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Purpose In the Guidelines for the Prevention and Control of Type 2 Diabetes in China (2017 edition), intensive lifestyle interventions are recommended for preventing the progression of impaired glucose tolerance (IGT) to type 2 diabetes mellitus. Acarbose and metformin can also be considered if intensive lifestyle modification has been ineffective for 6 months. But the effects of intensive lifestyle modification and glucose-lowering drug interventions that work best in the population with IGT are unclear. This network meta-analysis assessed the effectiveness of intensive lifestyle modification, acarbose, and metformin in treating populations with IGT. Methods We systematically searched both Chinese- and English-language databases, including China Knowledge, the Cochrane Library, Embase, PubMed, VIP, and Wanfang, for articles published between database inception and September 2019. Randomized, controlled clinical trials in patients with IGT treated with acarbose, metformin, and intensive lifestyle modification were assessed for eligibility. The data from all included studies were evaluated by 2 reviewers independently in accordance with the Cochrane Handbook for Systematic Reviews of Intervention version 6.0. A network meta-analysis was performed by using R software version 3.6.1. Findings The data from 53 randomized controlled trials were included in the review, with a sample size of 21,208 patients. Compared with the control group, the use of acarbose, metformin, and/or intensive lifestyle modification was associated with reduced rates of progression to diabetes (relative risks [RRs] [95% credible intervals]: acarbose, 0.37 [0.29–0.47]; metformin, 0.39 [0.30–0.50]; intensive lifestyle modification, 0.61 [0.50–0.73]). The surface under the cumulative ranking (SUCRA) value of acarbose was 88.35%, supporting that acarbose was more effective in reducing the rate of progression to diabetes compared with controls. With acarbose, metformin, and intensive lifestyle modification, the rates of achieving a normal glucose level were increased by RR = 2.1, 1.7, and 1.2, respectively when compared with control group. The SUCRA value of acarbose was 99.69%, supporting the optimal effect of acarbose in achieving a normal blood glucose level. Implications In this meta-analysis in patients with IGT, compared with controls, acarbose and metformin were associated with decreased rates of progression to diabetes and increased rates of achieving a normal glucose level. Acarbose use was associated with an increased rate of achieving a normal glucose level, while intensive lifestyle modification was not.

DOI: 10.11855/j.issn.0577-7402.2019.12.15

Objective To investigate the correlations of plasma methoxyadrenaline (MN) and methoxynorepinephrine (NMN) (collectively called MNs) to blood lipid, blood glucose and blood pressure in patients with pheochromocytoma (PCC) and paraganglioma (PGL) (collectively called PPGL). Methods The clinical data were retrospectively analyzed of 64 patients with pathologically confirmed PPGL in Chinese PLA General Hospital during Jan. 2017 to Jun. 2018. According to the tertiles plasma MN before operation, the 64 cases were divided into T1 (n=21), T2 (n=21) and T3 (n=22) group, and then were divided into T'1 (n=21), T'2 (n=21) and T'3 (n=22) group according to the tertiles plasma NMN before operation. The correlations were analyzed of plasma level of MNs to the blood lipid, blood glucose and blood pressure. Results The body mass index (BMI) value decreased significantly with the increase of plasma MNs level in patients with PPGL. With the increase of plasma NMN level, high density lipoprotein cholesterol (HDL-C) and systolic blood pressure (SBP) increased significantly (P

Background Long noncoding RNAs (lncRNAs) can regulate the expression of genes at almost every level. The altered expression of lncRNAs was observed in many kinds of cancers. Until recently, few studies have focused on the function of lncRNAs in the context of papillary thyroid carcinoma (PTC). Methods In the current study, we collected seven PTC and nodular goiter tissue samples and explored mRNA and lncRNA expression patterns in these samples by microarray. Results We observed aberrant expression of 94 lncRNAs and 99 mRNAs in the seven PTC samples as compared to the nodular goiter tissue [fold change (FC) ≥2.0; P

The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population.The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models.A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices).An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.

Objective To evaluate the diagnostic significance of ACTH-cortisol rhythm for subclinical Cushing's syndrome (SCS) in patients with adrenal incidentaloma (AI), and explore the best diagnostic cut-off value. Methods The clinical data were collected of patients with AI admitted in Chinese PLA General Hospital from Jan. 2008 to Dec. 2016, and retrospectively analyzed based on the current CS guidelines and confirmed CS by postoperative histopathology. Patients with SCS were set as test group, and with non-functional adrenal adenoma (NFA) as control group. Receiver operating characteristic (ROC) curve was used to evaluate the diagnosis value of ACTH-cortisol rhythm for SCS in patients with AI, and search for the best cut-off value and its corresponding sensitivity and specificity. Results A total of 161 patients with NFA (84 males and 77 females with average age 51.74 years) and 88 patients with SCS (26 males and 62 females with average age 51.02 years) were recruited in present study. ROC analysis showed that the optimal cut-off value for F0:00am/F8:00am was 0.3 (AUC=0.807(95%CI 0.751-0.862, SE=0.029), sensitivity 76.1%, specificity 78.3%, Youden index 0.544, positive predictive value 77.8%, negative predictive value 75.9%); the optimal cut-off value for F0:00am was 113.35nmol/L (AUC=0.841(95%CI 0.792-0.890, SE=0.025), sensitivity 78.4%, specificity 79.5%, positive predictive value 79.3%, negative predictive value 78.6%); the optimal cut-off for ACTH8:00am was 3.0pmol/L (AUC=0.833(95%CI 0.781-0.885), SE=0.027, sensitivity 79.5%, specificity 72.7%, Youden index 0.522, accuracy 76.1%, positive predictive value 74.4%, negative predictive value 78.0%). Conclusion The serum cortisol level at med night 0:00am (F0:00am) is the best parameter in diagnosis of SCS, 113.35nmol/L is recommended as the cut-off point. DOI: 10.11855/j.issn.0577-7402.2018.07.06

Objective To analyze the clinical data [tumor size and adrenal vein sampling (AVS)] of patients with Cushing syndrome (CS) caused by bilateral adrenocortical adenoma (BAA), and explore their role in determining the predominant side before operation. Methods The clinical data were retrospectively analyzed of 11 cases of CS caused by BAA admitted in the General Hospital of Chinese PLA from Jan. 2008 to Nov. 2017. Of the 11 cases, 7 and 4 presented clinical CS and subclinical CS (SCS), respectively. Operation was performed on the determined predominant side in patients with successful AVS, while the rest of patients were operated on the larger side of the tumor. Results Six patients underwent AVS and 3 cases got success, for whom the larger side of tumor was the predominant side in 2 patients and the smaller side of tumor was the predominant side in 1 case; The clinical manifestation after operation was better than before in 1 CS case, and no obvious change was observed in postoperative clinical manifestation in 2 SCS cases. All the patients were long-term followed up, during the period their endocrine indicators were better than those before the operation. Blood pressure and blood glucose in patients with hypertension and diabetes were easier to control than before. Eight cases were operated on the larger side of tumor. The typical symptoms and physical signs of 6 CS patients improved after operation, and the clinical manifestations of 2 SCS patients hadn't changed. Five patients were long-term followed up, and their endocrine indicators were better than those before operation. Conclusions Successful AVS may be acted as an important indicator in preoperative preparation and evaluation in patients with CS caused by BAA, but it has high technical requirements and low success rate. If AVS is unconditional, a long term following-up will be needed after resecting the larger side of tumor. DOI: 10.11855/j.issn.0577-7402.2018.07.04

Objective To explore the clinical value of 24h urinary aldosterone-to-active renin ratio (UARR) in different postures for screening primary aldosteronism (PA). Methods The clinical data were retrospectively analyzed of 123 PA and 155 essential hypertension (EH) patients admitted in Chinese PLA general hospital from Jan. 2012 to Dec. 2014. The UARR and plasma aldosterone-to-active renin ratio (ARR) in different postures were calculated, and the receiver operating characteristic (ROC) curve was applied to obtain the area under ROC curve (AUC) and the optimal cut-off point of UARR in different postures for PA screening, and all the results were compared with recognized screening parameters. Results The optimal cut-off point of erect UARR was 14.20nmol/[μg/(L·h)], the AUC, sensitivity and specificity were 0.954, 91.87% and 88.64%, respectively; the AUC, sensitivity and specificity of clinostatasm UARR were 0.918, 78.05% and 87.12%, respectively; the AUC of UARR was larger in erect position than in clinostatic (Z=2.572, P=0.01). The AUC, sensitivity and specificity of erect ARR were 0.929, 85.88% and 90.91%, respectively; and of clinostatic ARR were 0.913, 84.55% and 81.82%, respectively; the AUC of erect UARR was larger than the AUC of both erect and clinostatic ARR (Z=2.094, P=0.036; Z=2.675, P=0.008). Conclusion Both erect position UARR and ARR are the effective parameters for screening PA. DOI: 10.11855/j.issn.0577-7402.2018.07.05

Objective To discuss the clinical features of preoperative undiagnosed pheochromocytoma in patients with adrenal incidentaloma (AI). Methods The clinical data were retrospectively analyzed of 103 cases of pathologically diagnosed adrenal pheochromocytoma in patients with AI admitted in the General Hospital of Chinese PLA during Mar. 2012 to Dec. 2016. The cases were divided into two groups: patients preoperatively diagnosed as non-function adrenal tumor were assigned as group A (n=16), and preoperatively diagnosed as pheochromocytoma were assigned as group B (n=87). The clinical features, endocrine hormone levels and imaging features of the two groups were analyzed. Results The age when diagnosed as hypertension was higher in group A (55.5±9.1 years) than in group B (43.6±12.3 years, P

Objective To investigate the diagnostic value of different evaluation indexes of captopril challenge test (CCT) on primary aldosteronism. Methods The biochemical parameters were collected of patients with aldosterone producing adenoma (APA, 90 cases), with idiopathic hyperaldosteronism (IHA, 44 cases) and with essential hypertension (EH, 88 cases) who were diagnosed and undergone CCT in the General Hospital of PLA from Jan. 2014 to Mar. 2016. The clinical characteristics were compared, the receiver operating characteristic curve (ROC) was conducted to evaluate the diagnostic value of different evaluation indexes including the absolute value and suppression percentage of aldosterone, the increasing percentage of plasma renin activity (PRA) and the ratio of aldosterone/renin (ARR), and then the optimal diagnostic criteria and its sensitivity and specificity were determined. Results After CCT the suppression percentage of aldosterone in APA, IHA and EH groups were 0.3%, 0.7% and 4.0%, respectively. The increasing percentage of renin in APA, IHA and EH groups was 0(0, 1), 0.25(0, 1) and 0.97(0.23, 2.27), respectively. The increasing percentage of renin in primary aldosterone group was significantly lower than that in EH group (P

Objective To study the expression of leukemia-related protein 16 (LRP16) in human pituitary prolactin adenomas (PRL adenomas), and the relationship between LRP16 and estrogen receptor α (ERα). Methods From October 2009 to September 2014, thirty-one adult patients diagnosed and pathologically confirmed as pituitary prolactin (PRL) adenomas (observation group) and 22 pituitary non-PRL adenomas (control group) in the Chinese PLA General Hospital were verified by the pathological examination. Immunohistochemical method was used to detect the expression levels of LRP16, PRL and ERα. Results Of the patients in observation group, those aged under 30 were predominantly females, while male patients were more common in those aged over 30. LRP16 positively existed in 26 cases (83.9%, 26/31), and ERα was positive in 28 cases (90.3%, 28/31), the both ratios were significantly higher than those in control group. ERα and LRP16 increased synchronously both in expressive content and intensity, showing a certain positive correlation between them. Conclusions Higher body mass index may be a high-risk factor badly affected the occurrence, development and prognosis in male patients with pituitary PRL; LRP16 may take part in the proliferation and formation of pituitary PRL adenomas through ERα. DOI: 10.11855/j.issn.0577-7402.2017.07.05

Objective To analyze the relationship between the brain functional alterations of patients with Cushing's disease (CD) and patients' mental symptom by applying the Evaluating Emotional Scales and task functional magnetic resonance imaging (Task fMRI). Methods Task fMRI was performed on 8 patients with diagnosed CD admitted in the Department of Endocrinology of Chinese PLA General Hospital from Nov. 2015 to Nov. 2016 and 21 healthy people with matched age, gender and education level as control. Meanwhile, Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), Positive and Negative Affective Scale (PANAS) and Cushing Quality of Life Scale (Cushing QOL) were obtained to assess the brain functions. Results Significant depression and anxiety were observed in patients with CD, and their positive affective score was substantially lower while the negative affective score was relatively higher compared with that in the controls. Task fMRI revealed that, when watching the positive pictures, the activation degree of left cerebellum and right postcentral gyrus weakened in CD patients than in the controls, and the positive correlations existed between the activation degree of left cerebellum and the 16 o'clock adrenocorticotrophic hormone (ACTH) level, and between the activation degree of right postcentral gyrus and the urinary free cortisol (UFC) level in CD patients. In contrast, when watching the negative pictures, the activation degree of left cerebellum, bilateral parahippocampal gyrus and left inferior frontal gyrus was weakened in CD patients than in the controls, and the activation degree of left cerebellum was negatively correlated to the 0 o'clock cortisol level and SAS score, but is positively correlated to the UFC level. When watching the neutral pictures, the activation degree of left cerebellum and left parahippocampal gyrus was weakened in CD patients than in the controls. Conclusions CD patients may have impaired brain function with depression and anxiety mental symptoms. By Task fMRI, it can be found that the weakened activation degree of left inferior frontal gyrus, right postcentral gyrus, bilateral parahippocampal gyrus and left cerebellum may be related to CD patients' mental symptoms. DOI: 10.11855/j.issn.0577-7402.2017.07.02

Objective To evaluate the clinical characteristics of patients with growth-hormone adenoma (GHA) and summarize the diagnosis and treatment experience. Methods The clinical data of 338 GHA cases at the General Hospital of PLA from Jan. 1990 to Dec. 2016 were collected, of which 252 cases with more complete clinical data were retrospectively analyzed including their general situation, medical history, laboratory tests and auxiliary examinations, and treatment modalities and outcomes. Parts of the patients were followed up. Results The cases of hospitalized GHA patients have increased year by year since 1990, and the number of patients admitted in the last 3 years accounted for 56.2% of the total number of cases. The sex ratio for GHA patients was nearly 1:1. Age of visiting followed Gaussian distribution while the 41-50 age group occupied the largest part. The most typical sign is hand and foot enlargement (60.7%), followed by the hypertrophy of nasal ala. The most common symptoms are headache (42.5%), hypopsia, visual field defect and diplopia. More than half of GHA patients were complicated with prediabetes and diabetes (72.6%), sleep apnea (69.5%), goiter or thyroid nodularity (56.4%), cardiac insufficiency (57.0%) and colon polyp (54.1%); while the percentages of cases undergone the relevant examination in the total number of cases were as follows: 75g OGTT test (42.1%), polysomnography (23.4%), thyroid ultrasound (37.3%), echocardiogram (47.6%) and colonoscopy (14.7%); GHA was 23.37±1.42μg/L and IGF-1 was 804.28±273.93ng/ml on average; 85.0% of somatotroph tumors are macroadenoma. Surgery remains the mainstay of therapy to GHA, while medical therapy was selected by less patients. During the follow-up, only 38.0% of GHA patients can be contacted, among them the remission rate decreased to 40.5%. The positive rate of long-term remission evaluated by early postoperative GHA level was consistent with that confirmed by the long-term follow-up (χ2=3.368, P>0.05). Conclusions The number of hospitalized GHA patients have increased recent years. The common clinical signs and symptoms are somatic enlargement and nonspecific headache. Due to uncompleted screening, GHA associated complications are always misdiagnosed; It is essential to establish a sound model of follow-up to improve patients' quality of life. The early postoperative GHA levels may predict the prognosis of surgery. DOI: 10.11855/j.issn.0577-7402.2017.07.04

Pituitary adenomas represent one ofthe most common type ofcentral nervous system tumors. Since many signs and symptoms of pituitary adenomas overlap with those of other common diseases, missed diagnosis is more common. A long duration of active disease in patients with secreting pituitary adenomas is associated with an increased risk of complications and reduced quality of life. Therefore, correct, early diagnosis and treatment are crucial for these patients. Treatment options for pituitary adenomas include medical therapy, microscopic or endoscopic surgical resection, and radiation therapy. The recent progresses in diagnosis and treatment for pituitary adenomas have been discussed in present paper for improving our understanding of the disease. DOI: 10.11855/j.issn.0577-7402.2017.07.01

Objective To comparatively analyze the clinical characteristics of thyrotropin-secreting pituitary adenomas (TSH-omas). Methods The clinical features, laboratory variables, imaging and pathological results were retrospectively compared and analyzed of 26 cases with TSH-omas admitted in Chinese PLA General Hospital from Feb. 2006 to Oct. 2016 and 20 cases with TSH-omas admitted in Shanghai Huashan Hospital from Apr. 2006 to Apr. 2013. Results The female ratio was slightly higher in patients of Chinese PLA General Hospital than in Huashan Hospital [(57.7%(15/26) vs. 45.0%(9/20)], while the mean age was similar [39.5±14.1(18-67 years) vs. 40.0±14.5(17-74 years)]. The most common chief complaint was thyrotoxicosis [73.1%(19/26) vs. 55.0%(11/20)], and mild-to-moderate goiter was the most common symptom. The mean serum TSH levels in Chinese PLA General Hospital and in Huashan Hospital were 5.06(2.97-6.27)mU/L and 6.16(3.76-10.91)mU/L respectively, and patients with normal serum TSH levels were more common in Chinese PLA General Hospital than in Huashan Hospital [57.7%(15/26) vs. 40.0%(8/20)]. Microadenoma was more common in Chinese PLA General Hospital than in Huashan Hospital [34.62%(9/26) vs. 20.0%(4/20)], while macroadenoma was more common in Huashan Hospital than in Chinese PLA General Hospital [20.0%(4/20) vs. 7.7%(2/26)]. Microadenoma was more common in female patients of the both groups [66.7%(6/9) vs. 75.0%(3/4)], while macroadenoma was all found in male patients. Tumor invasion of surrounding tissue and structure was often found in macroadenoma. In terms of octreotide inhibition test, the range of 24h TSH inhibition rate was roughly the same in the two groups (37.4%-91.8% and 46.5%-94.1%, respectively). Mixed adenoma was rare among all the pathologically confirmed cases. In Chinese PLA General Hospitals, TSH immunoreactive negative neoplastic cells were found in 3 of 8 cases, and octreotide scanning showed negative in 2 of 12 cases. Conclusions Patients with TSH-omas in the two hospitals show similarities but also some significant differences in the clinical features. Overall, the domestic patients with TSH-omas are diagnosed without gender difference according to the reports in China. The mean age at diagnosis is significantly younger than that in foreign data. Microadenoma is more common in females, while macroadenoma is more common in males. Serum TSH levels can be normal in patients with TSH-omas. Immunostaining and/or octreotide scanning for TSH can be negative. DOI: 10.11855/j.issn.0577-7402.2017.07.03

Objective To explore the potential influence of gender on screening value of aldosterone-renin ratio (ARR) for primary aldosteronism (PA). Methods The biochemical parameters were collected of 451 PA patients and 300 essential hypertension (EH) patients who were diagnosed in the General Hospital of PLA from 1992 to 2014. Each group was then divided into two groups by gender. The clinical characteristics were compared and then the receiver operating characteristic curve (ROC) was conducted to evaluate the best cut-off value. Results The plasma aldosterone concentration (PAC), serum sodium and ARR were much higher, but the plasma rennin activity (PRA), serum potassium and BMI were much lower in PA patients than in EH patients (P0.05). The best cut-off value of ARR in male PA patients was 19.11, the relevant area under the curve (AUC) was 0.968, the sensitivity and specificity was 92.44% and 93.08%, and the Youden index (YI) was 0.86. The best cut-off value of ARR in female PA patients was 27.26, with AUC 0.956, sensitivity 92.07%, specificity 90.00% and YI 0.82, respectively. If the cut-off value was set at 27.26 in males, the specificity would rise a little, but the sensitivity and YI would sharply decrease. Similarly, the sensitivity would increase a little but the specificity and YI would fall substantially if the cut-off value in females was set at 19.11. The best cut-off value of ARR in men was smaller than the official value recommended by guidelines. Conclusion Gender is an important factor should be considered while ARR is used in PA screening, and the cut-off value of ARR in screening female PA patients should be setting higher. DOI: 10.11855/j.issn.0577-7402.2017.01.10

Objective To analyze the pathology of the patients with nonfunctional adrenal tumor (NFA), and explore the optimal diameter cut-off value. Methods The clinical data of 243 patients with NFA, evaluated in the Department of Endocrinology and operated in the Department of Urology of General Hospital of Chinese PLA from Feb. 1996 to Jan. 2016, were collected. The patients were divided into two groups according to pathology: those in real demand of surgery were classified to the surgery-need group (n=57), while the others were categorized as the surgery-unwanted group (n=186). The general situation, pathological type and tumor diameter of the two groups and the factors affecting the surgery were analyzed, and the ROC curve was used to explore the optimal surgery cut-off value, which represents the maximum value of the sum of sensitivity and specificity. Results Of the 57 patients in surgery-need group (27 males and 30 females), the lesions were on the right in 31 cases, on the left in 25 cases, and on bilateral sides in 1 case; the median of lesion diameter was 4.5cm, and the average age was 41.5±12.1 years old. Of the 186 patients in surgery-unwanted group (87 males and 99 females), the lesions were on the right in 99 cases, on the left in 86 cases, and on bilateral sides in 1 case; the median of lesion diameter was 3.0cm, and the average age was 50.6±10.9 years old. Logistic regression revealed that lesion diameter might be a risk factor (OR=1.340, 95%CI 1.266-1.418, P=0.000) and age be a protective factor (OR=0.942, 95%CI 0.929-0.955, P=0.000) for real demand of surgery. The area under the ROC curve (AUC) of lesion diameter was 0.757(95%CI 0.681-0.833). The optimal cut-off value was 4.1cm (sensitivity 60.7% and specificity 83.0%). Conclusions Younger patients with bigger lesion diameter may have greater possibility for surgery. The optimal surgery cut-off value of the lesion diameter is 4.1cm. DOI: 10.11855/j.issn.0577-7402.2016.11.11

Objective To investigate the effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on macrophage polarization under hypoxia. Methods hUC-MSCs were obtained by explants adherent culture and cultured under normoxia (21% O2) and hypoxia (5% O2). The multi-directional differentiation of hUC-MSCs was observed by osteogenic and adipogenic differentiation induction. Live/death staining was performed to detect the cell viability, and ELISA was executed to detect the protein content in supernatant of hUC-MSCs. Transwell chamber was employed to co-culture the hUC-MSCs cultured under normoxia and hypoxia and macrophage (THP-1) stimulated by lipopolysaccharide (IPS), then the polarization of THP-1 was detected by immunofluorescence, and the secretions of inflammatory factor and anti-inflammatory factor of THP-1 were detected by ELISA. Results hUC-MSCs cultured under hypoxia showed the ability of osteogenic and adipogenic multi-directional differentiation. Live/death staining showed the high cell viability of hUC-MSCs cultured under normoxia and hypoxia. The expression levels of prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase (IDO) were significantly higher in the hUC-MSCs cultured under hypoxia than in those cultured under normoxia. hUCMSCs cultured under hypoxia promoted the polarization of THP-1 to M2, obviously reduced the expression of TNF-α and IL-1β, and increased the expression of IL-10 significantly. Conclusion hUC-MSCs cultured under hypoxia may promote the polarization of THP-1 to M2 and improve the viability of anti-inflammatory. DOI: 10.11855/j.issn.0577-7402.2016.07.01

Objective To study the therapeutic effect of exosome derived from lipopolysaccharides (LPS) priming mesenchymal stem cells (MSCs) for diabetic wound healing. Methods Human umbilical cord MSCs were treated with LPS (100ng/ml) for 2 days, the supernatant were then collected, and exosomes were harvested by density gradient centrifugation and identified. Diabetic cutaneous wounds were prepared and the animals were divided into the following three groups: control group, untreated MSCs derived exosome (un-exosome) treatment group and LPS primed MSCs derived exosome (LPS-exosome) treatment group. Exosomes (60μg) were injected dispersively into the wound edge daily for 10 days. After treatment, the therapeutic results were evaluated by gross observation of the wounds, the expression levels of inflammation related factors and macrophage subtype markers in the injured sites were detected by qRT-PCR at day 3, 7 and 14 after treatment. Results Compared with control group, the diabetic wound healing was obviously improved in LPS-exosome treatment group after treatment for 7 and 14 days, with faster wound close, depressed expression of pro-inflammatory factors IL -1, IL -12 and M1 macrophage surface marker iNOS, and up-regulation of anti-inflammatory factors IL-10, TGF-βand M2 macrophage surface marker CD163, the differences were significant (P

Objective To compare the effects on type 2 diabetes of mesenchymal stem cells (MSCs) derived from bone marrow and adipose tissue. Methods Thirty type 2 diabetic rat models were established by an eight weeks high-fat diet (HFD) with a low dose streptozotocin (STZ, 25mg/kg), and randomly assigned into three groups (10 each): diabetes group (T2DM), bone marrow MSCs transplantation group (BMSC) and adipose tissue MSCs transplantation group (ADSC). Ten normal rats were set as control. MSCs were isolated from bone marrow or inguinal adipose tissue of normal rats. One week after STZ injection, 3×10 6 MSCs suspended in 1ml PBS were infused into rats via tail vein. The blood glucose was measured every day after MSCs transplantation, the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) were performed the 7th day after transplantation to evaluate the effects of MSCs on diabetic rats. Pancreatic tissues were collected for insulin/glucagon immunofluorescence staining. Results After MSCs transplantation, the blood glucose decreased gradually and continuously in type 2 diabetic rats, with glucose tolerance and insulin sensitivity improved greatly. The improved insulin sensitivity was further confirmed by a decreased HOMA-IR (homeostasis model of assessment for insulin resistance) index and increased pancreas islet β-cells (P

Objective To evaluate the temporary hypoglycemic effect of adipose mesenchymal stem cells (AD-MSCs) on type 2 diabetic rats, and further discuss the mechanisms of AD-MSCs regulating blood glucose through hepatic glycometabolism. Methods The type 2 diabetic rat model was established by intraperitoneal injection of a single small dose of streptozotocin (STZ, 25mg/kg) after a high-fat diet for 8 weeks. The content of blood glucose was determined by tail vein bleeding at indicated time points (0h, 3h, 6h, 12h, 24h) after infusion of AD-MSCs, concurrently the rats were executed and the liver tissues were collected (diabetes group, n=5, normal group, n=3) for detecting the mRNA and protein expressions of glucokinase (GK), pyruvate kinase (PK) and phosphofructokinase (PFK) (the key enzyme of glycolysis) by real-time qPCR and Western blotting. Results The infusion of AD-MSCs significantly decreased blood glucose in a short period [30.55±1.49mmol/L(0h), 18.90±0.85mmol/ L(3h), 23.70±1.13mmol/L(6h), 21.90±1.00mmol/L(12h), respectively]. PCR results showed that the expressions of GK and PFK increased in the liver tissue of type 2 diabetic rats 3h after AD-MSCs infusion, and the expression of PK increased significantly 6h after AD-MSCs infusion (P

Diabetes is a chronic metabolic disorder caused by relative or absolute insulin deficient or reduced sensitivity of target cells to insulin. Mesenchymal stem cells (MSCs) are adult stem cells with multiple differentiation potential, self-renewable and immunoregulatory properties. Accumulating evidences from clinic or animal experiments recent years showed that MSCs infusion could ameliorate hyperglycemia in diabetes. The research progress of MSCs in diabetes treatment is summarized and a corresponding perspective is herewith proposed in present paper. DOI: 10.11855/j.issn.0577-7402.2016.07.16

Objective To deepen the understanding of 45,X/46,XY mixed gonadal dysgenesis (45,X/46,XY MGD) by summarizing the respective clinical features of patients gathered from China, Brazil, Norway and Denmark suffering from the disease. Methods Comparative analysis was done with the clinical data of 7 patients suffering from 45,X/46,XY MGD diagnosed in the PLA General Hospital of China, and that of other domestic and foreign (Brazil, Norway and Denmark) cases summarized by Peking Union Medical College Hospital. Results Most of the patients of 45,X/46,XY MGD presented the Turner's syndrome-like clinical manifestations such as short stature, multiple naevi on face and lower hair line, etc. Cardiovascular and renal malformation could be found in some patients with 45,X/46,XY MGD. Regarding to the external genitalia, 42.9% (n=27) of the patients were considered to be ambiguous, with a variety of gonadal expression. Laboratory tests demonstrated elevation of follicle-stimulating and/or luteinizing hormone levels with decreased sex hormone levels in most of the patients with 45,X/46,XY MGD. Recombinant human growth hormone (RhGH), testosterone, artificial menstrual cycle and prophylactic gonadectomy were used as primary treatment. There were differences between the domestic and foreign patients in the reason to visit the hospital, and in the age for diagnosis. Chinese patients were always hospitalized for growth retardation, while the foreign patients might go to a doctor for consultation due to various reasons, such as abnormal genitalia, infertility, and fetal chromosomal abnormalities, and many of them might also be diagnosed as 45,X/46,XY MGD in prenatal period or at birth. That was why the average diagnostic age was 4.7 years younger in foreign patients than in Chinese patients. Conclusions No significant difference was found in the clinical characteristics of patients with 45,X/46,XY MGD among different countries and races. But the diagnostic age in Chinese patients is older, and the main reason to consult a doctor is growth retardation. DOI: 10.11855/j.issn.0577-7402.2016.01.14

The failure of pancreatic islet beta cells and insulin resistance are the main mechanism of the occurrence and development of diabetes. The current anti-diabetic drugs, which do not focus on the key pathogenesis of diabetes mellitus, can only eliminate or alleviate the symptoms, delay the progression of the disease, but can not cure the disease fundamentally. Stem cells, which have unique biological characteristics, extremely strong self-renewal ability, multi direction differentiation potential, and secretion of a variety of cytokines, have become a star in the diabetes treatment. Basic researches showed that stem cells may ameliorate hyperglycemia persistently and stably by improving the function of islet beta cells and increasing insulin sensitivity of peripheral target tissue. Some small-sample clinical trials have demonstrated its effectiveness and safety, while prospective largesample, randomized, placebo-controlled clinical trials may provide more evidence on its efficacy and safety, and pave the way for the clinical use of stem cell therapy for diabetes mellitus. DOI: 10.11855/j.issn.0577-7402.2015.07.01

Objective To investigate the effect and mechanism of bone marrow mesenchymal stem cell-conditioned medium (BMSC-CM) on pro-inflammatory cytokines-induced apoptosis of insulinoma cells (INS-1). Methods The conditioned medium containing various cytokines and growth factors was collected and condensed from the supernatants of culture medium of BMSC of rats at passage three. After exposed to the medium with a pro-inflammatory cytokines cocktail containing TNF-α, IL-1β and IFN-γ for 48 hours, INS-1 cells were cultured with BMSC-CM in different concentrations for another 12 hours. INS-1 cells were divided into the following five groups: control group, pro-inflammatory cytokines-treated group, 1× BMSC-CM-treated group, 2× BMSC-CM-treated group and 4× BMSC-CM-treated group. The survival rate of INS-1 cells was assessed by CCK8 assay. The incidence of cell apoptosis was measured using Annexin V/PI staining. Intracellular reactive oxygen species (ROS) production was determined with dichlorofluorescein diacetate (DCFH-DA). Results Compared with the control group, prolonged exposure to pro-inflammatory cytokines induced significant decrease in the viability of INS-1 cells (75.84%±1.53%) and a great increase in the incidence of cell apoptosis (17.23%±1.77%), and also in intracellular ROS level (34.3%±0.80%) with statistically significant difference (P

Prolactinoma is an estrogen-related tumor and leukemia-related protein 16 (LRP16) is correlated with the progression of estrogen-related tumors, but the regulatory mechanism between LRP16 and prolactinoma remain unclear. This study demonstrates a variation in LRP16 with estrogen receptor α (ERα) in prolactinoma models and the up and downregulation effects of LRP16 on prolactin secretion of pituitary adenomas cells (GH3 cells). In our study, 50 male SD rats (30-day-old) were randomly divided into five groups of 10 rats each. After 120 days of treatment, the rats were sacrificed, and the expression of LRP16 and ERα were examined by Western blot and immunohistochemistry to explore the changes in ERα, LRP16, and prolactin. After siRNA transfection of the respective genes, the GH3 cells were cultured, and their secretory function as well as the expression of ERα mRNA and prolactin were analyzed by enzyme-linked immunosorbent assay and real-time-polymerase chain reaction analysis. The results show that secretion of prolactin by GH3 cells can be affected by up and downregulating LRP16 expression, which may provide a novel medical therapy in clinical trials.

Objective To analyze the clinical characteristics and mutation of RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A (MEN2A). Methods The clinical data of a proband and other 10 family members were collected, the genomic DNA of their peripheral blood were extracted, the overall exons of RET proto-oncogene were amplified by PCR , and the PCR products were then purified and direct DNA sequence analysis was performed. Results Different clinical features were found in three of the family members. Three missense mutations, C634R and G691S in exon 11 and R982C in exon 18, were detected in RET proto-oncogene. The three of family members had shown MEN2A related signs, and no such mutations were detected in the other family members. Conclusions Genetic screening set the diagnosis of MEN2A at the gene level, and help analyze the family members at risk. Patients in this case may show typical clinical manifestations of MEN2A, which indicates that C634R mutation combined with G691S and R982C polymorphisms lead to the increase of downstream signal activation of the RET protein as the single C634R mutation along does.

Objective To investigate the clinical significance of serum thyrotrophic receptor antibody(TRAb) in the diagnosis of Graves’ disease(GD).Methods Serum level of TRAb was measured with enzyme-linked immunosorbent assay(ELISA) in 298 untreated patients with GD,212 cases with hypothyroidism,47 cases with subacute thyroiditis,161 cases with thyroid nodule and 73 health controls.ROC curve with SPSS 13.0 was drawn according to the data from patients with GD and subacute thyroiditis.Results The mean value of serum TRAb was significantly higher in Graves’ patients than in patients with other thyroid diseases.The positive rates of TRAb was highest in GD patients(93.3%),followed by the patients with subacute thyroiditis and hypothyroidism(14.9% and 11.3%),and the lowest in the patients with thyoid nodule(1.2%).Serum levels of TRAb in untreated GD showed various titers,and TRAb>30U/L was more commonly found(38.3%).ROC analysis showed that diagnostic code on TRAb for subacute thyroiditis and GD patients was 1.495U/L(93.5% sensitivity and 85.1% specificity),and the doubtable value interval of 1.11U/L to 13.65U/L was determined.Finally,there was a positive correlation between the serum titer of TRAb and TPOAb(P < 0.01).Conclusion TRAb measured by ELISA is a stimulating antibody,and may be used in the differential diagnosis of GD and subacute thyroiditis.

Objective To analyze the clinical characteristics of the syndrome of inappropriate antidiuretic hormone secretion(SIADH).Methods The clinical and biochemical data of sixty cases of SIADH diagnosed in Chinese PLA General Hospital from Jan.1990 to Oct.2010 were analyzed retrospectively.They were classified into malignant tumor(group A),pulmonary infection(group B),and central nervous system diseases(group C) according to different etiology,and their data were compared.Results The number of patients with diagnosis of SIADH was increasing significantly in recent 5 years,and it was higher than the total number diagnosed in the past 15 years before 1990.The SIADH patients were often admitted to various clinical department to which the patient first visited.The mean age of 60 SIADH patients(41 males and 19 females) was 58.9±15.4 years.Etiology of SIADH was diversified,and it was predominantly malignant tumor,pulmonary infection and central nervous system diseases.The clinical manifestations were mainly that of the digestive system and nervous system.The incidence of mental disorders was higher in patients with serious hyponatremia(57.6%) than in those with mild hyponatremia(11.1%,P < 0.05).Age,serum urea and serum creatinine were higher,while the urine osmolality was lower in patients suffering from lung infection than in those with malignant tumor and central nervous system disease.Other clinical symptoms and laboratory findings were not statistically different among the 3 groups.Conclusion The SIADH is prone to misdiagnosis because of different primary etiology and diverse clinical presentation,so it is important to screen SIADH in elderly patients and those with hyponatremia.

LRP16 was previously identified as an estrogen-induced gene in breast cancer cells. The responsiveness of LRP16 to estrogen and its functional effects in endometrial cancer (EC) cells are still unclear. Here, we show that the mRNA level and promoter activity of the LRP16 gene were significantly increased by 17beta-estradiol (E2) in estrogen receptor alpha (ER alpha)-positive Ishikawa human EC cells. Although the growth rate of Ishikawa cells was not obviously affected by ectopic expression of LRP16, the results of a Transwell assay showed an approximate one-third increase of the invasive capacity of LRP16-overexpressing cells. As a result of molecular screening, we observed that the expression of E-cadherin, an essential adhesion molecule associated with tumor metastasis, was repressed by LRP16. Further promoter analyses demonstrated that LRP16 inhibited E-cadherin transactivation in a dose-dependent manner. However, the inhibition was abolished by estrogen deprivation, indicating that the downregulation of E-cadherin transcription by LRP16 requires ER alpha mediation. Chromatin immunoprecipitation analyses revealed that the binding of ER alpha to the E-cadherin promoter was antagonized by LRP16, suggesting that LRP16 could interfere with ER alpha-mediated transcription. These results suggest that the upregulation of LRP16 by estrogen could be involved in invasive growth by downregulating E-cadherin in human ECs.

Angiotensin II type 1 receptor (AT1R) blockers (ARBs) have been shown to reduce the incidence of type 2 diabetes mellitus; however, the underlying molecular mechanism is unknown. Peroxisome proliferator-activated receptor γ (PPARγ) is the central regulator of insulin and glucose metabolism, which improves insulin sensitivity. Whether candesartan cilexetil, as a prodrug of the AT1R blocker candesartan, has PPARγ-activating properties remains to be elucidated. The aim of the present study was to investigate the effects of oral administration of candesartan cilexetil on glucose tolerance and the actions of PPARγ on liver and adipose tissue in the insulin-resistant obese rat induced by high-fat diet. Animals treated with candesartan cilexetil showed an improved glucose tolerance after oral glucose challenge. Whole-body insulin sensitivity was evaluated using the hyperinsulinemic-euglycemic clamp technique. During high-fat feeding in high-fat diet (HF) rats, the glucose infusion rate (GIR) was 52.3% lower than that in normal chow (NC) rats. However, the GIR was significantly enhanced following candesartan cilexetil treatment. Angiotensin II receptor antagonism also resulted in significant increases in PPARγ protein expression in adipose and liver tissue. These results indicate that PPARγ activation by candesartan cilexetil may provide novel therapeutic options in the treatment of patients with metabolic syndrome.

Pituitary tumor transforming gene (PTTG) is a proto-oncogene cloned from rat GH4 cells. This gene was able to induce cell transformation in vitro and is also associated with p53-dependent and -independent apoptosis. In this study, we cloned human PTTG (hPTTG) from a pituitary tumor and then stably transfected the hPTTG into HeLa and A549 cells. An overexpression of hPTTG significantly inhibited cell growth, which was determined by the adherent cell growth properties, colony formation in soft agar and [3H] thymidine incorporation, respectively, in HeLa and A549 cells. The inhibitory effect on cell growth was associated with the activation of p21WAF1/CIP1 in A549 cells, but not in HeLa cells. The hPTTG overexpression increased both the p21WAF1/CIP1 mRNA and protein expression levels as determined by both Northern and Western blot analysis, respectively, in A549 cells. The increased expression of p21WAF1/CIP1 mRNA was regulated at the transcription level and was independent on p53 expression because the luciferase activity increased after the co-transfection of hPTTG and p21WAF1/CIP1 promoter fragments with and without a p53 binding sequence. The subcellular distribution of hPTTG was dependent on cell type, and was predominantly in the nucleus in HeLa, Cos-7 and DU145 cells, but showed a diffuse distribution in both the nucleus and cytoplasm in A549, DLD-1 and NIH3T3 cells. These results indicate that an overexpression of hPTTG inhibits the cell growth due to different mechanisms, which are p21WAF1/CIP1 -dependent and -independent.

White blood cell (WBC) count has been associated with diabetic risk, but whether the correlation is independent of other risk factors has hardly been studied. Moreover, very few such studies with large sample sizes have been conducted in Chinese. Therefore, we investigated the relationship between WBC count and glucose metabolism in China. We also examined the relevant variables of WBC count. A total of 9,697 subjects (mean age, 58.0 ± 9.1 years) were recruited. The subjects were classified into four groups, including subjects with normal glucose tolerance, isolated impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus (T2DM). We found that WBC count increased as glucose metabolism disorders exacerbated. WBC count was also positively correlated with waist hip ratio, body mass index, smoking, triglycerides, glycosylated haemoglobin A1c (HbA1c) and 2-h postprandial glucose. In addition, high density lipoprotein and the female gender were inversely correlated with WBC levels. In patients with previously diagnosed T2DM, the course of T2DM was not correlated with WBC count. Our findings indicate that elevated WBC count is independently associated with worsening of glucose metabolism in middle-aged and elderly Chinese. In addition, loss of weight, smoking cessation, lipid-modifying therapies, and control of postprandial plasma glucose and HbA1c may ameliorate the chronic low-grade inflammation.

Obesity is associated with insulin resistance and some reproductive abnormalities. Circulating FFAs are often elevated in obese subjects and are also closely linked to insulin resistance. In this study, we demonstrated that saturated FFAs, such as palmitic acid and stearic acid, markedly suppressed the granulosa cell survival in a time- and dose-dependent manner. Polyunsaturated FFA, arachidonic acid, had no effect on the cell survival, even at supraphysiological concentrations. The suppressive effect of saturated FFAs on cell survival was caused by apoptosis, as evidenced by DNA ladder formation and annexin V-EGFP/propidium iodide staining of the cells. The apoptotic effects of palmitic acid and stearic acid were unrelated to the increase of ceramide generation or nitric oxide production and were also completely blocked by Triacsin C, an inhibitor of acylcoenzyme A synthetase. In addition, acylcoenzyme A, pamitoylcoenzyme A, and stearylcoenzyme A markedly suppressed granulosa cell survival, whereas arachidonoylcoenzyme A had no such effect, and this finding was consistent with the effect of the respective FFA form. Surprisingly, arachidonic acid instead showed a protective effect on palmitic acid- and stearic acid-induced cell apoptosis. A Western blot analysis showed the apoptosis of the granulosa cells induced by palmitic acid to be accompanied by the down-regulation of an apoptosis inhibitor, Bcl-2, and the up-regulation of an apoptosis effector, Bax. These results indicate that saturated FFAs induce apoptosis in human granulosa cells caused by the metabolism of the respective acylcoenzyme A form, and the actual composition of circulating FFAs may thus play a critical role in the apoptotic events of human granulosa cells. These effects of FFAs on granulosa cell survival may be a possible mechanism for reproductive abnormalities, such as amenorrhea, which is frequently observed in obese women.

We established a steroidogenic human ovarian granulosa-like tumor cell line, designated KGN, from a patient with invasive ovarian granulosa cell carcinoma. KGN had a relatively long population doubling time of about 46.4 h and had an abnormal karyotype of 45,XX, 7q-, -22. A steroid analysis of the cultured medium by RIA performed 5 yr after the initiation of culture showed that KGN was able to secrete pregnenolone and progesterone, and both dramatically increased after stimulation with (Bu)(2)cAMP. However, little or no secretion of 17alpha-hydroxylated steroids, dehydroepiandrosterone, androstenedione, or estradiol was observed. The aromatase activity of KGN was relatively high and was further stimulated by (Bu)(2)cAMP or FSH. These findings showed a pattern similar to that of steroidogenesis in human granulosa cells, thus allowing analysis of naturally occurring steroidogenesis in human granulosa cells. Fas-mediated apoptosis of KGN was also observed, which mimicked the physiological regulation of apoptosis in normal human granulosa cells. Based on these findings, this cell line is considered to be a very useful model for understanding the regulation of steroidogenesis, cell growth, and apoptosis in human granulosa cells.

To the Editor: We reported 2 cases of ectopic thyroid gland (ETG) masquerading as pituitary adenoma (PA). The first case was a 15-year-old boy with growth, and mental retardation whose height was 121 cm and weight was 44 kg on admission. Bone age development index was 40, while bone age showed 6–10 years old. Magnetic resonance imaging (MRI) revealed pituitary hyperplasia [Figure 1a]. Thyroid ultrasonography did not found thyroid on the anterior aspect of the neck and the normal position of thyroid gland. The peak value of growth hormone experiments was 1.8 μg/L. Gonad function indicated testosterone (T) 0.55 nmol/L, luteotropic hormone 150 mU/L. After treatment with eltroxin, the patient was 21 cm higher than before in one year and his intelligence improved significantly comparatively. MRI after treatment showed pituitary hyperplasia significantly regressed [Figure 1b]. The second case was a 27-year-old female with galactorrhea, amenorrhea, and infertility. MRI showed the signal was obviously abnormal (uniform strengthening) in the saddle pituitary, the size was 1.0 cm × 1.5 cm × 1.6 cm, which indicated the PA was huge [Figure 1c]. Thyroid function showed FT4 9.07 pmol/L, TSH >150 mU/L, and 15 minutes serum prolactin was 2.66 μg/L. Gonad function, 8 after midnight (AM) serum adreno-cortico-tropic-hormone, and 8 AM serum cortisol were normal. Thyroid ultrasonography did not found thyroid at the normal position. History revealed that the patient was found thyroglossal cyst in 15 years old and accepted total excision of thyroglossal duct cyst in 18 years old. Then eltroxin was prescribed, and the patient was pregnant successfully in 7 months. Now, her menstruation is normal, and galactorrhea is rarely happen. These two cases were ectopic thyroid masquerading as PA. At present, classification of PA is based on plasma hormone levels or immunohistochemical staining, clinical features are always complex and confusing. In these two cases, retardation, infertility, and amenorrhea were not arising from PA, while the primary ectopic thyroid was the culprit. It caused primary hypothyroidism, TSH cell proliferation, and compensatory pituitary gland hyperplasis. Figure 1 (a) Magnetic resonance imaging of the 15-year-old teenager with ectopic thyroid before the treatment showed pituitary hyperplasia (black arrow), sagittal T1-weighed contrast enhanced image; (b) magnetic resonance imaging of the 15-year-old teenager with ... ETG, the most frequent form of thyroid dysgenesis, refers to the presence of thyroid tissue in locations other than the normal anterior neck region.[1] It remains a rare disease.[1,2] Moreover, females account for 65–80% of ETG cases.[3] Although ETG has been understood gradually, diagnostic delay in ETG remains common, and this delay compounded with inappropriate therapeutic methods is responsible for the poor outcome in affected patients, especially in adolescents and women with childbearing age. When aberrant thyroid was totally excised, thyroid function would be absent or inadequate permanently. Substitute therapy would be essential, cost unpleasantly high and therapeutic period, unfortunately, life-long time. Thereby, thyroid function test and color Doppler ultrasonography are necessary when PA is considered. If ETG is suspected, preoperative analysis is of particular significance. A high index of clinical awareness and education of clinical practitioners will help a great deal in improving the ultimate outcome in patients with ETG. Financial support and sponsorship The work was supported by grants from the Chinese National Natural Science Fund (No. 30900543), the Clinical Science Fund of PLA General Hospital (No. 2013FC-TSYS-1028) and the Beijing Natural Science Fund (No. 7152136). Conflicts of interest There are no conflicts of interest.