Protective effects of recombinant lactoferrin with different iron saturations on enteritis injury in young mice.

Infant intestinal development is immature and, thus, is vulnerable to bacterial and viral infections, which damage intestinal development and even induce acute enteritis. Numerous studies have investigated that lactoferrin (LF) has protective effects on the intestine and may play a role in preventing intestinal inflammation in infants. Lactoferrin is divided into 2 types, namely apo-LF and holo-LF, depending on the degree of iron saturation, which may affect its bioactivities. However, the role of LF iron saturation in protecting infant intestinal inflammation has not been clearly clarified. Therefore, in this study, young mice models with intestinal damage induced by lipopolysaccharides (LPS) in vivo and primary intestinal epithelial cells in vitro were constructed to enteritis injury in infants for investigation. The apo-LF and holo-LF were subsequently applied to the mouse models to investigate and compare their levels of protection in the intestinal inflammatory injury, as well as to identify which LF was most active. Moreover, the specific mechanism of the LF with optimal iron saturation was further investigated through Western blot assay. Results demonstrated that disease activity index, shortened length of colon tissue, and histopathological score were significantly decreased in the apo-LF group compared with those of the LPS group and the holo-LF group. In the apo-LF group, the concentration of LPS in the intestinal tract and the number of gram-negative bacteria colonies decreased significantly and the expression levels of proinflammatory factors in the colon tissue were downregulated, in comparison with those in the LPS group. The findings of this study thus verify that apo-LF can significantly alleviate enteritis injury caused by LPS, through regulating the PPAR-γ/PFKFB3/NF-κB inflammatory pathway.

[Effects of moderate dose rosuvastatin on carotid plaque in patients with diabetes mellitus evaluated by magnetic resonance imaging].

Objective: To observe the effect of lipid regulating therapy on carotid atherosclerotic plaque in diabetic patients. Methods: The REACH study, conducted between March 2009 and February 2012, enrolled asymptomatic patients with magnetic resonance imaging (MRI) confirmed carotid atherosclerotic plaque, who had never taken lipid-lowering drugs. Patients were treated with a moderate dose of rosuvastatin for 24 months. Blood lipid levels were measured and carotid MRI was performed at baseline, 3 and 24 months after treatment. The volume of carotid wall and lipid-rich necrotic core (LRNC) were measured by image analysis software. This study retrospectively analyzed patients in the REACH study. Patients were divided into diabetes group and non-diabetic group. The changes of blood lipid level and MRI parameters of carotid atherosclerotic plaque were compared between the two groups and their correlation was analyzed. Results: A total of 38 patients with carotid atherosclerotic plaque were included in this study, including 13 patients (34.2%) in the diabetic group and 25 patients (65.8%) in the non-diabetic group. Baseline parameters were comparable between the two groups, except higher HbA1c level in diabetes group (P<0.05). Compared with baseline, the total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels were significantly decreased at 3 and 24 months in both two groups (P<0.05). The change of high-density lipoprotein cholesterol (HDL-C) in diabetes group was not obvious, while it was significantly increased in non-diabetic group at 24 months ((1.38±0.33) mmol/l vs. (1.26±0.26) mmol/l, P<0.05). MRI results showed that the volume and percentage of LRNC remained unchanged at 3 months, slightly decreased at 24 months (64.86 (45.37, 134.56) mm3 vs. 75.76 (48.20, 115.64) mm3, P>0.05) and (15.84% (11.47%, 24.85%) vs. 16.95% (11.64%, 22.91%), P>0.05) in diabetic group. In non-diabetic group, the volume and percentage of LRNC were significantly decreased at 3 months (63.01 (44.25, 188.64) mm3 vs. 72.49 (51.91, 199.59) mm3, P<0.05) and (13.76% (8.81%, 27.64%) vs. 16.04% (11.18%, 27.05%), P<0.05) respectively. Both parameters further decreased to (55.63 (27.18, 179.40) mm3) and (12.71% (8.39%, 24.41%)) at 24 months (both P<0.05). Wall volume, lumen volume and percent wall volume (PWV) were not affected post therapy in both two groups(P>0.05). There were no correlations between the changes of plaque parameters including volume and percentage of LRNC, wall volume, lumen volume, PWV and the changes of blood lipid parameters (TC, LDL-C, HDL-C and TG) in 3 and 24 months (P>0.05). Conclusion: Lipid-lowering therapy possesses different effects on carotid atherosclerotic plaque in diabetic and non-diabetic patients, and the LRNC improvement is more significant in non-diabetic patients as compared to diabetic patients.

Effects of riboflavin supplementation on performance, nutrient digestion, rumen microbiota composition and activities of Holstein bulls.

To investigate the influences of dietary riboflavin (RF) addition on nutrient digestion and rumen fermentation, eight rumen cannulated Holstein bulls were randomly allocated into four treatments in a repeated 4 × 4 Latin square design. Daily addition level of RF for each bull in control, low RF, medium RF and high RF was 0, 300, 600 and 900 mg, respectively. Increasing the addition level of RF, DM intake was not affected, average daily gain tended to be increased linearly and feed conversion ratio decreased linearly. Total tract digestibilities of DM, organic matter, crude protein (CP) and neutral-detergent fibre (NDF) increased linearly. Rumen pH decreased quadratically, and total volatile fatty acids (VFA) increased quadratically. Acetate molar percentage and acetate:propionate ratio increased linearly, but propionate molar percentage and ammonia-N content decreased linearly. Rumen effective degradability of DM increased linearly, NDF increased quadratically but CP was unaltered. Activity of cellulase and populations of total bacteria, protozoa, fungi, dominant cellulolytic bacteria, Prevotella ruminicola and Ruminobacter amylophilus increased linearly. Linear increase was observed for urinary total purine derivatives excretion. The data suggested that dietary RF addition was essential for rumen microbial growth, and no further increase in performance and rumen total VFA concentration was observed when increasing RF level from 600 to 900 mg/d in dairy bulls.

MRI findings for diagnosis of postoperative foreign body granulomas versus recurrent tumours in patients of brain tumour surgery.

AIM: To evaluate the postoperative magnetic resonance imaging (MRI) findings of intracranial foreign body granulomas (FBGs) and true recurrent tumours (RTs) and thus lead to a basis for management decision-making. MATERIALS AND METHODS: Twenty-two patients with previous brain tumour surgery were diagnosed clinically with RT and underwent surgery. Re-operative pathology revealed FBG in eight patients and RT in 14 patients. MRI findings before the initial operation were compared to those before the re-operation. RESULTS: Features of FBGs versus RTs on MRI were as follows: (1) mean lesion size: 1.3 ± 0.7 (0.5-2.6) versus 3.2 ± 1.7 (1.1-6.3) cm (p=0.001, odds ratio [OR] = 4.18); (2) hypointensity on T2-weighted imaging (WI): 6/8 (75%) versus 0/14 (0%; p<0.001, OR=75.4); (3) non-restricted diffusion on diffusion-WI (DWI): 6/8 (75%) versus 2/14 (14.3%; p=0.008, OR=18); and (4) "ring and bubble" appearance on contrast-enhanced T1WI: 7/8 (87.5%) versus 2/14 (14.3%; p=0.001, OR=42). In comparison with their original tumours, the FBGs in the FBG group showed significantly lower T2 signal intensity, lower signal on DWI, and more cases of non-restricted diffusion on DWI (p=0.04, 0.04, 0.04, respectively). CONCLUSION: On brain MRI, FBGs can be differentiated from RTs by their relatively smaller size, hypointensity on T2WI, lack of restricted diffusion on DWI, and "ring and bubble" appearance on contrast-enhanced T1WI. Comparing the MRI findings of the focal lesion in the tumour bed with those of the original tumour is suggested to enhance diagnostic confidence.

Inhibitory effects of lactoferrin on pulmonary inflammatory processes induced by lipopolysaccharide by modulating the TLR4-related pathway.

This study tested the ability of lactoferrin to modulate pulmonary inflammation. To construct in vitro and in vivo inflammatory lung models, cells from the human lung adenocarcinoma cell line (A549) were exposed to lipopolysaccharide (LPS, 1 µg/mL), and mice (CD-1) were intratracheally administered LPS [10 mg/kg of body weight (BW), tracheal lumen injection], respectively. The A549 cells were preincubated with lactoferrin (10 mg/mL), and the mice were intraperitoneally injected with lactoferrin (100 mg/kg of BW), followed by LPS treatment. The concentrations of proinflammatory cytokines (IL-1ß and TNF-α) in culture medium of A549 cells and in bronchoalveolar lavage fluid of the mice were determined using enzyme-linked immunosorbent assays. The toll-like receptor 4-related pathway (TLR4/MyD88/IRAK1/TRAF6/NFκB) was determined at gene and protein expression levels in A549 cells and mouse lung tissue. Results showed that LPS treatment significantly elevated the concentrations of IL-1ß and TNF-α in the A549 cell culture medium and in bronchoalveolar lavage fluid of the mice; it also elevated both the mRNA and protein expressions of TLR4 and the TLR4 downstream factors in A549 cells and mouse lung tissue. Nevertheless, lactoferrin apparently depressed the releases of IL-1ß and TNF-α from A549 cells and lung tissues stimulated by LPS, and significantly suppressed the TLR4 signaling pathway. Lactoferrin also promoted the enhancement of miR-146a expression in A549 cells and mouse lung tissue. Moreover, 100°C heating for 3 min caused total loss of the previously listed bioactivity of lactoferrin. Collectively, we proved that lactoferrin intervened in LPS-induced inflammation in the pulmonary cell model and in the mouse model, through inhibiting the TLR4-related pathway.

[Lymphoplasmacytic lymphoma: a clinicopathological and prognostic analysis of 27 cases].

Objective: To study the clinical manifestations, pathologic features, diagnosis and differential diagnosis, treatment and prognosis of lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Methods: Twenty-seven cases of LPL from January 2016 to December 2020 at Guangdong Provincial People's Hospital were collected. The clinical data, histomorphology, immunophenotype, MYD88 L265P mutation, treatment and prognosis were analyzed retrospectively. Results: There were 19 males and 8 female patients, with median age of 63 years. The most common initial symptoms were fatigue related to anemia. Bone marrow was involved in all cases, lymphadenopathy was seen in 11 cases and splenomegaly in 10 cases. Monoclonal IgM type protein was detected in 25 cases, meeting the diagnostic criteria of WM. Microscopically, bone marrow and lymph nodes were infiltrated by small lymphocytes, plasmacytoid lymphocytes or plasma cells. The cells expressed pan B-cell markers and showed immunoglobulin light chain restriction. There was no expression of CD5, and low expression of CD23 and CD10; Ki-67 index was usually low. The positive rate of MYD88 L265P mutation was 73.9% (17/23). Most of the patients were treated with rituximab combined with alkylating agents, nucleoside analogues or immunomodulators, and the few patients with relapse or progression were treated with Ibutinib. During the 3-168 months' follow-up period, recurrence or progression were seen in nine cases. Thrombocytopenia, elevated ß2-microglobulin and high-risk group were associated with recurrence or progression of the disease (P<0.05). The overall survival (OS) and progression-free survival (PFS) of the high-risk patients were significantly lower than those of the low-medium risk patients (P<0.05). Conclusions: LPL/WM is an exclusive diagnosis; the detection of MYD88 L265P mutation has high diagnostic value, but it is not specific. These cases should be assessed comprehensively for their clinical manifestation, serum IgM protein level and immunophenotype. The overall prognosis of LPL/WM is good, but there are still a small number of high-risk patients with rapid progress, and so the symptomatic patients should be diagnosed accurately and treated in a timely manner.

[Clinicopathological features of autoimmune gastritis].

Objective: To study the clinicopathological characteristics and pathologic diagnosis of autoimmune gastritis. Methods: Fourteen biopsies of autoimmune gastritis were collected from January 2018 to March 2019 at Guangdong Provincial People's Hospital. Their clinical data, histological features and immunohistochemical (IHC) results were analyzed, with review of relevant literature. Results: All 14 patients' ages ranged from 41 to 79 years (mean 55 years). There were 12 females and 2 males. All patients had non-specific symptoms, but they all had positive serum anti-parietal cell antibody and/or anti-intrinsic factor antibody. Seven patients had variable degree of anemia. Two patients had concomitant H. pylori infection. Two patients presented with multiple protruding polyps in corpus/fundus, 0.2 to 0.9 cm in diameter, or multiple large lobulated and broad based polyps (0.8 to 3.5 cm in diameters). The former cases were diagnosed as type 1 neuroendocrine tumors, the latter were multiple hyperplastic polyps. Microscopically, autoimmune gastritis showed typical morphology, characterized by diffuse corpus-restricted atrophic gastritis with variable proportions of intestinal metaplasia, or pseudopyloric metaplasia, pancreatic, acinar metaplasia, foveolar hyperplasia and hyperplasia of the endocrine-like cells (ECL cells). Hyperplasia of ECL cells often needed IHC staining to confirm. CgA/Syn IHC stain highlighted linear and micronodular ECL cell hyperplasia. In the absence of concurrent or past H. pylori infection, the antrum was usually normal. Gastrin IHC stain showed hyperplasia of gastrin-producing cells (G cells) in the antrum. Two cases were in the early phase, six were in florid phase, and six were end phase. Conclusions: Most patients of autoimmune gastritis have non-specific symptoms or are asymptomatic and show various endoscopic findings. There are three histologic phases of autoimmune gastritis. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis. Pathologists can make preferred diagnosis of autoimmune gastritis depending on the histologic clues and prompt appropriate and timely management for the patients.

Kisspeptin regulation of human decidual stromal cells motility via FAK-Src intracellular tyrosine kinases.

STUDY QUESTION: Can of Clinical Genetics, Maastricht University Medical Centre, Maastricht kisspeptin and its analogues regulate the motility of human decidual stromal cells and what intracellular signaling pathways are involved? SUMMARY ANSWER: Kisspeptin analogue-mediated cell motility in human decidual stromal cells via the focal adhesion kinase (FAK)-steroid receptor coactivator (Src) pathway suggesting that kisspeptin may modulate embryo implantation and decidual programming in human pregnancy. WHAT IS KNOWN ALREADY: The extravillous trophoblast invades the maternal decidua during embryo implantation and placentation. The motile behavior and invasive potential of decidual stromal cells regulate embryo implantation and programming of human pregnancy. STUDY DESIGN, SIZE, DURATION: Human decidual stromal cells were isolated from healthy women undergoing elective termination of a normal pregnancy at 6- to 12-week gestation, after informed consent. PARTICIPANTS/MATERIALS, SETTING, METHODS: Kisspeptin analogues were synthetic peptides. Cell motility was estimated by an invasion and migration assay. Immunoblot analysis was performed to investigate the expression of kisspeptin receptor and the effects of kisspeptin analogues on the phosphorylation of FAK and Src. Small interfering RNAs (siRNAs) were used to knock down the expression of kisspeptin receptor, FAK, Src, matrix metallo-proteinases (MMPs) 2 and 9, and extracellular signal-regulated protein kinase (ERK) 1/2. MAIN RESULTS AND THE ROLE OF CHANCE: The kisspeptin receptor was expressed in human decidual stromal cells. Kisspeptin agonist decreased, but antagonist increased, cell motility. Kisspeptin agonist decreased the phosphorylation of FAK and Src tyrosine kinases, whereas antagonist increased it. These effects on phosphorylation were abolished by kisspeptin receptor siRNA. The activation of cell motility by kisspeptin analogues was suppressed by siRNA knockdown of endogenous FAK (decreased 66%), Src (decreased 60%), kisspeptin receptor (decreased 26%), MMP-2 (decreased 36%), MMP-9 (decreased 23%), and ERK 1/2 inhibitor (decreased 27%). LIMITATIONS, REASONS FOR CAUTION: Human decidual stromal cells were obtained from women having terminations after 6-12 weeks of pregnancy and differences in timing could affect their properties. WIDER IMPLICATIONS OF THE FINDINGS: Kisspeptin acting within the endometrium has a potential modulatory role on embryo implantation and decidual programming of human pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grant NSC-104-2314-B-182A-146-MY2 (to H.-M.W.) from the Ministry of Science and Technology, Taiwan, and grants CMRPG3E0401 and CMRPG3E0402 (to H.-M.W.). This work was also supported by grants from the Canadian Institutes of Health Research to P.C.K.L. P.C.K.L. is the recipient of a Child & Family Research Institute Distinguished Investigator Award. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

A genome-wide association study for extremely high intelligence.

We used a case-control genome-wide association (GWA) design with cases consisting of 1238 individuals from the top 0.0003 (~170 mean IQ) of the population distribution of intelligence and 8172 unselected population-based controls. The single-nucleotide polymorphism heritability for the extreme IQ trait was 0.33 (0.02), which is the highest so far for a cognitive phenotype, and significant genome-wide genetic correlations of 0.78 were observed with educational attainment and 0.86 with population IQ. Three variants in locus ADAM12 achieved genome-wide significance, although they did not replicate with published GWA analyses of normal-range IQ or educational attainment. A genome-wide polygenic score constructed from the GWA results accounted for 1.6% of the variance of intelligence in the normal range in an unselected sample of 3414 individuals, which is comparable to the variance explained by GWA studies of intelligence with substantially larger sample sizes. The gene family plexins, members of which are mutated in several monogenic neurodevelopmental disorders, was significantly enriched for associations with high IQ. This study shows the utility of extreme trait selection for genetic study of intelligence and suggests that extremely high intelligence is continuous genetically with normal-range intelligence in the population.

[Value of ceramide in the diagnosis and risk prediction of coronary artery disease].

Objective: To evaluate the clinical values of 4 types of ceramides (Cer1, Cer2, Cer3, Cer4) in the coronary artery stenosis, clinical diagnosis and risk prediction. Methods: A total of 890 patients with coronary heart disease (CHD) in Beijing Anzhen Hospital between March 2018 and August 2018 were enrolled. The relationships between different degrees of coronary artery stenosis and ceramide levels was investigated. Diagnostic value of ceramides on acute myocardial infarction was analyzed. Meanwhile, Major adverse cardiac and cerebrovascular events (MACCE) in 1 year after discharging were collected to evaluate the predictive value of ceramides on risk of CHD and stroke. Results: This study showed that there were no significant differences of ceramide levels in CHD patients with different degrees of coronary artery stenosis (P>0.05), and the area under receiver operating characteristic (ROC) curve in the diagnosis of acute myocardial infarction patients was 0.725. Conclusions: Ceramide is proved to be helpful in the diagnosis of acute myocardial infarction and MACCE prediction. The relationships between ceramide and degrees of coronary artery stenosis as well as the prognosis of CHD need further elucidation.

[Clinical and pathological characteristics of cardiac tumors: analyses of 689 cases at a single medical center].

Objective: To study the clinicopathological characteristics of cardiac neoplasms. Methods: A total of 689 cases of cardiac neoplasms from January 1st 1992 to December 31th 2017 at Guangdong Provincial People's Hospital were collected. The clinical data and histologic features were analyzed along with a review of literature. The pathological diagnosis and classification were based on the criteria of WHO 4th edition(2015). Results: Among 689 cases of cardiac neoplasms, 259 were male and 430 were female patients, with age from 0 to 84 years (mean of 48 years). The peak incidence was between the fourth and sixth decade. Among patients younger than 20 years, there were 24 males and 12 females. 674 cases(674/689,97.8%)were primary cardiac tumors and 15 cases were secondary tumors (15/689,2.2%). Amongst the primary cardiac neoplasms, 625 cases were benign(625/674,92.7%), 7 cases were borderline (7/674, 1.0%), and 42 cases were malignant (42/674, 6.2%). The incidences of benign, borderline and malignancy heart tumors among patients below 20 years old were lower than those of patients over 20 years of age (4.8% vs. 95.2%; 3/9 vs. 6/9; 5.5% vs. 94.5%, respectively). Of the benign tumors, 406 cases were female and 219 cases were male. More male than female patients were seen in borderline and malignancy cardiac tumor categories (6∶3; 34∶21). Of 625 benign tumors, 577 cases were myxoma(85.6%), which mainly occurred in patients over 20 years of age(85.9% vs. 14.1%) with a female predominance. Non-myxomas mainly occurred in children and adolescent patients compared to adult (55.6% vs. 44.4%, P<0.01) with a male predominance. Overall, 524 tumors originated from the left atrium, 84 cases from the right atrium, 26 cases from the pericardium, 23 cases from the right ventricular, and 11 cases from the left ventricle. However, 21 cases were multicentric or involving cardiac valves. Benign tumors mainly involved left heart(76.3%) vs. right heart(81/625, 12.6%). The mostly common location of borderline tumors was right heart(5/9). Malignant tumors tended to involve the right heart(22/55,40.0%) and pericardium(18/55, 32.7%). Conclusions: Although the incidence of cardiac neoplasms is low,various tumor types can occur, most of which are myxoma with a female predominance. Non-myxomas mainly occur in children and adolescents with a male predominance.

Long-term shunt patency and overall survival of transjugular intrahepatic portosystemic shunt placement using covered stents with bare stents versus covered stents alone.

AIM: To investigate the long-term shunt patency and overall survival of transjugular intrahepatic portosystemic shunt (TIPS) placement using covered stents with or without bare stents over a follow-up period up to 7 years. MATERIALS AND METHODS: A total of 154 patients undergoing TIPS placement were enrolled and analysed retrospectively. They were divided into two groups: those undergoing TIPS placement using covered with bare stents (group A, n=42) and those without bare stents (group B, n=112). RESULTS: The cumulative 5-year primary patency rate was significantly lower in group A than in group B (group A: 0% versus group B: 66.7%; p<0.001). The cumulative 5-year overall survival rates were comparable between the two groups (group A: 76% versus group B: 58.7%; p=0.214). The baseline portal vein thrombosis (hazard ratio [HR]:4.610; 95% confidence interval [CI]:2.691-7.897; p=0.000), portal pressure decrement (HR: 0.911; 95% CI: 0.845-0.982; p=0.015), and group (HR: 0.419; 95% CI: 0.239-0.736; p=0.002) were independent predictors for shunt dysfunction, while hepatocellular carcinoma (HR: 6.615; 95% CI: 2.863-15.283; p=0.000) and ascites (HR: 2.166; 95% CI: 1.298-3.615; p=0.003) were independent predictors for mortality. CONCLUSIONS: Although TIPS placement using covered with bare stents led to lowered long-term shunt patency than using covered stents alone, the overall survival rates were similar.

[Expression of ßF1 and T cell receptor γ in T lymphoblastic lymphoma/leukemia].

Objective: To evaluate the expression of ßF1 and T cell receptor (TCR)γ in T lymphoblastic lymphoma/leukemia(T-LBL/ALL), and investigate the clinicopathological features. Methods: Fifty-one cases of T-LBL/ALL were collected at Guangdong General Hospital from 2010 to 2016, the expression of ßF1 and TCRγ was assessed by immunohistochemistry. Results: There were 13 cases of children and adolescents, and 38 cases of adults. The expression rates of ßF1 and TCRγ were 27.5%(14/51) and 15.7%(8/51) respectively. The proportion of adults in αß T-LBL/ALL, TCR-silent T-LBL/ALL and γδ T-LBL/ALL was 7/14, 79.3%(23/29)and 8/8 respectively, and the difference was significant (P=0.023). There was no statistical difference in sex, LDH, bone marrow involvement and Ann arbor stage among these three groups(P>0.05). γδ T-LBL/ALLs included 6 cases of CD4(-)/CD8(-) phenotype, whereas αß T-LBL/ALL included 7 cases of CD4(+) /CD8(+) phenotype. There was significant difference in CD4/CD8 expression among these three groups(P<0.01). Conclusions: γδ T-LBL/ALL occurred only in adults, with predominantly CD4(-)/CD8(-) phenotype. αß T-LBL/ALL occurred more common in children and adolescents, with predominantly CD4(+) /CD8(+) phenotype.

[Clinicopathologic features of myxoid adrenocortical adenomas].

Objective: To study the clinicopathologic characteristics, immunophenotype, pathologic diagnosis and differential diagnosis of myxoid adrenocortical adenomas. Methods: The clinical data, histological features and immunohistochemical results of 4 cases of myxoid adrenocortical adenomas were analyzed, which were collected from January 2014 to December 2016 at Guangdong General Hospital, with review of literature. Results: Four cases of myxoid adrenocortical adenomas were presented. The patients ages ranged from 26 to 45 years (mean =35 years). Microscopically, it showed a typical morphology, characterized by small-sized tumor cell cords or pseudo-glands embedded in an abundant extracellular myxoid matrix. Immunohistochemical staining showed tumor cells were strongly positive for Melan A, vimentin and focally for α-inhibin, one case showed strong and diffuse positivity for CAM5.2, and two cases showed diffuse positivity for synaptophysin, while negative for CgA, S-100 protein, epithelial antigen, CK7, CK20 and CKpan. Conclusions: Myxoid adrenocortical adenomas are extremely rare, which may cause confusion with metastatic well-differentiated neuroendocrine tumours, sex cord-stromal tumoursor metanephric adenoma. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis, and unnecessary treatment.

[HER2 status in gastric adenocarcinoma of Chinese: a multicenter study of 40 842 patients].

Objective: To investigation HER2 status in gastric adenocarcinoma of Chinese and contributing factors to the HER2 expression. Methods: HER2 status of 40 842 gastric adenocarcinomas and clinical data were retrospectively collected from 23 hospitals dated from 2013 to 2016. The association between HER2 positivity and clinicopathologic features was analyzed. Results: Of the 40 842 patients the median age was 62 years, the male female ratio was 2.6∶1.0. The rate of HER2 positivity was 8.8% (3 577/40 842). HER2 expression was related to the tissue type, tumor location, Lauren classification and tumor differentiation (P values: 0.009, 0.001, <0.01 and <0.01, respectively). Different HER2 expression status was observed between primary and recurrent tumors in 7.6% (48/635) cases. The rates of HER2 positivity ranged from 2% to 10% among different institutions. The rates of HER2 FISH amplification were dramatically different among the 23 hospitals (0-100%) with an average rate of 10% (810/8 156) in patients with HER2 IHC 2+ . Conclusions: HER2 expression is associated with clinicopathologic characteristics. HER2 re-assessment of tumor tissue and use of in situ hybridization techniques increase HER2 positivity. The current retrospective study should reflect the HER2 status in gastric adenocarcinoma of Chinese patients.

[Effect of lipid-induced macrophage M1/M2 polarization on lipid metabolism in hepatocytes].

Objective: This study aims to explore the effect of lipid-induced macrophage M1/M2 polarization on lipid metabolism in hepatocytes. Methods: RAW264.7 macrophages were incubated with different kinds of fatty acids including saturated fatty acids-palmitic acid (PA), monounsaturated fatty acids-oleic acid (OA) and polyunsaturated fatty acids-docosahexaenoic acid (DHA), and cell culture supernatants were collected to prepare conditioned medium (CM). Hepatocytes were isolated by in situ perfusion of the liver with collagenase in mice, and a macrophage-hepatocyte CM co-culture system was established. Macrophage M1/M2 phenotype markers were detected by Real-time PCR. Lipid synthesis and decomposition related mRNA and protein expressions in hepatocytes were detected by Real-time PCR and Western Blot. Lipid depositions in hepatocytes were detected by oil red O staining. An analysis of variance was used for comparison of means between multiple groups. Results: Compared with control groups, PA polarized macrophages to a M1 phenotype (expression of TNF-α and IL-6 significantly increased, F≥22.68, P < 0.01), OA polarized macrophages to a M1/M2 mixed phenotype (expression of IL-6, Mrc2 and IL-10 increased F≥4.94, P < 0.05) and DHA polarized macrophages to a M2 phenotype (expression of Mrc2 and IL-10 significantly increased, F≥4.94, P < 0.01). CM-PA significantly increased lipid synthesis related genes, including SREBP1C, ACC1 mRNA expression (F≥5.66, P < 0.01) and FASN, ACC1 protein expression (F≥38.34, P < 0.05) in hepatocytes, and decreased lipid decomposition gene ACOX1 protein expression (F=154.48, P < 0.01). CM-OA affected several lipid metabolism genes expression. CM-DHA significantly increased CPT1A mRNA expression (F = 10.30, P < 0.01) and ACOX1, CPT1A protein expression (F≥47.06, P < 0.05), and decreased SREBP1C, ACC1 protein expression (F≥65.84, P < 0.05) in hepatocytes. Massive lipid droplets were deposited in hepatocytes in CM-PA treated hepatocytes, and a few amount of lipid droplets were deposited in CM-DHA treated hepatocytes. Conclusion: Different fatty acids affect the balance of lipid metabolism in hepatocytes and liver by inducing macrophage M1 / M2 polarization, thus promoting or delaying the progression of non-alcoholic fatty liver disease.

The CHRM3 gene is implicated in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia.

BACKGROUND: The genetic influences in human brain structure and function and impaired functional connectivities are the hallmarks of the schizophrenic brain. To explore how common genetic variants affect the connectivities in schizophrenia, we applied genome-wide association studies assaying the abnormal neural connectivities in schizophrenia as quantitative traits. METHOD: We recruited 161 first-onset and treatment-naive patients with schizophrenia and 150 healthy controls. All the participants underwent scanning with a 3 T-magnetic resonance imaging scanner to acquire structural and functional imaging data and genotyping using the HumanOmniZhongHua-8 BeadChip. The brain-wide association study approach was employed to account for the inherent modular nature of brain connectivities. RESULTS: We found differences in four abnormal functional connectivities [left rectus to left thalamus (REC.L-THA.L), left rectus to right thalamus (REC.L-THA.R), left superior orbital cortex to left thalamus (ORBsup.L-THA.L) and left superior orbital cortex to right thalamus (ORBsup.L-THA.R)] between the two groups. Univariate single nucleotide polymorphism (SNP)-based association revealed that the SNP rs6800381, located nearest to the CHRM3 (cholinergic receptor, muscarinic 3) gene, reached genomic significance (p = 1.768 × 10-8) using REC.L-THA.R as the phenotype. Multivariate gene-based association revealed that the FAM12A (family with sequence similarity 12, member A) gene nearly reached genomic significance (nominal p = 2.22 × 10-6, corrected p = 0.05). CONCLUSIONS: Overall, we identified the first evidence that the CHRM3 gene plays a role in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia. Identification of these genetic variants using neuroimaging genetics provides insights into the causes of variability in human brain development, and may help us determine the mechanisms of dysfunction in schizophrenia.

Elevated serum complement C3 levels are related to the development of prediabetes in an adult population: the Tianjin Chronic Low-Grade Systematic Inflammation and Health Cohort Study.

AIMS: To investigate whether serum complement C3 is related to the prevalence and incidence of prediabetes in an adult population. METHODS: A cross-sectional (n = 10 206) and prospective cohort study (n = 3333), with a mean (range; 95% CI) follow-up of 2.63 (1-6; 2.58-2.68) years, was conducted in people recruited from the Health Management Centre of Tianjin Medical University General Hospital in Tianjin, China. Measurement of serum C3 concentration, blood fasting glucose, oral glucose tolerance, HbA1c and other potential confounding factors was performed at baseline and each year during the follow-up. Prediabetes was defined according to the criteria of the American Diabetes Association. Adjusted logistic and Cox proportional hazards regression models were used to assess the relationships between C3 quintiles and prediabetes. RESULTS: The prevalence and incidence of prediabetes were 38.5% and 119 per 1000 person-years, respectively. In cross-sectional analysis, after adjustment for potential confounders, the odds ratios of prediabetes for increasing quintiles of C3 were 1.00 (reference), 1.32 (95% CI 1.14-1.53), 1.37 (95% CI 1.18-1.59), 1.75 (95% CI 1.51-2.03), 2.25 (95% CI 1.93-2.62; P for trend < 0.0001). In the cohort analysis, the multiple-adjusted hazard ratio of prediabetes in the highest quintile of baseline C3 was 1.43 (95% CI 1.15, 1.78; P for trend < 0.001), when compared with the lowest quintile. CONCLUSIONS: These findings indicate that elevated serum C3 levels are significantly related to an increased risk of developing prediabetes in an adult population, suggesting that C3 can be used as a biomarker in high-risk individuals to improve primary prevention of prediabetes and diabetes.

A dynamic model for the outbreaks of hand, foot, and mouth disease in Taiwan.

The first large outbreak of hand, foot, and mouth disease (HFMD) with severe complications primarily caused by enterovirus 71 was reported in Taiwan in 1998. Surveillance of HFMD to evaluate the spread of HFMD with and without infection control policy is needed. We developed a new dynamic epidemic Susceptible-Infected-Recovered (SIR) model to fit the surveillance data on containing valuable information on the severity of HFMD in order to accurately estimate the basic reproductive number (R 0) of HFMD. After fitting the empirical data, in conjunction with other relevant parameters extracted from the literature, the estimated transmission coefficients were close to 5 × 10-7 (per day) and the proportion of severe HFMD cases ranged between 0 and 0·0036 (per day). Taking into account the distribution of all parameters considered in our dynamic epidemic model, the R 0 computed was 1·37 (95% confidence interval 0·24-5·84), suggesting a higher likelihood of the spread of HFMD if no infection control policy is provided. The isolation strategy against the spread of HFMD not only delayed the epidemic peak with the delayed time ranging from 4 weeks for only 20% isolation to 47 weeks for 100% isolation but also reduced total number of HFMD cases with the percentage of reduction ranging from 1·3% for only 20% isolation to 13·3% for 100% isolation. The proposed model can also be flexible for evaluating the effectiveness of two other possible policies for containing HFMD, quarantine and vaccination (if the vaccine can be developed).

[Effect of Toll-like receptor 2 on the inhibition role of sevoflurane on airway inflammation in asthmatic mice].

OBJECTIVE: To investigate the effect of Toll-like receptor 2 (TLR2) on the inhibition role of sevoflurane on airway inflammation in asthmatic mice. METHODS: The lung tissue samples of C(57) BL/6 mice used in this study were from previous research, including control group, asthma group and sevoflurane group, 8 samples in each group. Twenty-four specific pathogen free female TLR2 gene deletion (TLR2(-/-)) mice were randomly assigned to control group, asthma group and sevoflurane group, with 8 mice in each group. Asthma group and sevoflurane group were then sensitized and challenged with ovalbumin (OVA) to establish asthma model, combined with repeated inhalation of 3% sevoflurane in sevoflurane group. In C(57) mice, expression levels of TLR2 were detected using Western blotting analyses. In TLR2(-/-) mice, numbers of differential inflammatory cells were investigated; levels of tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay (ELISA); lung tissue inflammation was detected with HE staining. RESULTS: In lung tissues from C(57) mice, levels of protein expression of TLR2 in asthma group (0.547±0.042) were higher than those in control group (0.312±0.023) (P=0.023) and sevoflurane group (0.287±0.033) (P=0.020). In TLR2(-/-) mice, the number of total cells ((83.13±19.43)×10(3)/ml), numbers of differential inflammatory cells and TNF-α level ((546±16) pg/ml) in BALF in sevoflurane group were lower than those in asthma group ((206.43±41.82)×10(3)/ml, (732±41) pg/ml), but still higher than those in control group ((44.64±7.17)×10(3)/ml, (380±24) pg/ml) (all P<0.05); lung tissue inflammation was inhibited in sevoflurane group than in asthma group, but still more obvious than that in control group. CONCLUSION: Toll like receptor 2 involved in the anti-inflammatory effect of sevoflurane on asthmatic airway inflammation in mice.