Elevated matrix metalloproteinase-9 in patients with systemic sclerosis

Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of cancer, autoimmune disease, and various pathologic conditions characterized by excessive fibrosis. In this study, we investigated the expression of MMP-9 and its clinical significance in systemic sclerosis (SSc). The patients (n = 42) with SSc had higher concentrations of MMP-9 and of tissue inhibitor of metalloproteinase-1 (TIMP-1) and a higher ratio of MMP-9 to TIMP-1 in sera than healthy controls (n = 32). Serum MMP-9 concentrations were significantly higher in the diffuse type (n = 23) than the limited type of SSc (n = 19). Serum concentrations of MMP-9 correlated well with the degree of skin involvement, as determined by the Rodnan score and with serum concentrations of transforming growth factor β. Moreover, dermal fibroblasts from patients with SSc produced more MMP-9 than those from healthy controls when they were stimulated with IL-1β, tumor necrosis factor α, or transforming growth factor β. Such an increase in MMP-9 production was partially blocked by treatment with cyclosporin A. In summary, the serum MMP-9 concentrations were elevated in SSc patients and correlated well with skin scores. The increased MMP-9 concentrations may be attributable to overproduction by dermal fibroblasts in SSc. These findings suggest that the enhanced production of MMP-9 may contribute to fibrogenic remodeling during the progression of skin sclerosis in SSc

Hypolipidemic effect of Salicornia herbacea in animal model of type 2 diabetes mellitus

To control blood glucose level as close to normal is a major goal of treatment of diabetes mellitus. Hyperglycemia and hyperlipidemia are the major risk factors for cardiovascular complications, the major cause of immature death among the patients with type 2 diabetes. The purpose of this study is to determine the hypoglycemic and hypolipidemic effects of Salicornia herbacea in animal model of type 2 diabetes and to investigate the possible mechanisms for the beneficial effects of S. herbacea. S. herbacea was extracted with 70% ethanol and desalted with 100% ethanol. Three week-old db/db mice (C57BL/KsJ, n=16) were fed AIN-93G semipurified diet or diet containing 1% desalted ethanol extract of S. herbacea for 6 weeks after 1 week of adaptation. Fasting plasma glucose, triglyceride, and total cholesterol were measured by enzymatic methods and blood glycated hemoglobin (HbA1C) by the chromatographic method. Body weight and food intake of S. herbacea group were not significantly different from those of the control group. Fasting plasma glucose and blood glycated hemoglobin levels tended to be lowered by S. herbacea treatment. Consumption of S. herbacea extract significantly decreased plasma triglyceride and cholesterol levels (p<0.05). The inhibition of S. herbacea extract against yeast α-glucosidase was 31.9% of that of acarbose at the concentration of 0.5 mg/mL in vitro. The inhibitory activity of ethanol extract of S. herbacea against porcine pancreatic lipase was 59.0% of that of orlistat at the concentration of 0.25 mg/mL in vitro. Thus, these results suggest that S. herbacea could be effective in controlling hyperlipidemia by inhibition of pancreatic lipase in animal model of type 2 diabetes

Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed. Cell Rep 2015 Jul 14; 12(2):272-285

Genetic Associations of Type 2 Diabetes with Islet Amyloid Polypeptide Processing and Degrading Pathways in Asian Populations

10.1371/journal.pone.0062378PLoS ONE86

Clinical outcomes of balloon-occluded retrograde transvenous obliteration for the treatment of gastric variceal hemorrhage in Korean patients with liver cirrhosis: a retrospective multicenter study

Background/AimsThis study evaluated the clinical outcomes of balloon-occluded retrograde transvenous obliteration (BRTO) for the treatment of hemorrhage from gastric varices (GV) in Korean patients with liver cirrhosis (LC).MethodsWe retrospectively analyzed data from 183 LC patients who underwent BRTO for GV bleeding in 6 university-based hospitals between January 2001 and December 2010.ResultsOf the 183 enrolled patients, 49 patients had Child-Pugh (CP) class A LC, 105 had CP class B, and 30 had CP class C at the time of BRTO. BRTO was successfully performed in 177 patients (96.7%). Procedure-related complications (e.g., pulmonary thromboembolism and renal infarction) occurred in eight patients (4.4%). Among 151 patients who underwent follow-up examinations of GV, 79 patients (52.3%) achieved eradication of GV, and 110 patients (72.8%) exhibited marked shrinkage of the treated GV to grade 0 or I. Meanwhile, new-appearance or aggravation of esophageal varices (EV) occurred in 54 out of 136 patients who underwent follow-up endoscopy (41.2%). During the 36.0±29.2 months (mean±SD) of follow-up, 39 patients rebled (hemorrhage from GV in 7, EV in 18, nonvariceal origin in 4, and unknown in 10 patients). The estimated 3-year rebleeding-free rate was 74.8%, and multivariate analysis showed that CP class C was associated with rebleeding (odds ratio, 2.404; 95% confidence-interval, 1.013-5.704; P=0.047).ConclusionsBRTO can be performed safely and effectively for the treatment of GV bleeding. However, aggravation of EV or bleeding from EV is not uncommon after BRTO; thus, periodic endoscopy to follow-up of EV with or without prophylactic treatment might be necessary in LC patients undergoing BRTO

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of an association with T2D for PEPD5 and HNF4A6,7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks