Novel Loss-of-Function Variant in HNF1a Induces ß-Cell Dysfunction through Endoplasmic Reticulum Stress.

Heterozygous variants in the hepatocyte nuclear factor 1a (HNF1a) cause MODY3 (maturity-onset diabetes of the young, type 3). In this study, we found a case of novel HNF1a p.Gln125* (HNF1a-Q125ter) variant clinically. However, the molecular mechanism linking the new HNF1a variant to impaired islet ß-cell function remains unclear. Firstly, a similar HNF1a-Q125ter variant in zebrafish (hnf1a+/-) was generated by CRISPR/Cas9. We further crossed hnf1a+/- with several zebrafish reporter lines to investigate pancreatic ß-cell function. Next, we introduced HNF1a-Q125ter and HNF1a shRNA plasmids into the Ins-1 cell line and elucidated the molecular mechanism. hnf1a+/- zebrafish significantly decreased the ß-cell number, insulin expression, and secretion. Moreover, ß cells in hnf1a+/- dilated ER lumen and increased the levels of ER stress markers. Similar ER-stress phenomena were observed in an HNF1a-Q125ter-transfected Ins-1 cell. Follow-up investigations demonstrated that HNF1a-Q125ter induced ER stress through activating the PERK/eIF2a/ATF4 signaling pathway. Our study found a novel loss-of-function HNF1a-Q125ter variant which induced ß-cell dysfunction by activating ER stress via the PERK/eIF2a/ATF4 signaling pathway.

Reversible Transformation between Isolated Skyrmions and Bimerons.

Skyrmions and bimerons are versatile topological spin textures that can be used as information bits for both classical and quantum computing. The transformation between isolated skyrmions and bimerons is an essential operation for computing architecture based on multiple different topological bits. Here we report the creation of isolated skyrmions and their subsequent transformation to bimerons by harnessing the electric current-induced Oersted field and temperature-induced perpendicular magnetic anisotropy variation. The transformation between skyrmions and bimerons is reversible, which is controlled by the current amplitude and scanning direction. Both skyrmions and bimerons can be created in the same system through the skyrmion-bimeron transformation and magnetization switching. Deformed skyrmion bubbles and chiral labyrinth domains are found as nontrivial intermediate transition states. Our results may provide a unique way for building advanced information-processing devices using different types of topological spin textures in the same system.

Breastfeeding on childhood obesity in children were large-for-gestational age: retrospective study from birth to 4 years.

Our aim was to assess effects of breast-feeding (BF) in the association between large-for-gestational age (LGA) and body mass index (BMI) trajectories on childhood overweight from 1 to 4 years old. A total of 1649 healthcare records of mother-child pairs had detailed records of feeding practices and were included in this retrospective cohort study. Data were available in Medical Birth Registry of Xiamen between January 2011 and March 2018. Linear and logistic regression models were used to access the difference between BF and no-BF group. For offspring were LGA and BF was significantly associated with a lower BMI Z-score from 1 to 4 years old after adjustment confounders in Model 1 to 3 [difference in BMI Z-score in Model 1: estimated ß: -0.07 [95%CI: -0.13 to -0.01]; Model 2: estimated ß: -0.07 (-0.13 to -0.004); Model 3: estimated ß: -0.06 (-0.12 to -0.001); P = 0.0221, 0.0371, 0.0471]. A significantly lower risk of childhood overweight was observed in Model 1 [odd ratio (OR): 0.85 (95%CI, 0.73 to 1.00)], P = 0.0475) with adjustment for maternal pre-pregnancy BMI. Furthermore, Model 2 and Model 3 showed LGA-BF infants had a lower risk for childhood overweight then LGA-no-BF infants [OR: 0.87 and 0.87 (95%CI, 0.73 to 1.03; 0.74 to 1.03)], however, there was no statistical significance (P = 0.1099, and 0.1125)]. BF is inversely related to BMI Z-score and risk for overweight in children were LGA from 1 to 4 years old. Adjustment for maternal pre-pregnancy BMI, the protective association between BF and childhood overweight was more significant.

Circulating branch chain amino acids and improvement in liver fat content in response to exercise interventions in NAFLD.

Nonalcoholic fatty liver disease is likely to be associated with increased circulating branched-chain amino acids. We investigated the relationship between changes in branched-chain amino acids levels in the serum and improvement in liver fat content caused by exercise intervention in individuals with nonalcoholic fatty liver disease. The exploratory study included 208 central obesity and nonalcoholic fatty liver disease individuals from an exercise intervention randomized clinical trial for nonalcoholic fatty liver disease. The participants were randomly assigned to control, moderate, and vigorous-moderate exercise groups for 12 months. Changes in total branched-chain amino acids, leucine, isoleucine, and valine levels from baseline to 6 months were calculated. Liver fat content was determined by proton magnetic resonance spectroscopy. Reductions in circulating levels of total branched-chain amino acids, leucine, and valine levels from baseline to 6 months were significantly associated with the improvement of liver fat content at 6 months and 12 months (p < 0.01 for all) after adjustments for age, sex, total energy intake, protein intake, intervention groups, HOMA-IR, BMI, liver fat content, total branched-chain amino acids, leucine, and valine at baseline, respectively. These associations were still significant after further adjustments for changes in HOMA-IR and BMI from baseline to 6 months (p < 0.05 for all). Our findings indicated that reductions in circulating branched-chain amino acids levels were associated with an improvement in liver fat content by exercise intervention among patients with nonalcoholic fatty liver disease, which was independent of changes in BMI or HOMA-IR.

Confinement and Protection of Skyrmions by Patterns of Modified Magnetic Properties.

Magnetic skyrmions are versatile topological excitations that can be used as nonvolatile information carriers. The confinement of skyrmions in channels is fundamental for any application based on the accumulation and transport of skyrmions. Here, we report a method that allows effective position control of skyrmions in designed channels by engineered energy barriers and wells, which is realized in a magnetic multilayer film by harnessing the boundaries of patterns with modified magnetic properties. We experimentally and computationally demonstrate that skyrmions can be attracted or repelled by the boundaries of areas with modified perpendicular magnetic anisotropy and Dzyaloshinskii-Moriya interaction. By fabricating square and stripe patterns with modified magnetic properties, we show the possibility of building reliable channels for confinement, accumulation, and transport of skyrmions, which effectively protect skyrmions from being destroyed at the device edges. Our results are useful for the design of spintronic applications using either static or dynamic skyrmions.

Identification of transcriptomic signatures and crucial pathways involved in non-alcoholic steatohepatitis.

PURPOSE: Our study aimed to uncover the crucial genes and functional pathways involved in the development of non-alcoholic steatohepatitis (NASH). METHODS: Liver transcriptome datasets were integrated with Robust rank aggregation (RRA) method, and transcriptomic signatures for NASH progression and fibrosis severity in NAFLD were developed. The functions of transcriptomic signatures were explored by multiple bioinformatic analyses, and their diagnostic role was also evaluated. RESULTS: RRA analyses of 12 transcriptome datasets comparing NASH with non-alcoholic fatty liver (NAFL) identified 116 abnormally up-regulated genes in NASH patients. RRA analyses of five transcriptome datasets focusing fibrosis severity identified 78 abnormally up-regulated genes in NAFLD patients with advanced fibrosis. The functions of those transcriptomic signatures of NASH development or fibrosis progression were similar, and were both characterized by extracellular matrix (ECM)-related pathways (Adjusted P < 0.05). The transcriptomic signatures could effectively differentiate NASH from NAFL, and could help to identify NAFLD patients with advanced fibrosis. Gene set enrichment analysis and weighted gene co-expression network analysis further validated the key role of ECM-related pathways in NASH development. The top 10 up-regulated genes in NASH patients were SPP1, FBLN5, CHI3L1, CCL20, CD24, FABP4, GPNMB, VCAN, EFEMP1, and CXCL10, and their functions were mainly related to either ECM-related pathways or immunity-related pathways. Single cell RNA-sequencing analyses revealed that those crucial genes were expressed by distinct cells such as hepatocytes, macrophages, and hepatic stellate cells. CONCLUSIONS: Transcriptomic signatures related to NASH development and fibrosis severity of NAFLD patients are both characterized by ECM-related pathways, and fibrosis is a main player during NASH progression. This study uncovers some novel key genes involved in NASH progression, which may be promising therapeutic targets.

Self-Assembled Hexagonal Superparamagnetic Cone Structures for Fabrication of Cell Cluster Arrays.

In this study, we demonstrated that arrays of cell clusters can be fabricated by self-assembled hexagonal superparamagnetic cone structures. When a strong out-of-plane magnetic field was applied to the ferrofluid on a glass substrate, it will induce the magnetic poles on the upper/lower surfaces of the continuous ferrofluid to increase the magnetostatic energy. The ferrofluid will then experience hydrodynamic instability and be split into small droplets with cone structures because of the compromising surface tension energy and magnetostatic energy to minimize the system's total energy. Furthermore, the ferrofluid cones were orderly self-assembled into hexagonal arrays to reach the lowest energy state. After dehydration of these liquid cones to form solid cones, polydimethylsiloxane was cast to fix the arrangement of hexagonal superparamagnetic cone structures and prevent the leakage of magnetic nanoparticles. The U-343 human neuronal glioblastoma cells were labeled with magnetic nanoparticles through endocytosis in co-culture with a ferrofluid. The number of magnetic nanoparticles internalized was (4.2 ± 0.84) × 106 per cell by the cell magnetophoresis analysis. These magnetically labeled cells were attracted and captured by hexagonal superparamagnetic cone structures to form cell cluster arrays. As a function of the solid cone size, the number of cells captured by each hexagonal superparamagnetic cone structure was increased from 48 to 126 under a 2000 G out-of-plane magnetic field. The local magnetic field gradient of the hexagonal superparamagnetic cone was 117.0-140.9 G/mm from the cell magnetophoresis. When an external magnetic field was applied, we observed that the number of protrusions of the cell edge decreased from the fluorescence images. It showed that the local magnetic field gradient caused by the hexagonal superparamagnetic cones restricted the cell growth and migration.

Coexistence of ovarian serous papillary cystadenofibroma and type A insulin resistance syndrome in a 14-year-old girl: A case report.

BACKGROUND: Type A insulin resistance syndrome is a rare disorder caused by mutations in the gene encoding the insulin receptor. Its coexistence with ovarian serous papillary cystadenofibroma is even rarer. CASE SUMMARY: A 14-year-old girl developed type A insulin resistance syndrome and showed high fasting insulin, glucose, and hemoglobin A1c (HbA1c) levels. The girl suffered from ovarian serous papillary cystadenofibroma. The laboratory results were as follows: fasting insulin was 2624.90 pmol/L and HbA1c was 8.5%. A heterozygous missense mutation on exon 20 of the insulin receptor gene (c.3601C>T, Arg1201Trp) was observed. The histopathological diagnosis was a cystic lesion that extended to the upper right uterus, indicating a right ovarian serous papillary cystadefibroma accompanied by focal interstitial hyperplasia. The patient was treated with metformin for over 6 mo. Additionally, laparoscopic resection (bilateral) of the ovarian lesion and laparoscopic intestinal adhesiolysis were performed under general anesthesia. Diet therapy combined with exercise was then initiated. The patient had an uneventful recovery. The patient also showed improved blood glucose control, with reduced levels of fasting insulin (857.84 pmol/L) and HbA1c (7.0%). CONCLUSION: Insulin resistance may play a significant role in the induction of tumors. It is important to investigate further the association between insulin resistance and tumors and the underlying mechanism.

Effects of maternal hepatitis B surface antigen positive status on the pregnancy outcomes: A retrospective study in Xiamen, China, 2011-2018.

OBJECTIVE: Hepatitis B virus infection is a major social and economic burden in developing countries, especially in China. We aimed to evaluate the effects of hepatitis B surface antigen (HBsAg) positive status on the pregnancy outcomes in the Chinese population. METHODS: This retrospective cohort study was performed using data from the Medical Birth Registry of Xiamen, China, from January 2011 to March 2018. Multivariate logistic regression analysis was used to assess the association between the HBsAg status and pregnancy outcomes. RESULTS: This study included 3,789 HBsAg-positive women and 29, 648 non-exposed women. The HBsAg-positive pregnant women were slightly older in age (29.3±4.3 vs. 28.9±4.4, P< 0.001). Additionally, pregnant women with a positive HBsAg status had higher odds of gestational diabetes mellitus (GDM) (adjusted odds ratio [aOR], 1.13; 95% confidence interval [CI], 1.03-1.23), and cesarean delivery (aOR, 1.12; 95%CI, 1.03-1.21). The risk of infants being large or small-for-gestational age, having low-birth weight, and of macrosomia, preterm birth, and stillbirth did not differ significantly between the HBsAg-positive and-negative women. CONCLUSION: In Xiamen, China, the slightly higher risk of GDM and cesarean section in women positive for HBsAg should not be neglected. Further studies should be conducted to evaluate the effects of HBsAg positivity on the pregnancy outcomes in different ethnic populations.

Adverse pregnancy outcomes on the risk of overweight offspring: a population-based retrospective study in Xiamen, China.

The growth trajectory of Chinese preschoolers still remains unclear. Our objective was to determine whether there was an association between adverse pregnancy outcomes and overweight offspring. We analyzed population-based retrospective cohort data from the Medical Birth Registry of Xiamen, which comprised 33,157 children examined from 1 to 6 years of age. Longitudinal analyses were used to evaluate the growth trajectories of offspring body mass index (BMI). Multivariate logistic regression was used to assess the effects of two adverse pregnancy outcomes, gestational diabetes mellitus (GDM) and being large-for-gestational age (LGA), on childhood overweight. Offspring of mothers with GDM and LGA has a higher annual BMI z-score from 1 to 6 years of age (all P < 0.05). But, a higher annual BMI z-score was only observed in children aged 1-5 years in models 1-3. Overall BMI z-score of offspring aged 1-6 who were born to mothers with GDM and LGA were also higher in models 1-3 (all P < 0.05). Additionally, offspring of mothers with GDM and LGA had a higher risk for overweight in model 1, from 1 to 6 years of age (odds ratio (OR), 1.814; 95% confidence interval (CI), 1.657-1.985; P < 0.0001). However, this association was attenuated after adjusting for maternal pre-pregnancy BMI (OR, 1.270; 95% CI, 0.961-1.679; P = 0.0930). Offspring of mothers with GDM and LGA had a higher BMI z-score and increased risk for overweight. Indeed, intrauterine exposure to maternal GDM and LGA could bias offspring to overweight, whereas maternal pre-pregnancy BMI may play a key role in offspring overweight for children born to mothers with GDM and LGA.

Assessment of the optimal cutoff value of fasting plasma glucose to establish diagnosis of gestational diabetes mellitus in Chinese women.

Our aim is to assess the optimal cutoff value of fasting plasma glucose (FPG) in Chinese women at 24-28 weeks' gestation by performing oral glucose tolerance test (OGTT) to improve diagnostic rate of gestational diabetes mellitus (GDM). Data were derived from the Medical Birth Registry of Xiamen. A FPG cutoff value of 5.1 mmol/L confirmed the diagnosis of GDM in 4,794 (6.10%) pregnant women. However, a FPG cutoff value of 4.5 mmol/L should rule out the diagnosis of GDM in 35,932 (45.73%) pregnant women. If we use this cutoff value, the diagnosis of GDM to about 27.3% of pregnant women will be missed. Additionally, a 75-g OGTT was performed in pregnant women with FPG values between 4.5 and 5.1 mmol/L, avoiding the performance of formal 75-g OGTT in about 50.37% pregnant women. Meanwhile, according to maternal age and pre-pregnancy BMI categories, with FPG values between 4.5 mmol/L and 5.1 mmol/L, which had high sensitivity, to improve the diagnostic rate of GDM in all groups. Further researches are needed to present stronger evidences for the screening value of FPG in establishing the diagnosis of GDM in pregnant women.

Effects of Prepregnancy Body Mass Index, Weight Gain, and Gestational Diabetes Mellitus on Pregnancy Outcomes: A Population-Based Study in Xiamen, China, 2011-2018.

BACKGROUND: It is unclear that how prepregnancy body mass index (BMI), gestational weight gain (GWG), and gestational diabetes mellitus (GDM) affect pregnancy outcomes in -China. Thus, we explored how BMI, GWG, and GDM affect the risks of adverse pregnancy outcomes. METHODS: We performed a retrospective, population-based study included all births in Xiamen, China, 2011-2018. Demographic data and pregnancy outcomes of 73,498 women were acquired from the Medical Birth Registry of Xiamen. Women were categorized into groups on prepregnancy BMI and GWG in order to assess the risk of pregnancy outcomes. Multivariable logistic regression was performed to evaluate risk factors. RESULTS: Overall, 6,982 (9.37%) women were obese, and 8,874 (12.07%) women were overweight. Obese women are more vulnerable to cesarean delivery, preterm birth, large-for-gestational age (LGA), and macrosomia (crude OR [cOR] 2.00, 1.89-2.12; 1.35, 1.20-1.51; 2.12, 1.99-2.26; 2.53, 2.25-2.86, respectively, adjusted ORs 1.73, 1.62-1.84; 1.25, 1.10-1.42; 2.03, 1.90-2.18; 2.77, 2.44-3.16, respectively). Similar results were observed in overweight women (cORs 1.49, 1.42-1.57; 1.02, 0.91-1.15; 1.60, 1.50-1.70; 2.01, 1.78-2.26, respectively). Furthermore, women who gain weight in excessive group were 1.43, 2.06, and 2.16 times to deliver cesarean, LGA, and macrosomia, respectively. Additionally, GDM women were easily subjected to cesarean section, preterm birth, LGA, low birth weight, and macrosamia (cORs 1.52, 1.55, 1.52, 1.37, 1.27, respectively). CONCLUSIONS: Obesity prior to pregnancy, excessive GWG, and GDM were all associated with increased odds of cesarean, LGA, and macrosomia. Blood glucose and weight control before and during pregnancy are needed that may reduce the complications of pregnancy.

The relationship between ACE/AGT gene polymorphisms and the risk of diabetic retinopathy in Chinese patients with type 2 diabetes.

AIMS: This study aims to investigate the association between renin-angiotensin system gene polymorphism and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes. METHODS: We consecutively included 1491 patients for the assessment of ACE I/D and AGT M/T gene polymorphisms in 345 DR cases and 1146 patients without retinopathy (DNR). Albuminuria was defined by urine albumin creatinine ratio and albumin excretion rate. RESULTS: Compared with the NDR patients, the DR cases displayed a higher proportion of diabetic nephropathy (32.68% vs. 6.52%, χ2 = 150.713, p < 0.001). The DR cases and DNR individuals did not differ in the frequency of genotypes and alleles of ACE I/D and AGT M/T (all p > 0.05). Intriguingly, DR patients with obesity showed higher frequency of DD (χ2 = 4.181, p = 0.041), but no significant difference exists in the other stratified BMI and hypertension analyses (all p > 0.05). Binary logistic regression displays that the association of the ACE and AGT gene polymorphisms in DR patients is not significant after adjusting for confounding covariates in all the comparisons. CONCLUSIONS: The ACE and AGT gene polymorphisms are not associated with the progress of diabetes developing into retinopathy in Chinese patients with type 2 diabetes. However, more investigations are needed to further prove the association.

Human amylin induces CD4+Foxp3+ regulatory T cells in the protection from autoimmune diabetes.

Autoimmune diabetes is a disorder of immune homeostasis that leads to targeted insulin-secreting islet ß cell destruction characterized by insulitis. Human amylin (hA) is an important neuroendocrine hormone co-secreted with insulin by pancreatic ß cells. Here, we report hA immune-modulatory action through inducing regulatory T cells. We ex vivo-treated human peripheral blood mononuclear cells (hPBMCs) with hA for 24 h and counted CD4+Foxp3+ regulatory T cells (Treg) using flow cytometry. Diabetic status was monitored and splenic Treg were measured in non-obese diabetic (NOD) male mice. NOD mice were intraperitoneally injected once daily with hA (n = 25) or solvent for control (n = 25) for 7 months continuously. Spleen tissues were collected at the end of intervention and processed for flow cytometry and Western blot. We found a 2.9-fold (p < 0.05) increase of CD4+Foxp3+ Treg in hPBMCs treated with 10 nmol/L hA compared with negative control. Incidence of diabetes in hA-treated NOD mice decreased 44% (p = 0.045) in the 6th month and 57% (p = 0.0002) in the 7th month. Meanwhile, the hA treatment induced a 1.5-fold increase of CD4+Foxp3+ Treg from mouse splenocytes (p = 0.0013). Expression of transforming growth factor-ß (TGF-ß) and toll-like receptor-4 (TLR-4) were upregulated in hA-treated mice. Human amylin might protect against autoimmune diabetes via the induction of CD4+Foxp3+ Treg, which suggests a novel approach to improve autoimmune conditions.

JAK2/STAT3 pathway is involved in the protective effects of epidermal growth factor receptor activation against cerebral ischemia/reperfusion injury in rats.

Cerebral ischemia and reperfusion is a common pathophysiologic process, which is involved in stroke and brain trauma. Recent studies revealed that activating epidermal growth factor receptor (EGFR) ameliorates cerebral ischemia/reperfusion (I/R) injury, however, the precise mechanisms remain to be illuminated. In this study, the neurological behavior was evaluated by Longa score. The infarct volume was performed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining and the expression of p-EGFR, p-STAT3, connexin (Cx43), Bax and Bcl-2 were detected by Western blot. The neurological behavior and infarct volume were increased in rats with cerebral I/R injury. Epidermal growth factor (EGF) pretreatment significantly decreased neurological deficit and infarct volume. However, the antagonist of EGFR, AG1478 attenuated the EGF-induced reduction of neurological deficit and infarct volume. Moreover, the inhibitor of JAK2/STAT3, AG490 undermined the protective effects stimulated by activating EGFR in rats with I/R injury. In addition, EGF pretreatment increased the expression of Bcl-2 and reduced the expression of Bax and Cx43, and the effects were abolished after using AG1478 and AG490. These findings implicate that JAK2/STAT3 pathway plays the vital role in I/R injury protection from activating EGFR. And the neuroprotective effects may associate with inhibiting the Cx43 expression and the inhibition of apoptosis.

[Protective effects of P2X7 receptor inhibition in cerebral ischemia/reperfusion injury in rats].

OBJECTIVE: To investigate the protective effects of P2X7 receptor (P2X7R) inhibitor against cerebral ischemia/reperfusion (I/R) injury in rats and the possible mechanisms.
 Methods: The neurological deficit of rats was evaluated by Longa score. The infarct volume was examined by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The expression levels of extracellular signal-regulated kinase (ERK), phosphorylation extracellular signal-regulated kinas p-ERK), connexin 43 (Cx43), Bax, Bcl-2 and cleaved caspase-3 were detected by Western blot.
 Results: Compared with sham group, the neurobehavioral score (P<0.05) and cerebral infarct volume (P<0.01) of rats in I/R group was increased. Compared with I/R group, brilliant blue G (BBG, the antagonist of P2X7R) or PD98059 (the inhibitor of EKR kinase) could reduce the neurobehavioral score (P<0.01) and cerebral infarct volume significantly (P<0.05). The neurobehavioral score and cerebral infarct volume was further decreased (P<0.05) when rats were treated with both BBG and PD98059. Compared with I/R group, the expression levels of p-ERK, Cx43, cleaved caspase-3 and the ratio of Bax/Bcl-2 were decreased by BBG or PD98059 pretreatment, and the protective effects were further enhanced when rats were treated with both BBG and PD98059 (P<0.05).
 Conclusion: Inhibition of P2X7R reduces the cerebral I/R injury of rats. ERK inhibition is probably involved in the protective effects of P2X7R inhibitor against cerebral I/R injury, which may be related to the reduction of Cx43 and cleaved caspase-3, and the ratio of Bax/Bcl-2.

Climates on incidence of childhood type 1 diabetes mellitus in 72 countries.

We are aimed to systematically assess the worldwide trend in incidence of childhood type 1 diabetes mellitus (CT1DM) from 1965 to 2012 and to discuss whether climate affect incidence of CT1DM. We searched the relevant literatures in detail to judge the effect of different climates on incidence of CT1DM. The climates included Mediterranean, monsoon, oceanic, continental, savanna, and rainforest. According to different climates, we further researched relevant factor such as sunshine durations and latitudes. The overall incidence of CT1DM in 72 countries was 11.43 (95% CI 10.31-12.55) per 100,000 children/yr. The incidence of CT1DM in Oceanic climate [10.56 (8.69-12.42)] is highest compared with other climates; the incidence in 40°-66°34'N/S [14.71 (12.30-17.29)] is higher than other latitude groups; the incidence in sunshine durations with 3-4 hours per day [15.17 (11.14-19.20)] is highest compared with other two groups; the incidence of CT1DM from 2000 to 2012 [19.58 (14.55-24.60)] is higher than other periods; all p < 0.01. Incidence of CT1DM was increasing from 1965 to 2012, but incidence in Oceanic climate is higher than other climates. Furthermore, it is higher in centers with higher latitude and lower sunshine durations. The climates might play a key role in inducing CT1DM.

Efficacy and safety of pramlintide injection adjunct to insulin therapy in patients with type 1 diabetes mellitus: a systematic review and meta-analysis.

AIMS: We aim to assess the efficacy and safety of pramlintide plus insulin therapy in patients with type 1 diabetes. METHODS: We included clinical studies comparing pramlintide plus insulin to placebo plus insulin. Efficacy was reflected by glycemic control and reduction in body weight and insulin use. Safety concerns were hypoglycemia and other adverse events. Subgroup analysis was performed for different doses (30, 60, 90 µg/meal) and durations (≤4, 26, 29, >29 weeks) of the treatment. RESULTS: A total of 10 randomized placebo-controlled studies were included for this meta-analysis (pramlintide, n=1978; placebo, n=1319). Compared with controls, patients given pramlintide had significantly lower HbA1c (p < 0.001), total daily insulin dose (p = 0.024), mean mealtime insulin dose (p < 0.001), body weight (p < 0.001) and postprandial glucose level (p = 0.002). The addition of pramlintide increased the incidence of nausea (p < 0.001), vomiting (p < 0.001), anorexia (p < 0.001) and hypoglycemia (p < 0.05) at the initiation of the treatment. The efficacy and adverse reactions of pramlintide were largely significant for the different doses and durations of the treatment. CONCLUSIONS: The addition of pramlintide to insulin therapy in patients with type 1 diabetes improves glycemic control and reduces insulin requirement and body weight while bringing transient hypoglycemia and digestive disorders.

The Yin and Yang of regulatory T cell and therapy progress in autoimmune disease.

Autoimmune diseases (ADs) are primarily mediated by the failure of immunological self-tolerance. Regulatory T cells (Tregs) play a critical role in the maintenance of induced tolerance to peripheral self-antigens, suppressing immoderate immune responses deleterious to the host and preventing the AD development. Tregs and suppressive cytokines are homeostatic with effective cells plus pro-inflammatory cytokines in healthy hosts which is defined as "Yang", and ADs are usually induced in case of disturbed homeostasis, which is defined as "Yin". Indeed, the Yin-Yang balance could explain the pathogenic mechanism of ADs. Tregs not only suppress CD4+ and CD8+ T cells but also can suppress other immune cells such as B cell, natural killer cell, DC and other antigen-presenting cell through cell-cell contact or secreting suppressive cytokines. In Tregs, Foxp3 as an intracellular protein displays a more specific marker than currently used other cell-surface markers (such as CD25, CD40L, CTLA-4, ICOS and GITR) in defining the naturally occurring CD4+ Tregs. Though the precise mechanism for the opposite effects of Tregs has not been fully elucidated, the importance of Tregs in ADs has been proved to be associated with kinds of immunocytes. At present, the surface marker, frequency and function of Tregs existed conflicts and hence the Tregs therapy in ADs faces challenges. Though some success has been achieved with Tregs therapy in few ADs both in murine models and humans, more effort should paid to meet the future challenges. This review summarizes the progress and discusses the phenotypic, numeric and functional abnormalities of Tregs and is the first time to systematically review the progress of Tregs therapy in kinds of ADs.