDL74, rHDL129, rHDL195 and rHDL228) by mixing wild type or those mutants with dipalmitoyl phosphatidylcholine and examined their in vivo effects upon LPS-induced endotoxemia in mice. RESULTS: At 24 h post-injection, mice receiving rHDL74 [TNF-alpha: (24 +/- 3) pg/ml; IL-1beta: (45 +/- 5) pg/ml] had a significant decrease of plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) as compared with control mice receiving either saline or rHDLwt [TNF-alpha: (135 +/- 12) pg/ml; IL-1beta: (82 +/- 8) pg/ml, P < 0.05]. Administration of rHDL74 to mice injected with LPS also led to a protection of lung against acute injury and attenuation of endotoxin-induced clinical symptoms in mice as compared with controls injected with LPS only. CONCLUSION: Compared with rHDLwt, rHDL74 exhibits higher anti-inflammation capabilities. And it may be a potential clinical candidate for therapy for endotoxin-induced septic shock.

Association of the T1799A BRAF mutation with tumor extrathyroidal invasion, higher peripheral platelet counts, and over-expression of platelet-derived growth factor-B in papillary thyroid cancer.

The relationship among BRAF mutation, platelet counts, and platelet-derived growth factor (PDGF) with respect to clinicopathological outcomes of papillary thyroid cancer (PTC) may play a role in PTC pathogenesis but remains undefined. We examined the T1799A BRAF mutation by direct genomic DNA sequencing in 108 primary PTC samples from a Chinese cohort and analyzed its relationship with clinicopathological, hematological, and other laboratory results as well as the levels of expression of PDGF in tumors. We found that the BRAF mutation was significantly associated with extrathyroidal invasion and advanced tumor stages III and IV. Specifically, extrathyroidal invasion was seen in 30/54 (56%) PTC with BRAF mutation versus 18/54 (33%) PTC without the mutation (P=0.02). Tumor stages III and IV were seen in 16/54 (30%) PTC with BRAF mutation versus 7/54 (13%) PTC without the mutation (P=0.04). The BRAF mutation was also significantly associated with a higher platelet count, with 249.28+/-53.76 x 10(9)/l in the group of patients with BRAF mutation versus 207.79+/-58.98 x 10(9)/l in the group without the mutation (P=0.001). An association of higher platelet accounts with extrathyroidal invasion was also seen, with 242.66+/-51.85 x 10(9)/l in patients with extrathyroidal invasion versus 218.49+/-59.10 x 10(9)/l in patients without extrathyroidal invasion (P=0.03). The BRAF T1799A-positive PTC tissues harbored a significantly higher level of PDGF-B than BRAF T1799A-negative PTC tissues. The data suggest that the BRAF T1799A mutation is associated with aggressive pathological outcomes of PTC in which high platelet counts and increased PDGF production may play a role.