A dense mapping study of six European AITD susceptibility regions in a large Chinese Han Cohort of Graves' disease.

OBJECTIVE: We aimed to investigate the six susceptibility loci of GD identified from European population in Chinese Han population and further to estimate the genetic heterogeneity of them in stratification of our GD patients. DESIGN: Dense mapping studies based on GWAS. PATIENTS: A total of 1536 GD patients and 1516 controls in GWAS stage and 1994 GD patients and 2085 controls and 5033 GD patients and 5389 controls in two replication stages. MEASUREMENTS: Based on our previous GWAS data, independently GD-associated SNPs in each region were identified by TagSNP analysis and logistic regression analysis. The association of these SNPs was investigated in 1994 GD patients and 2085 controls, and then, the significantly associated SNPs (P < 0.05) were further genotyped in a second cohort including 5033 GD patients and 5389 controls. RESULTS: After the first replication stage, four SNPs from three regions with Pfirst  < 0.05 were further selected and genotyped in another independent cohort. The association of two SNPs with GD was confirmed in combined Chinese cohorts: rs12575636 at 11q21 (Pcombined  = 7.55 × 10-11 , OR = 1.27) and rs1881145 in TRIB2 at 2p25.1 (Pcombined  = 5.59 × 10-8 , OR = 1.14). Further study disclosed no significant difference for these SNPs between GD subsets. However, eQTL data revealed that SESN3 could be a potential susceptibility gene of GD in 11q21 region. CONCLUSIONS: Out of the six susceptibility loci of GD identified from European population, two risk loci were confirmed in a large Chinese Han population. There is variability in GD genetic susceptibility in different ethnic groups. SESN3 is a potential susceptible gene of GD in 11q21.

Altered polarization, morphology, and impaired innate immunity germane to resident peritoneal macrophages in mice with long-term type 2 diabetes.

Type 2 diabetes (T2D) is associated with perturbed innate immunity. Macrophages, bridging innate immunity and metabolic disturbances, play important roles in controlling immune homeostasis. However, the effect of long-term diabetic milieu (DM) on the functions and phenotypes of macrophages is still not clear. In this study, we used resident peritoneal macrophages (RPMs) from 5-month-old db/db mice to investigate the changes of macrophages. It was found that RPMs in db/db mice significantly reduced phagocytosis and adhesion capacity. After standardization with body weight, the number of F4/80(+) RPMs markedly reduced in db/db mice, and, furthermore, the macrophages skewed to M2-polarizated macrophages. The results of morphology found that the RPMs shape of db/db mice was nearly round, but the RPMs shape of control mice was spindle-shaped and irregular. In this study, we found the cell numbers, morphology, and innate immunity functions of RPMs in 5-month-old type 2 diabetic mice (db/db mice) obtained by abdominal cavity lavage were significantly altered. Importantly, we also found the remarkably increased M2-RPMs in diabetic mice for the first time.

Endoscopic nasobiliary drainage and percutaneous transhepatic biliary drainage for the treatment of acute obstructive suppurative cholangitis: a retrospective study of 37 cases.

BACKGROUND/AIMS: This study compared the effectiveness and safety of endoscopic nasobiliary drainage(ENBD) to percutaneous transhepatic biliary drainage(PTBD) for the treatment of acute obstructive suppurative cholangitis (AOSC). METHODOLOGY: AOSC patients were assigned to undergo either ENBD (n=22) or PTBD(n=15). RESULTS: In the ENBD group, the procedure was successfully completed in 19 patients (86.4%), where- as it was converted to PTBD in 3 patients (13.6%) due to the failure of antegrade cholangiography. All the patients in the PTBD group underwent first- or second-look PTBD successfully. CONCLUSIONS: ENBD is effective for the treatment of AOSC, facilitating subsequent endoscopic or surgical intervention. PTBD is an effective and safe alternative to ENBD in patients unsuitable for ENBD.

NIHSS-the Alberta Stroke Program Early CT Score mismatch in guiding thrombolysis in patients with acute ischemic stroke.

OBJECTIVE: This study investigates the mismatch between the National Institutes of Health Stroke Scale (NIHSS) score and the computed tomography (CT) findings measured by the Alberta Stroke Program Early CT Score (ASPECTS) for predicting the functional outcome and safety of intravenous thrombolysis (IVT) treatment in patients with acute ischemic stroke (AIS). METHODS: This prospective observational study includes patients with AIS who underwent CT imaging within 4.5 h of the onset of symptoms. Patients were divided into the NIHSS-ASPECTS mismatch (NAM)-positive and NAM-negative groups (group P and N, respectively). The clinical outcome was assessed using the Modified Rankin Scale (mRS). Safety outcomes included progression, symptomatic intracerebral hemorrhage (sICH), intracerebral hemorrhage (ICH), adverse events, clinical adverse events, and mortality. RESULTS: A total of 208 patients were enrolled in the study. In group P, IVT treatment was associated with a good functional outcome at 3 months (p = 0.005) and 1 year (p = 0.001). A higher percentage of patients with favorable mRS (0-2) (p = 0.01) and excellent mRS (0-1) (p = 0.011) functional outcomes was obtained at 1 year in group P with IVT treatment. Group N did not benefit from the same treatment (p = 0.352 and p = 0.480 at 3 months and 1 year, respectively). There were no statistically significant differences in sICH, ICH, mortality rates, or other risks between the IVT and conventional treatment groups. CONCLUSION: IVT treatment is associated with a good functional outcome in patients with NAM, without increasing the risks of sICH, ICH, mortality, or other negative outcomes. NAM promises to be an easily obtained indicator for guiding the treatment decisions of AIS.

[Effectiveness of intravenous immunoglobulin therapy in treating unexplained recurrent spontaneous abortion and its effect on the level of serum soluble human leucocyte antigen G].

OBJECTIVE: To explore the effectiveness of intravenous immunoglobulin (IVIG) in treating patients with unexplained recurrent spontaneous abortion (URSA) and the effect of IVIG on the level of soluble human leucocyte antigen G (sHLA-G). METHODS: This prospective trial conducted at PUMC Hospital between 2004 and 2008 included 60 women with URSA. The patients were allocated into IVIG group (30 cases) and control group (30 cases). IVIG was intravenously used before conception at a dose of 0.2g/kg; once pregnancy was confirmed,IVIG was continued every 4 weeks till the 20th gestational week. Traditional Chinese medicine or/and progesterone were used in control group. The outcome of pregnancy was evaluated by live birth rate and effective rate(defined as the embryo living 4 week longer than previous pregnancy). Serum samples were collected randomly before pregnancy and in the 6th-8th gestational week from IVIG group (15 samples),control group (15 samples),and healthy women (20 samples). The levels of sHLA-G,interferon γ (IFN-γ), interleukin-2 (IL-2), and interleukin-10 (IL-10) were determined by enzyme-linked immunosorbant assay (ELISA). RESULTS: The pregnancy rate was 93.3% in IVIG group. The live birth rate and effective rate were 85.7% (24/28) and 92.9% (26/28) in IVIG group,which were significantly higher than those in control group [56.7% (17/30) (P=0.021) and 63.3% (19/30) (P=0.011)]. Emesis occurred in one woman (3.3%) in IVIG group had during IVIG infusion but was relieved by lowering the speed of infusion. The mean sHLA-G level was (61.37∓35.57) U/ml in control group and (62.70∓37.24) U/ml in IVIG group (P>0.05); both of them were significantly lower than that of healthy women (88.49∓25.37) U/ml (Pü0.05). After pregnancy was achieved, the levels of sHLA-G and IL-10 were (34.19∓14.21) U/ml and (11.71∓2.75) pg/ml, respectively in the IVIG group, which were significantly higher than those in control group [(23.71∓12.83) U/ml and (8.71∓3.01) pg/ml, respectively] (P=0.008). CONCLUSIONS: Low-dose IVIG before and after pregnancy is a safe and effective in treating URSA. IVIG improves the development of fetus by up-regulating sHLA-G and IL-10 levels.

Ufm1 inhibits LPS-induced endothelial cell inflammatory responses through the NF-κB signaling pathway.

Endothelial cell dysfunction and inflammatory responses are important early contributors to the occurrence and development of atherosclerosis (AS), which still remains to be decoded. Ubiquitin-fold modifier 1 (Ufm1) is a new member of the ubiquitin-like protein family, and its biological function remains largely unknown, particularly in endothelial cell injury and inflammatory responses. In the present study, we showed that Ufm1 was highly expressed in both the nucleus and cytoplasm of human umbilical vein endothelial cells (HUVECs). We also demonstrated that the Ufm1 expression level was increased following lipopolysaccharide (LPS)­induced inflammation in HUVECs. Moreover, overexpression of Ufm1 in HUVECs alleviated the inflammatory responses induced by LPS treatment. Additionally, we found that Ufm1 overexpression inhibited the nuclear translocation of nuclear factor-κB (NF-κB) after LPS treatment, suggesting its implication in the LPS/Toll-like receptor 4 (TLR4)/NF-κB pathway. Taken together, in addition to decoding its expression pattern in endothelial cells, we showed for the first time that Ufm1 is upregulated in LPS-induced inflammation and Ufm1 plays an inhibitory role in inflammatory responses by targeting NF-κB nuclear translocation. Thus, Ufm1 may be a novel gene that protects against inflammatory responses.

Overexpression of mimecan in human aortic smooth muscle cells inhibits cell proliferation and enhances apoptosis and migration.

The pathogenesis of atherosclerosis is multifactorial. The proliferation and migration of vascular smooth muscle cells (VSMCs) are significant in the genesis and development of atherosclerosis plaques, and the degradation of VSMCs plays a crucial role in the process. Mimecan is a member of the Keratan sulfate family of proteoglycans, which are leucine-rich proteoglycans. It has been demonstrated that mimecan is associated with arteriogenesis and atherosclerosis. In the present study, the effect of mimecan on the characteristics of cultured human aortic smooth muscle cells (HASMCs) was investigated. In vitro, human mimecan was stably overexpressed in HASMCs using a lentiviral system. It was observed that the proliferation rate of HASMCs transduced with mimecan was lower compared with that of control cells; overexpression of mimecan induced HASMC apoptosis. To determine the effect of mimecan on HASMC migration, a Transwell cell culture chamber and sterile cloning cylinder assays were used, and it was noted that mimecan enhanced the migration of HASMCs horizontally and vertically. These data indicated that mimecan may be involved in the pathogenesis of atherosclerosis by regulating the proliferation, apoptosis and migration of VSMCs.

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway.

AIM: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. METHODS: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE－/－ mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. RESULTS: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor α (LXRα) activation, which was confirmed by the observation that LXRα siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. CONCLUSIONS: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXRα-dependent pathway.

[Effect of combined continued hormone replacement therapy on knee osteoarthritis symptom of postmenopausal women].

OBJECTIVE: To study the effect of combined continued estrogen and progestin replacement therapy on knee osteoarthritis (OA) symptoms of postmenopausal women. METHODS: Sixty-four postmenopausal women with radiological knee OA and symptoms aged 45-75 were divided into treatment group and control group. They were given estradiol velerate (E2V) 1.0 mg/d and medroxyprogestetone acetate (MPA) 2 mg/d (treatment group) or placebo (control group) for 6 months. Calcium 400 mg/d were given to all cases. Then 0-100 mm visual analon scale (VAS) was used to evaluate the severity of knee pain at baseline and after 1, 3, 6 month of treatment. RESULTS: Significant differences on pain at night and tenderness around knee were seen in the treatment group compared with the control group after 1 months of treatment (P = 0.036 and 0.035, respectively). The improvement of pain at night, during walk and morning stiffness between the two groups showed significant difference after 6 months (P = 0.026, 0.027, and 0.011, respectively). CONCLUSION: Combined estrogen and progestin replacement therapy can relieve the knee OA symptoms of postmenopausal women.

Comparison of follicle-stimulating hormone, estradiol, ovarian volume, and antral follicle count, based on the Stages of Reproductive Aging Workshop system, among community-based women in China.

OBJECTIVE: This study aims to describe changes in follicle-stimulating hormone (FSH), estradiol (E2), ovarian volume (OV), and antral follicle count (AFC), and to examine their relationships at the same menopause stage, based on the Stages of Reproductive Aging Workshop (STRAW) system, among Chinese women in community settings. METHODS: Prospective longitudinal study design was used to analyze the sex hormone levels, OV, and AFC of 327 community women aged 30 to 65 years. They were followed up at 1 year. RESULTS: Significant differences in FSH, E2, and OV were observed at baseline and on follow-up (all P<0.001). Significant differences in E2 were observed between baseline and follow-up for women in premenopause (-2.743, P=0.006) and late postmenopause (-5.213, P<0.001). There were significant differences in FSH between baseline and follow-up in early menopausal transition (MT) (-2.430, P=0.015) and late MT (-3.737, P<0.001). There were significant differences in OV between baseline and follow-up in late MT (-3.805, P<0.001) and early postmenopause (-4.341, P<0.001). There were significant differences in AFC between baseline and follow-up in premenopause (-2.046, P=0.041). CONCLUSIONS: These results suggest the existence of significant associations between FSH, E2, OV, AFC, and menopause status, supporting the use of the STRAW system among community-based women in China. Further study of the MT is recommended to confirm the appropriateness of the STRAW system for Chinese women.

Glucocorticoids decrease body weight and food intake and inhibit appetite regulatory peptide expression in the hypothalamus of rats.

The aim of the present study was to investigate the effects of glucocorticoids (GCs) on appetite and gene expression of the hypothalamic appetite regulatory peptides, neuropeptide Y (NPY), agouti-related protein (AGRP) and cocaine and amphetamine-regulated transcript (CART), in non-obese and obese rats. Both non-obese and obese rats were randomly assigned to three groups: normal saline, low- and high-dose GC groups (NSG, LDG and HDG, respectively), which received an intraperitoneal injection with normal saline (0.2 ml/100 g) or hydrocortisone sodium succinate at 5 and 15 mg/kg, respectively, for 20 days. The expression levels of NPY, AGRP and CART mRNA in the hypothalamus were measured by real-time quantitative PCR. Non-obese and obese rats were found to undergo weight loss after GC injection, and a higher degree of weight loss was observed in the HDG rats. The average and cumulative food intakes in the obese and non-obese rats injected with high-dose GC were lower compared to that in the NSG (p<0.05). mRNA expression levels of the orexigenic neuropeptides, NPY and AGRP, and the anorexigenic neuropeptide, CART, were significantly lower in the HDG than levels in the NSG for both the obese and non-obese rats (p<0.05). GC treatment decreased appetite and body weight, induced apparent glucolipid metabolic disturbances and hyperinsulinemia, while down-regulated mRNA expression levels of the orexigenic neuropeptides, NPY and AGRP, and anorexigenic neuropeptide, CART, in the hypothalamus in the rats. The mechanism which induces this neuropeptide expression requires further study.

Serum lipid profile changes during the menopausal transition in Chinese women: a community-based cohort study.

OBJECTIVE: The aim of this study was to examine the changes in serum lipid profile related to the stages of the menopausal transition as defined by prospective menstrual pattern. METHODS: A total of 593 healthy women aged 35 to 64 years were followed annually for up to 3 years (average, 1.6 y), and 1,549 observations were provided. Blood samples were collected from all participants. Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, TC/HDL-C, estradiol, and follicle-stimulating hormone were assessed. Menopause status was defined by the menstrual change criteria of the Stages of Reproductive Aging Workshop. RESULTS: After adjusting for age, body mass index, physical activity, and antihypertensive medication use, TC, TG, and TC/HDL-C increased to peak in the late perimenopause (increased by 7.1 mg/dL in TC, 12.3 mg/dL in TG, and 0.19 in TC/HDL-C; all P < 0.05) compared with the premenopause status group. We did not find any statistically significant difference between the premenopause and postmenopause status groups in all lipid profile variables. Among postmenopausal women, only TG decreased by 8.2 mg/dL in the late postmenopause (P < 0.01). In contrast, there is no significant change in HDL-C among the different menopause status groups. CONCLUSIONS: Our data suggest that the menopausal transition instead of menopause per se is associated with serum lipid profile in community-based women in China. Late perimenopause status is significantly associated with accelerated increase in TC, TG, and TC/HDL-C. HDL-C seemed to have no relationship with menopause status.

Glucocorticoids decrease serum adiponectin level and WAT adiponectin mRNA expression in rats.

OBJECTIVE: Accumulating evidence suggests that adiponectin plays an important role in the genesis of obesity and insulin resistance. Although it has been shown that glucocortocoids (GC) inhibit adiponectin expression in vitro, there exist discrepant results in vivo. In this study, we observe the effect of GC on the serum adiponectin level and adiponectin expression in white adipose tissue (WAT) in male SD rats. METHODS: An obese rat model was made by a high-fat diet. Both non-obese and obese rats were randomly divided into normal saline (intraperitoneal injection with normal saline 0.2ml/100gday for 20 days, NS), a low dose GC group (intraperitoneal injection with hydrocortisone sodium succinate 5mg/kgday for 20 days, LDG) and a high dose GC group, respectively (intraperitoneal injection with hydrocortisone sodium succinate 15mg/kgday for 20 days, HDG). Serum adiponectin levels were detected by ELISA and the adiponectin mRNA level was assayed by Northern blot. RESULTS: The serum adiponectin level significantly decreased after 80 days of the high-fat diet (P<0.05), while it was not decreased after 80 days of the chow diet (P>0.05). The serum adioponectin levels in both the non-obese and obese rats were significantly decreased after a 20-day GC injection period (P<0.01). The adiponectin mRNA levels in epididymal fat after high dose GC injection, in both non-obese and obese rats were also decreased (P<0.001). CONCLUSIONS: A high-fat diet decreased serum adiponectin levels in the rat. GC decreased serum adiponectin levels, and this might be due to inhibited adiponectin mRNA expression in WAT. High-fat diet and GC have a synergistic effect on inhibiting adiponectin expression in rats.

[Evaluation of C-reactive protein levels in serum and gingival crevicular fluid in type 2 diabetes patients with periodontitis].

PURPOSE: To observe the relationship of the C-reactive protein (CRP) levels and the severity of the periodontal inflammation and the diabetes glycemic control. METHODS: The CRP levels in serum and in gingival crevicular fluid(GCF) in type 2 diabetes patients with chronic periodontitis, patients with periodontitis alone, patients with type 2 diabetes alone and healthy people were assayed. Glycosylated hemoglobin (HbAlc) in serum was detected. Probing depth (PD) and sulcus bleeding index (SBI) were recorded. The data were analyzed by non-paired t test and Spearman correlation analysis with SPSS 10.0 software package. RESULTS: The serum CRP levels in type 2 diabetes patients with periodontitis and periodontitis and type 2 diabetes were significantly higher than those in healthy group(P<0.01). Serum CRP levels in type 2 diabetes patients with periodontitis were the highest and were significantly higher than that in periodontitis group(P<0.01) and type 2 diabetes group(P<0.05). However, the CRP levels in GCF in each group were far lower than those in serum and no difference was detected in the four groups (P>0.05). The CRP levels in serum didn't correlate to the CRP levels in GCF (P>0.05).The CRP levels in serum correlated to PD, SBI and HbAlc(P<0.01). CONCLUSION: CRP may be involved in the interaction of chronic periodontitis and type 2 diabetes. The CRP levels in GCF could not reflect the inflammation of the periodontitis or the condition of diabetes.

A novel, complex heterozygous mutation within Gsalpha gene in patient with McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is caused by embryonic somatic mutations leading to the substitution of His or Cys for Arg at amino acid 201 of the alpha-subunit of the signal transduction protein Gs (Gsalpha). The mutations have been found in many affected tissues of patients with MAS. Recently, a new missense mutation was detected in a patient with MAS, leading to the substitution of glycine for arginine at amino acid 201 of the Gsalpha gene, whereas no mutations have been reported at other sites in this gene. In the present study, we identified the activating mutations in the gene encoding Gsalpha protein in the osseous lesions of fibrous dysplasia and peripheral blood leukocyte in a 17-yr-old male patient with MAS. In addition, a heterozygous mutation encoding substitution of Arg201 of Gsalpha with His was found. Interestingly, we also found the other two types of mutations within the Gsalpha gene in the patient's affected osseous tissue. One is a combination mutation in the same allele at codons 209 and 210 of the Gsalpha gene, and the other the missense mutation at codon 235.