Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Glargine Promotes Human Colorectal Cancer Cell Proliferation via Upregulation of miR-95.

Several studies have shown a correlation between glargine use and cancer risk. However, the role of glargine in carcinogenesis, especially in colorectal cancer (CRC), is still inconclusive. The aim of this study was to investigate the influence of glargine on proliferation of CRC cells and its possible mechanism. Effect of glargine on the cell proliferation was tested in HCT-116 and SW480 cells by MTT assay, and apoptosis was measured by flow cytometry. The expression of microRNA-95 (miR-95) and sorting nexin 1 (SNX1) protein was also determined by real-time PCR and Western blotting, respectively. The results showed that high dose glargine (from 150 to 300 nM) promoted proliferation and inhibit2ed apoptosis of CRC cells compared with untreated cells. Moreover, glargine could upregulate miR-95 and downregulate SNX1 protein expression in CRC cells. These data show that glargine may indeed trigger cellular proliferation in CRC, probably by regulating miR-95.

Genetic polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and risk of vitiligo in Han Chinese populations: a genotype-phenotype correlation study.

BACKGROUND: Recent evidence has revealed an elevation of total homocysteine (tHcy) in patients with vitiligo. Methylenetetrahydrofolate reductase (MTHFR) is one of the main enzymes regulating homocysteine (Hcy) metabolism. Thus, polymorphisms of MTHFR could potentially contribute to the development of vitiligo by affecting MTHFR activity and tHcy levels. OBJECTIVES: To evaluate the potential association between MTHFR polymorphisms and vitiligo susceptibility. METHODS: In total, 1000 patients with vitiligo and 1000 age- and sex-matched controls were enrolled in this hospital-based case-control study. Two single-nucleotide polymorphisms of the MTHFR gene (rs1801133 C>T and rs1801131 A>C) were selected and genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR, respectively. The MTHFR activity concentration and tHcy level in serum were measured by enzyme-linked immunosorbent assay. RESULTS: We found that allele T of rs1801133 in the MTHFR gene was associated with a significantly reduced risk of vitiligo (adjusted odds ratio 0·58, 95% confidence interval 0·43-0·76, P < 0·001). In addition, the patients with vitiligo had a lower activity concentration of MTHFR and higher level of tHcy than the controls. Correlation between these markers and the risk of vitiligo was also observed. Furthermore, the individuals with a no-risk genotype (CT + TT) of rs1801133 and higher activity concentration of MTHFR or lower level of tHcy had a significantly decreased risk of vitiligo. CONCLUSIONS: Our data suggest that MTHFR gene polymorphisms may play a vital role in genetic susceptibility to vitiligo.

Induction of apoptosis in sea bream fibroblasts by Vibrio harveyi haemolysin and evidence for an anti-apoptotic role of heat shock protein 70.

In this study, we exposed black sea bream, Mylio macrocephalus (Basilewsky), fibroblast (BSF) and silver sea bream, Sparus sarba Forsskål, fibroblast (SSF) cell lines to a recombinant Vibrio harveyi haemolysin (VHH) and investigated mechanisms involved in apoptosis. A decrease in mitochondrial membrane potential, followed by an increase in caspase 3 activity, occurred within 2-8 h of VHH exposure, in both cell lines; however, VHH did not alter cellular levels of reactive oxygen species. As heat shock protein 70 (HSP70) is known to prevent the onset of apoptosis in certain mammalian cells, we aimed to test whether such a protective effect is operative in VHH-exposed fibroblasts. The amounts of HSP70 were elevated in SSF and BSF via an acute heat shock or an acute heat shock followed by a 6 h recovery. It was found that the VHH-mediated reduction in mitochondrial membrane potential was suppressed in cells that had a 6 h post-heat shock recovery, and the protective effect of heat shock-induced HSP70 was attenuated following treatment of cells with the HSP70 inhibitor, quercetin. This study demonstrates how haemolysin causes cell death via induction of apoptosis and provides evidence as to the role of HSP70 as an anti-apoptotic factor.

Effect of polyethylene Glycol Loxenatide (long-acting GLP-1RA) on lipid, glucose levels and weight in type 2 diabetes mellitus patients with obesity.

OBJECTIVE: To explore the effect of polyethylene glycol loxenatide (long-acting GLP-1R agonist) on the lipid, glucose levels, and weight in type 2 diabetes mellitus patients with obesity. PATIENTS AND METHODS: A total of 40 obese patients with type 2 diabetes mellitus in our hospital from July 2019 to June 2020 were randomly divided into a control group and a study group. The study group was treated with metformin and polyethylene glycol loxenatide injection, while the control group was treated with metformin. RESULTS: Before treatment, there was no significant difference in FPG (Fasting Blood Glucose) and PPG (Post Prandial Glycaemia) levels between the study group and the control group (p>0.05). After a treatment period, the FPG and PPG levels in the study group were significantly lower than those in the control group (p<0.05). With the longer treatment time, the patient's weight and BMI were lower (p<0.05). The weight and BMI of patients changed the least after one month of treatment, and the weight and BMI changed the most after more than seven months of treatment. After a period of treatment, the levels of FPG and PPG in the blood of male patients in the study group were significantly lower than those of female patients (p<0.05). After treatment, the TG level of the study group was significantly lower than that of the control group (p<0.05). In comparison, the HDL-C level was significantly higher than that of the control group (p<0.05). CONCLUSIONS: Lipid and glucose levels of type 2 diabetes mellitus patients with obesity have decreased after 12 weeks of polyethylene glycol loxanatide use. The weight of type 2 diabetes mellitus patients with obesity has changed after using polyethylene glycol loxenatide for a period of treatment. Among them, there is a certain relationship between body weight and treatment time, gender, and original body weight, which is worthy of further research and promotion in clinical practice.

Comparison of component separation technique, partition technique, and extended anterolateral thigh flap in complex abdominal wall closure.

PURPOSE: This study tries to compare three methods in complex abdominal wall reconstruction. METHODS: A retrospective review was conducted at a single medical center between December 2008 and May 2019. Forty-seven patients who received abdominal fascia repair were enrolled. The patients were divided into three groups: A [component separation technique (CST)], B (partition technique), and C [extended anterolateral thigh (ALT) flap]. All relevant patient information was collected. Statistical analysis including one-way analysis of variance, Chi-square test, and the receiver operating characteristic curve were used. RESULTS: There were no significant differences between the group results related to gender, age, BMI, follow-up, diabetes mellitus, tobacco, or short-, and long-term complications. However, there were significant differences in fascia defect size between groups (group A: 7.6 cm vs. group B: 10.76 cm vs. group C: 13.64 cm). The averaged operative time in group C (339.25 mins) was significantly longer than that in group A (145.40 mins) and B (152.37 mins). The hospitalization in group C (24.1 days) was significantly longer than that in group A (8.2 days) and B (10.3 days). The complication thresholds of group A and group B are 9.45 cm and 11.75 cm, respectively. CONCLUSION: This study suggests that extended ALT flap provides the largest fascia defect closure, followed orderly by partition technique and CST, but requires longer operative time and hospitalization. There are no significant differences in postoperative complications between three groups. A prospective study with indications based on these findings is suggested.

CK19 mRNA expression in the bone marrow of patients with esophageal squamous cell carcinoma and its clinical significance.

The 5-year survival rate in resectable patients with esophageal cancer is only 20% to 36%. Regional relapse and distant metastasis are responsible for the failure of treatment and the majority of cancer-related deaths. Earlier detection of metastases, especially micrometastases, has the potential for more accurate risk stratification in subsequent therapy decisions. No effective techniques have yet been found to detect metastases in erroneously thought to have early stage disease. This study was designed to investigate the clinical significance of bone marrow micrometastases detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in patients with esophageal cancer. Expression of CK19 mRNA in the bone marrow of 61 patients with esophageal squamous cell carcinoma (ESCC) and 15 benign pulmonary and esophageal disease patients was assessed via RT-PCR. Correlation of CK19 mRNA expression to the clinicopathologic features and prognosis of the 61 patients was analyzed: 21.3% (13/61) were positive for expression of CK19 mRNA in patients with ESCC. No CK19 mRNA was detected of the 15 benign pulmonary and esophageal disease patients. CK19 mRNA expression did not correlate with the clinicopathologic features of the patients with ESCC, but patients with CK19 mRNA-positive bone marrow had earlier recurrence and shorter survival after surgery. In multivariate analysis, CK19 mRNA was found to be an independent predictor of a poor outcome. CK19 mRNA may be used as a molecular maker to detect bone marrow micrometastases in patients with ESCC and may help to select the proper therapy and predict the prognosis.

Hsa_circRNA_101036 acts as tumor-suppressor in oral squamous cell carcinoma cells via inducing endoplasmic reticulum stress.

OBJECTIVE: Endoplasmic reticulum (ER) stress has an effect on cancer cell proliferation and survival. TMTC1 has been reported to be involved in cell proliferation and inflammation, and development of ER. Hsa_circRNA_101036 is an exon circRNA formed by splicing of TMTC1 mRNA precursor. This study intends to explore the effect of hsa_circRNA_101036 on the malignant behavior of oral squamous cell carcinoma through endoplasmic reticulum stress. MATERIALS AND METHODS: We firstly evaluated the levels of Hsa_circRNA_101036 in human oral mucous fibroblasts (hOMF), and in several OSCC cell lines, including FaDu, OECM1, SAS, HSC3. Then, we studied the effects of overexpression of Hsa_circRNA_101036 on the cell proliferation, apoptosis, invasion, migration, and cytokine release in OSCC cells. Finally, we evaluated the levels of CHOP that are critical in ER and the ROS levels in OSCC cells. RESULTS: We found that compared with hOMF, a significantly lower mRNA expression of Hsa_circRNA_101036 was found in OECM1 and HSC3 cells. In OECM1 and HSC3 cells, with overexpression of Hsa_circRNA_101036, a significant decrease in cell proliferation, apoptosis, invasion, migration, and cytokine release was found. A significantly increased ROS, as well as increased protein level of CHOP, P38 and Bcl-2, was found in cells with Hsa_circRNA_101036 overexpression. CONCLUSIONS: This study indicated that Hsa_circRNA_101036 may acts as a tumor suppressor in OSCC via regulating the ER in cancer cells.

Overexpression of XIST facilitates cell proliferation, invasion and suppresses cell apoptosis by reducing radio-sensitivity of glioma cells via miR-329-3p/CREB1 axis.

OBJECTIVE: Glioma is a malignant brain cancer capable of spreading to the microenvironment. Long non-coding RNA (lncRNA) X inactive specific transcript (XIST) was recognized as a significant regulator in many cancers. However, the molecular mechanism of XIST in glioma cell radio-sensitivity requires further exploration. PATIENTS AND METHODS: The expression of XIST, microRNA (miR)-329-3p and cyclic AMP response element-binding protein 1 (CREB1) was evaluated by quantitative Real-time polymerase chain reaction (qRT-PCR). Cell viability and apoptosis were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry, respectively. Transwell assay was performed to detect cell invasion. Protein expression of gamma-H2AX (γ-H2AX) and CREB1 was determined by Western blot. The correlation between miR-329-3p and XIST or CREB1 was determined by dual-luciferase reporter assay. Animal models were established by subcutaneously injecting U251 cells transfected with sh-XIST and sh-NC. RESULTS: XIST and CREB1 were overexpressed whereas miR-329-3p was low-expressed in glioma tumors and cells compared with the normal counterparts. XIST knockdown inhibited cell proliferation, invasion and induced cell apoptosis by enhancing cell sensitivity to X-ray radiation in glioma. Then, we discovered that miR-329-3p directly interacted with XIST or CREB1 in glioma. In addition, miR-329-3p inhibitor abolished XIST silencing-induced regulatory effects on cell proliferation, apoptosis, invasion, and radio-sensitivity. Meanwhile, miR-329-3p inhibitor counteracted CREB1 silencing-induced inhibition on cell progression and facilitation on radio-sensitivity in glioma. Moreover, we found that XIST could increase CREB1 expression by sponging miR-329-3p. Animal experiments revealed that XIST silencing restrained tumor growth in vivo. CONCLUSIONS: XIST accelerates cell proliferation, invasion and inhibits cell apoptosis by repressing radio-sensitivity of glioma via enhancing CREB1 expression through sponging miR-329-3p, representing prospective methods for glioma treatment.

Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo.

BACKGROUND AND PURPOSE: The clinical use of arsenic trioxide (As(2)O(3)), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As(2)O(3). The present study was designed to evaluate the effects of resveratrol on As(2)O(3)-induced apoptosis and cardiac injury. EXPERIMENTAL APPROACH: In a mouse model of As(2)O(3)-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured. KEY RESULTS: In the mouse model, resveratrol reduced As(2)O(3)-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As(2)O(3)-treated mice; these changes were prevented by pretreatment with resveratrol. In As(2)O(3)-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As(2)O(3)-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol. CONCLUSIONS AND IMPLICATIONS: Our results showed that resveratrol significantly attenuated As(2)O(3)-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As(2)O(3). These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As(2)O(3)-exposed patients.

Intermedin1-53 protects cardiac function in rats with septic shock via inhibiting oxidative stress and cardiomyocyte apoptosis.

OBJECTIVE: To investigate the protective effect of intermedin1-53 (IMD1-53) on cardiac function in rats with septic shock and its underlying mechanism. MATERIALS AND METHODS: Twenty-four male Sprague-Dawley (SD) rats were randomly assigned into three groups, namely the control group (NC group), septic shock group (ET group) and IMD1-53 treatment group (IMD group), with 8 rats in each group. Levels of hemodynamic indicators, blood glucose, lactate acid, CK-MB (creatine kinase-MB) and cTnI (cardiac troponin I) in rats were determined. Cardiac tissues of rats were collected for TUNEL (terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling) staining. Protein levels of caspase-3, caspase-9, Bax, Bcl2, iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) in cardiac tissues were detected by Western blot. Moreover, activities of SOD (superoxide dismutase), CAT (catalase) and MDA (malondialdehyde) in myocardial homogenate were determined, thereby exploring the effect of IMD1-53 on oxidative stress and cardiomyocyte apoptosis in rats with septic shock induced by endotoxin. RESULTS: Lower levels of mean arterial blood pressure (MABP), maximum rate of left ventricular diastolic pressure (+LVdp/dtmax) and left ventricular systolic pressure (LVSP) were observed in ET group than those of NC group (p < 0.05). Levels of lactic acid, blood glucose, CK-MB and cTnI in ET group were remarkably increased than those of NC group (p < 0.05). Moreover, activities of SOD and CAT in myocardial homogenate of ET group were remarkably reduced in comparison with those of NC group (p < 0.05). Protein levels of caspase-3, caspase-9, Bcl-2, Bax, iNOS and COX-2 in ET group were all remarkably elevated than those of NC group (p < 0.05). The above indicators were all significantly improved in IMD group than those of ET group (p < 0 05). CONCLUSIONS: IMD1-53 can protect cardiac function in rats with septic shock via inhibiting oxidative stress and cardiomyocyte apoptosis.

Application of data mining to predict the dosage of vancomycin as an outcome variable in a teaching hospital population.

OBJECTIVE: Data mining is a process used to extract potentially valuable information hidden in large volumes of raw data. The aim of this study was to explore the possibility of using easy to implement and effective supervised learning techniques to predict the dosage of vancomycin. METHODS: To reach this goal, we considered the prediction of the dosage of vancomycin as a classification problem. We chose the C4.5 decision tree technique for the dosage prediction process and supplied it with a boosting technique to enhance its performance. RESULTS: The potential predictor variables were collected from 833 patients with methicillin-resistant Staphylococcus aureus, or penicillin intolerance who were being treated with vancomycin and undergoing therapeutic drug monitoring (TDM) after attainment of steady state blood concentrations. Attributes tested as potential predictors included age, sex, weight, serum creatinine concentration, dosing interval, and variables from 1-compartment model kinetics such as Kd, Vd, and t(1/2). CONCLUSIONS: The results showed that the proposed method can utilize a variety of parameters to predict the dosage of vancomycin in the population used and that it performs well over a range of patient ages and renal function. The method may offer an alternative to existing methods used to support decision-making in clinical practice.

Metastasis associated in colon cancer 1 (MACC1) promotes growth and metastasis processes of colon cancer cells.

OBJECTIVE: Colon cancer (CC) is the third most common malignancy with high mortality rate in the world. The impacts of metastasis associated in colon cancer 1 (MACC1) on growth and metastasis processes of CC were investigated by overexpression and interference lentivirus infection. MATERIALS AND METHODS: Firstly, overexpression and interference plasmids were constructed with GV115 vector and lentivirus were packaged using 293T cells. Human CC cell lines SW1116 and HCT116 were used and divided into four groups respectively, namely control group, blank group, MACC1 siRNA group (infected with interference lentivirus) and MACC1 group (infected with overexpression lentivirus). Then, cell proliferation and clone formation were examined. Besides, migration and invasion of cells were investigated by wound healing and transwell assays, respectively. Additionally, liver metastasis was evaluated in nude xenografts model. RESULTS: Overexpression and interference lentivirus of MACC1 were successfully constructed. After infected with overexpression lentivirus, cell proliferation, clone formation number, cell invasion and migration capabilities of CC cells were significantly increased (p < 0.05). Furthermore, decreased cell proliferation, smaller and fewer clones, as well as weakened cell migratory and invasive capabilities were observed in SW1116 and HCT116 cells treated with interference lentivirus of MACC1 (p < 0.05). Additionally, liver metastasis rate was higher in SW1116 cells with a higher expression level of MACC1 than that in HCT116 cells with a lower MACC1 expression level. CONCLUSIONS: MACC1 promotes the growth and metastasis processes of CC cells.

Pleuromutilin and its derivatives-the lead compounds for novel antibiotics.

Due to the rapid onset of resistance to most antibacterial drugs, research efforts are focusing on new classes of antibacterials with different mechanisms of action from clinically used antibacterials. Pleuromutilin derivatives have received more and more scientific attention for their unique mechanism of action. Two pleuromutilin derivatives, tiamulin and valnemulin have been successfully developed as antibiotics for veterinary use. Retapamulin, another pleuromutilin derivative has been approved for use in humans in April 2007 by Food and Drug Administration (FDA). It has been shown that there is rarely cross-resistance between pleuromutilin derivatives and other antimicrobial agents, and the development of resistance bacterial is still low. This review will demonstrate mechanism of action of pleuromutilin derivatives and reveal the structure-activity relationship (SAR) of pleuromutilin derivatives. Additionally, the pleuromutilin antibacterial derivative agents in the market, such as tiamulin, valnemulin and retapamulin, will be discussed. It is proposed that new antibacterial agents might be developed from pleuromutilin derivatives in the future.

A validated HPLC method for the determination of eriocalyxin B in plasma and its application to pharmacokinetic studies.

The purpose of this study was to determine EriB in plasma by using the method of HPLC and collect the preclinical pharmacokinetic parameters of EriB.The analysis involved a simple liquid-liquid extraction. After making alkaline with NaOH, plasma was extracted with diethyl ether and the organic extract was then evaporated. From there, the residue was reconstituted in to the mobile phase. Chromatographic separation was achieved on the C18 column using acetonitrile and 0.1% triethylamine as mobile phase delivered at 1.0 ml/min. The UV detector wavelength was set at 233 nm. Standard curves were linear over the concentration range of 50-2 500 ng/ml.The mean predicted concentrations of the quality control (QC) samples deviated by less than 3% from the corresponding nominal values; the intra-assay and inter-assay precision of the assay were within 10% relative standard deviation. The extraction recovery of EriB was more than 80%.The developed method has been applied to the pharmacokinetic study of EriB in rats.

Comparison of different primers for rapid detection of Vibrio parahaemolyticus using the polymerase chain reaction.

AIMS: The aim of this study was to compare different primers for rapid and effective detection of Vibrio parahaemolyticus by polymerase chain reaction (PCR). METHODS AND RESULTS: A total of four pairs of primers, three previously published and one based on a newly developed V. parahaemolyticus metalloprotease (vpm) gene, have been assayed for PCR detection of V. parahaemolyticus. They have been tested for specificity and sensitivity on a total of 101 strains including reference and environment isolates belonging to V. parahaemolyticus and other species in Vibrio. Of the four sets of primers tested, the one designed on the basis of the metalloprotease gene (675 bp) gave optimal results with bacterial strains examined as they only amplified the specific fragment in strains that had been genetically and biochemically assessed as V. parahaemolyticus and the limit of detection was 4 pg of purified target DNA. CONCLUSIONS: The primers designed on the metalloprotease gene gave optimal results for specific, sensitive and rapid detection of V. parahaemolyticus by PCR. SIGNIFICANCE AND IMPACT OF THE STUDY: PCR amplification with the optimal primer set VPM1/VPM2 could facilitate the rapid diagnosis and surveillance of potentially pathogenic strains of V. parahaemolyticus and reduce food-borne illness.