Image-based modeling of hemodynamics in coronary artery aneurysms caused by Kawasaki disease

Kawasaki Disease (KD) is the leading cause of acquired pediatric heart disease. A subset of KD patients develops aneurysms in the coronary arteries, leading to increased risk of thrombosis and myocardial infarction. Currently, there are limited clinical data to guide the management of these patients, and the hemodynamic effects of these aneurysms are unknown. We applied patient-specific modeling to systematically quantify hemodynamics and wall shear stress in coronary arteries with aneurysms caused by KD. We modeled the hemodynamics in the aneurysms using anatomic data obtained by multi-detector computed tomography (CT) in a 10-year-old male subject who suffered KD at age 3?years. The altered hemodynamics were compared to that of a reconstructed normal coronary anatomy using our subject as the model. Computer simulations using a robust finite element framework were used to quantify time-varying shear stresses and particle trajectories in the coronary arteries. We accounted for the cardiac contractility and the microcirculation using physiologic downstream boundary conditions. The presence of aneurysms in the proximal coronary artery leads to flow recirculation, reduced wall shear stress within the aneurysm, and high wall shear stress gradients at the neck of the aneurysm. The wall shear stress in the KD subject (2.95-3.81 dynes/sq cm) was an order of magnitude lower than the normal control model (17.10-27.15 dynes/sq cm). Particle residence times were significantly higher, taking 5 cardiac cycles to fully clear from the aneurysmal regions in the KD subject compared to only 1.3 cardiac cycles from the corresponding regions of the normal model. In this novel quantitative study of hemodynamics in coronary aneurysms caused by KD, we documented markedly abnormal flow patterns that are associated with increased risk of thrombosis. This methodology has the potential to provide further insights into the effects of aneurysms in KD and to help risk stratify patients for appropriate medical and surgical interventions.     

Meta-analysis of the relationship between single nucleotide polymorphism rs72689236 of caspase-3 and Kawasaki disease

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology, for which a genetic influence is suspected. But whether single nucleotide polymorphism (SNP) of caspase-3 rs72689236 is associated with Kawasaki disease is controversial. The aim of our study is to assess the association between the SNP of caspase-3 and risk for Kawasaki disease. We searched PubMed, MEDLINE, EMBASE, Springer, Elsevier Science Direct, Cochrane Library Google scholar, CNKI (China National Knowledge Infrastructure, in Chinese) and Wanfang database (in Chinese) to identify studies investigating the association between rs72689236 polymorphism and Kawasaki disease occurrence. There were five eligible studies, which included 4,241 (case group 1,560; control group 2,681) participants in this meta-analysis. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated in a fixed-effects model (the Mantel–Haenszel method) or a random-effects model (the DerSimonian and Laird method) when appropriate. Significant associations were found under the overall ORs for A-allele comparison (A vs. G, pooled OR 1.33, 95 % CI 1.21–1.46), AA versus GG comparison (pooled OR 1.64, 95 % CI 1.35–2.00), GA versus GG comparison (pooled OR 1.42, 95 % CI 1.24–1.63), recessive model (AA vs. GG + GA, pooled OR 1.37, 95 % CI 1.15–1.64) and dominant model (AA + GA vs. GG, pooled OR 1.47, 95 % CI 1.29–1.67). This meta-analysis suggested that SNP rs72689236 of caspase-3 might be associated with susceptibility of Kawasaki disease and the allele A might increase the risk of Kawasaki disease in Asian samples such as Japanese and Chinese. In addition, individual studies with large sample size are needed to further evaluate the associations in various ethnic populations.     

A functional polymorphism,rs28493229, in <Emphasis Type="Italic">ITPKC</Emphasis> and risk of Kawasaki disease: an integrated meta-analysis

Kawasaki disease (KD) is a multi-systemic vasculitis which preferentially affects infants and children. A single nucleotide polymorphism (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) was identified to be associated with the increased risk of KD; however, in more recent studies associations have been controversial. Thus, we performed a meta-analysis, integrating case–control and transmission/disequilibrium test (TDT) studies, to investigate the relationship between this polymorphism and risk of KD. A total of ten case–control and two TDT studies, comprising 3,821 cases, 12,802 controls and 949 families, were included in this meta-analysis. There was a significant association between the C allele of rs28493229 and the increased risk of KD (OR = 1.53, 95 % CI = 1.34?1.74, P < 0.001), by the random-effects model because of heterogeneity (Q = 27.67, P _{heterogeneity} = 0.004). Nevertheless, it was screened out by meta-regression analysis that the coronary artery lesions (CALs) status of KD could partly explain the heterogeneity, with consistently significant associations in both subgroups after stratification by CALs status. Moreover, estimates before and after the deletion of each study were similar in sensitivity analysis, indicating robust stability of the meta-analysis. This meta-analysis reveals that the functional polymorphism rs28493229 in ITPKC significantly contributes to the risk of KD.     

Influence of morphology and hemodynamic factors on rupture of multiple intracranial aneurysms: matched-pairs of ruptured-unruptured aneurysms located unilaterally on the anterior circulation

Background

The authors evaluated the impact of morphological and hemodynamic factors on the rupture of matched-pairs of ruptured-unruptured intracranial aneurysms on one patient’s ipsilateral anterior circulation with 3D reconstruction model and computational fluid dynamic method simulation.

Methods

20 patients with intracranial aneurysms pairs on the same-side of anterior circulation but with different rupture status were retrospectively collected. Each pair was divided into ruptured-unruptured group. Patient-specific models based on their 3D-DSA images were constructed and analyzed. The relative locations, morphologic and hemodynamic factors of these two groups were compared.

Results

There was no significant difference in the relative bleeding location. The morphological factors analysis found that the ruptured aneurysms more often had irregular shape and had significantly higher maximum height and aspect ratio. The hemodynamic factors analysis found lower minimum wall shear stress (WSSmin) and more low-wall shear stress-area (LSA) in the ruptured aneurysms than that of the unruptured ones. The ruptured aneurysms more often had WSSmin on the dome.

Conclusions

Intracranial aneurysms pairs with different rupture status on unilateral side of anterior circulation may be a good disease model to investigate possible characteristics linked to rupture independent of patient characteristics. Irregular shape, larger size, higher aspect ratio, lower WSSmin and more LSA may indicate a higher risk for their rupture.

     

Computational modeling of blood component transport related to coronary artery thrombosis in Kawasaki disease

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case—mechanical or biochemical—could help define improved strategies for thrombosis prevention tailored for each patient.     

Bicuspid aortic valve hemodynamics induces abnormal medial remodeling in the convexity of porcine ascending aortas

The type-I bicuspid aortic valve (BAV), which differs from the normal tricuspid aortic valve (TAV) most commonly by left-right coronary cusp fusion, is frequently associated with secondary aortopathies. While BAV aortic dilation has been linked to a genetic predisposition, hemodynamics has emerged as a potential alternate etiology. However, the link between BAV hemodynamics and aortic medial degeneration has not been established. The objective of this study was to compare the regional wall shear stresses (WSS) in a TAV and BAV ascending aorta (AA) and to isolate ex vivo their respective impact on aortic wall remodeling. The WSS environments generated in the convex region of a TAV and BAV AA were predicted through fluid–structure interaction (FSI) simulations in an aorta model subjected to both valvular flows. Remodeling of porcine aortic tissue exposed to TAV and BAV AA WSS for 48 h in a cone-and-plate bioreactor was investigated via immunostaining, immunoblotting and zymography. FSI simulations revealed the existence of larger and more unidirectional WSS in the BAV than in the TAV AA convexity. Exposure of normal aortic tissue to BAV AA WSS resulted in increased MMP-2 and MMP-9 expressions and MMP-2 activity but similar fibrillin-1 content and microfibril organization relative to the TAV AA WSS treatment. This study confirms the sensitivity of aortic tissue to WSS abnormalities and demonstrates the susceptibility of BAV hemodynamic stresses to focally mediate aortic medial degradation. The results provide compelling support to the important role of hemodynamics in BAV secondary aortopathy.     

Diet as prophylaxis and treatment for venous thromboembolism?

Background

Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored.

Methods and Findings

The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment. Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial.

Conclusions

Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials.     

<Emphasis Type="Italic">Sorting nexin 24</Emphasis> genetic variation associates with coronary artery aneurysm severity in Kawasaki disease patients

Background

The sorting nexin (SNX) family is involved in endocytosis and protein trafficking and plays multiple roles in various diseases. The role of SNX proteins in Kawasaki disease (KD) is not known. We attempted to test whether genetic SNX variation associates with the risk of coronary artery aneurysm (CAA) formation in KD.

Methods and results

Chi-square tests were used to identify SNX24 genetic variants associated with KD susceptibility and CAA formation in KD; models were adjusted for fever duration and time of first administration of intravenous immunoglobulin. We obtained clinical characteristics and genotypes from KD patients (76 with CAA and 186 without CAA) in a population-based retrospective KD cohort study (n?=?262). Clinical and genetic factors were associated with CAA formation in KD. In addition, endothelial cell inflammation was evaluated. Significant correlation was observed between KD with CAA complications and the rs28891 single-nucleotide polymorphism in SNX24. Patients with CC?+?CT genotypes had lesser CAA complications. In lipopolysaccharide-treated human umbilical vein endothelial cells, siRNA knockdown of SNX24 significantly decreased gene expression of the proinflammatory cytokines IL-1 beta, IL-6, and IL-8.

Conclusions

Polymorphisms in SNX24 may be used as genetic markers for the diagnosis and prognosis of CAA formation in KD.

     

Genetic variants of glutamate receptor gene family in Taiwanese Kawasaki disease children with coronary artery aneurysms

Background

Patients with Kawasaki disease (KD), a pediatric systemic vasculitis, may develop coronary artery aneurysm (CAA) as a complication. To investigate the role of glutamate receptors in KD and its CAA development, we performed genetic association studies.

Methods and results

We examined the whole family of glutamate receptors by genetic association studies in a Taiwanese cohort of 262 KD patients. We identified glutamate receptor ionotropic, kainate 1 (GRIK1) as a novel susceptibility locus associated with CAA formation in KD. Statistically significant differences were noted for factors like fever duration, 1st Intravenous immunoglobulin (IVIG) used time (number of days after the first day of fever) and the GRIK1 (rs466013, rs425507, and rs38700) genetic variants. This significant association persisted even after using multivariate regression analysis (Full model: for rs466013: odds ratio =2.12; 95% CI =1.22-3.65; for rs425507: odds ratio =2.16; 95% CI =1.26-3.76; for rs388700: odds ratio =2.16; 95% CI =1.26-3.76).

Conclusions

We demonstrated that GRIK1 polymorphisms are associated CAA formation in KD, even when adjusted for fever duration and IVIG used time, and may also serve as a genetic marker for the CAA formation in KD.

     

Transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis

Sorafenib in combination with Transarterial chemoembolization (TACE) is increasingly used in patients with unresectable hepatocellular carcinoma (HCC), but the current evidence is still controversial. The aim of this systematic review was to evaluate the effectiveness and safety of TACE plus sorafenib versus TACE alone for unresectable HCC. We searched PubMed, EMBASE and the Cochrane Library for clinical trials comparing TACE plus sorafenib with TACE alone for unresectable HCC. The study outcomes included overall survival (OS), time to progression (TTP), objective response and adverse events (AEs). Six studies including 1,181 patients were included. Meta-analysis of all studies suggested that the combination therapy group had significant longer OS than TACE group [hazard ratio (HR) = 0.64, 95 % confidence interval (CI) = 0.43–0.97], but the pooled HR of randomized controlled trials (RCTs) failed to achieve statistical significance. For TTP, meta-analysis in both RCTs subgroup and retrospective studies subgroup suggested that combination therapy was superior to TACE group. The combination therapy was also associated with better response to treatment (risk ratio = 1.45, 95 % CI = 1.04–2.02) when both RCTs and retrospective studies were pooled. However, the sorafenib associated AEs were more frequent in the combination therapy group. In conclusion, the combination of TACE and sorafenib is likely to improve OS, TTP and response to treatment when compared with TACE monotherapy. The combination group is also associated with more sorafenib-related AEs.     

Urinary Colorimetric Sensor Array and Algorithm to Distinguish Kawasaki Disease from Other Febrile Illnesses

Objectives

Kawasaki disease (KD) is an acute pediatric vasculitis of infants and young children with unknown etiology and no specific laboratory-based test to identify. A specific molecular diagnostic test is urgently needed to support the clinical decision of proper medical intervention, preventing subsequent complications of coronary artery aneurysms. We used a simple and low-cost colorimetric sensor array to address the lack of a specific diagnostic test to differentiate KD from febrile control (FC) patients with similar rash/fever illnesses.

Study Design

Demographic and clinical data were prospectively collected for subjects with KD and FCs under standard protocol. After screening using a genetic algorithm, eleven compounds including metalloporphyrins, pH indicators, redox indicators and solvatochromic dye categories, were selected from our chromatic compound library (n = 190) to construct a colorimetric sensor array for diagnosing KD. Quantitative color difference analysis led to a decision-tree-based KD diagnostic algorithm.

Results

This KD sensing array allowed the identification of 94% of KD subjects (receiver operating characteristic [ROC] area under the curve [AUC] 0.981) in the training set (33 KD, 33 FC) and 94% of KD subjects (ROC AUC: 0.873) in the testing set (16 KD, 17 FC). Color difference maps reconstructed from the digital images of the sensing compounds demonstrated distinctive patterns differentiating KD from FC patients.

Conclusions

The colorimetric sensor array, composed of common used chemical compounds, is an easily accessible, low-cost method to realize the discrimination of subjects with KD from other febrile illness.     

Associations of platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphisms with circulating PAF-AH levels and risk of coronary heart disease or blood stasis syndrome in the Chinese Han population

The circulating level of platelet-activating factor acetylhydrolase (PAF-AH) is a novel biomarker to predict the presence of coronary heart disease. PAF-AH gene polymorphisms may be responsible for the variance of circulating PAF-AH levels in individuals. However, the association of PAF-AH gene polymorphisms with circulating PAF-AH levels and the susceptibility to coronary heart disease (CHD) remains unsolved. Blood stasis syndrome (BSS) of CHD is the most common type of TCM syndromes, and a previous study discovered its relationship with the elevated circulating PAF-AH levels. However, the association of gene polymorphisms and CHD with BSS is unclear at present. In this study, four polymorphisms (R92H, I198T, A379V, V279F) of the PAF-AH gene were genotyped in 570 CHD patients, of which 299 had BSS. In addition, 317 unaffected individuals from the same hospitals served as controls. Plasma PAF-AH levels were measured in 155 controls and 271 CHD patients selected randomly, including 139 CHD patients with BSS. In the Chinese Han population, plasma PAF-AH levels in CHD patients with BSS or without BSS were significantly higher (12.9 ± 6.5 and 11.1 ± 5.0 μM, respectively) than in controls (9.3 ± 5.2 μM); this difference still remained significant after adjustment for traditional risk factors or the inflammatory factors. The R92H polymorphism was highly related to the plasma PAF-AH levels and the risk of CHD, especially among patients with BSS, even with the adjustment for the effects of traditional factors. The I198T polymorphism was highly associated with risk of CHD with BSS, but was associated with neither the risk of CHD with no BSS nor with elevated plasma PAF-AH levels.     

Bone Metabolism Status and Associated Risk Factors in Elderly Patients with Chronic Obstructive Pulmonary Disease (COPD)

The prevalence of osteoporosis in older patients with chronic obstructive pulmonary disease (COPD) is higher than in the age-matched elderly patients, but the exact cause in relation to COPD is not clear. We hypothesized that the underlying causes for this difference are related to bone metabolism with the possible risk factors that include the duration of COPD, GOLD grade, cor pulmonale, the frequencies of acute exacerbations within the past year, smoking and inhaled corticosteroid therapy. We conducted a matched-pair study of 100 patients aged older than 65 years at the Southwest Hospital from May to November 2012. The enrolled patients with COPD were matched to controls for age and gender. Clinical characteristics of cohorts were recorded. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry and osteoporosis was diagnosed according to the definition of WHO. All cohorts accepted bone metabolism marker measurement, including Procollagen type 1 aminoterminal propeptide (P1NP), β-C-telopeptides of type I collagen (βCTX), and N-terminal midmolecule fragment osteocalcin (N-MID OC). Statistical analysis was calculated using the student’s t test, ANOVA and multiple regression analysis at a significance level set at a p < 0.05. Circulating biochemical markers of bone formation (P1NP), resorption (βCTX) and turnover (N-MID OC) were significantly lower in the COPD group than control group, while mean 25-OH Vitamin D was similar in two groups. The P1NP, βCTX, and N-MID OC were still lower in men with COPD, but only P1NP was lower in women with COPD compared to that of controls. Multiple regression analysis in COPD group suggests that age, the frequency of acute exacerbation, and BMD are independent risk factors for P1NP. The frequency of acute exacerbation within the past one year and 25-OH D level are independent risk factors for βCTX; the frequency of acute exacerbation is the only independent risk factor for N-MID OC. These were significant differences in bone metabolism in patients with or without COPD. These results should help us to further understand the cause of osteoporosis and fractures and conduce to prevent osteoporosis in patients with COPD.     

Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins—lipid-lowering agents with anti-thrombotic and anti-inflammatory properties—in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy.     

Biochemical differentiation of clones of OcaOxalis tuberosa,Oxalidaceae) by Their tuber proteins and the properties of these proteins

Tuber proteins of oca (Oxalis tuberosa) were separated for clone (cultivar) differentiation by gel electrophoresis in polyacrylamide. The patterns of native proteins and especially of esterases in a porosity gradient with and without urea were suitable for differentiation, whereas SDS-electrophoresis of protomers or focusing of native proteins yielded more or less the same patterns for 23 different accessions. The main proteins are quite acidic (isoelectric points pH 4.7–4.9) and have a relative molecular weight of 17–18 KD (Kilo-Dalton). Amino acid analysis of the protein precipitate by propan-2-ol from tuber sap revealed proteins rich in aspartic and glutamic acid (one third of all amino acids) with a considerable share of essential ones.     

SNPs in MicroRNA-Binding Sites in the ITGB1 and ITGB3 3′-UTR Increase Colorectal Cancer Risk

The purpose of the study was to investigate the potential associations between single-nucleotide polymorphisms (SNPs) in microRNA (miRNA)-binding sites in the integrin beta-1 (ITGB1) gene and integrin beta-3 (ITGB3) gene 3′-untranslated regions, and colorectal cancer (CRC) susceptibility in a Chinese population. A hospital-based case–control study was performed in 200 patients with CRC and 200 matched healthy donors. Two SNPs in miRNA binding of ITGB1 and ITGB3 genes (rs17468 and rs2317676) were genotyped by polymerase chain reaction-restrict fragment length polymorphism assay. The association between genotypes and CRC risk was evaluated by computing the odds ratio (OR) and 95 % confidence interval (CI) from multivariate unconditional logistic regression analyses. The frequency of the T genotype in ITGB1 rs17468 and G genotype in ITGB3 rs2317676 occurred more frequently in CRC patients than in controls (P < 0.05). We found that CT and TT genotypes of rs17468 were associated with a significantly increased risk of CRC (OR = 1.67, 95 % CI = 1.090–2.559 for CT + TT vs. CC), also the AG and GG genotype in ITGB3 rs2317676 (OR = 1.65, 95 % CI = 1.114–2.458 for AG + GG vs. AA). In conclusion, our results showed that both the ITGB1 rs17468 SNP and ITGB3 rs2317676 SNP were associated with an increased risk of CRC, which suggests that these 2 SNPs might contribute to CRC risk in a Chinese population.     

Adult ADHD and suicide

While suicidal behaviour has been implicated in a plethora of psychiatric disorders including depression, psychoses and substance abuse, its association with adult ADHD is largely under-researched. Given that emotional instability and the high prevalence of comorbid conditions such as mood disorders and alcohol/drug dependence are typical for ADHD, the question of suicide risk must not be neglected in this patient group. A review of the current literature focusing on this issue provides strong evidence that ADHD patients are at a significant risk for experiencing suicidal ideations and committing suicide. For daily clinical practice, it is therefore essential to incorporate this aspect into the diagnostic and therapeutic process and to take preventive measures.     

Association Between Single Nucleotide Polymorphisms of Sterol Regulatory Element Binding Protein-2 and Liver X Receptor α Gene and Risk of Polycystic Ovary Syndrome in a Chinese Han Population

To investigate associations of single nucleotide polymorphisms (SNPs) rs2228314 of sterol regulatory element-binding protein-2 (SREBP-2) or rs11039155 of liver X receptor α (LXRα) with susceptibility to polycystic ovary syndrome (PCOS) in a Chinese Han population. SREBP-2 rs2228314 and LXRα rs11039155 polymorphisms were genotyped in patients with PCOS and age- and sex-matched PCOS-free controls from a Chinese Han population. A total of 605 patients with PCOS and 615 controls were recruited in this study. We found that GC and CC genotypes of rs2228314, and variant C, were associated with a significantly increased risk of PCOS. In addition, GA and AA genotypes of rs11039155, as well as variant A, were also associated with a significantly increased risk of PCOS. Our results showed that SREBP-2 rs2228314 G to C change and variant C genotype as well as LXRα rs11039155 G to A change and variant A may contribute to PCOS in Chinese Han population.     

Relative mRNA expression and immunolocalization for transforming growth factor-beta (TGF-β) and their effect on in vitro development of caprine preantral follicles

This study aimed to evaluate the immunolocalization and messenger RNA (mRNA) expression for transforming growth factor-beta (TGF-β) and its receptors (TGF-βRI and RII), as well as mRNA expression for P450 aromatase and FSH receptor in caprine preantral follicles. The effects of TGF-β, FSH alone, or in association on the in vitro follicular development were also assessed. Immunohistochemical analyses showed the expression of TGF-β and its receptors in oocytes of all follicle stages and granulosa cells of primary and secondary follicles. mRNA for TGF-β receptors and for FSH receptor (FSHR) was present in preantral follicles as well as in oocytes and granulosa cells of antral follicles. Isolated secondary follicles were cultured in α-minimum essential medium (MEM) alone or supplemented with either FSH (100 ng/ml), TGF-β (10 ng/ml), or TGF-β + FSH for 18 d. TGF-β increased significantly oocyte diameter when compared to FSH alone and control. After 18 d of culture, all groups showed a significant reduction in P450 aromatase and FSHR mRNA levels in comparison to fresh control. In contrast, treatment with FSH significantly increased the mRNA expression for TGF-β in comparison to fresh control and other treatments. In conclusion, the findings showed that TGF-β and its receptors are present in caprine ovarian follicles. Furthermore, they showed a positive effect on oocyte growth in vitro.     

MiR-199a is overexpressed in plasma of type 2 diabetes patients which contributes to type 2 diabetes by targeting GLUT4

Decreased GLUT4 expression and impaired GLUT4 cell membrane translocation are involved in type 2 diabetes mellitus (T2DM) pathogenesis so the factors impacting GLUT4 expression may be associated with T2DM. In this study, we identified four miRNAs: miR-31, miR-93, miR-146a, and miR-199a which suppress GLUT4 expression in HEK293T cells. Subsequently, we determined expression of these four miRNAs in plasma samples of T2DM patients, T2DM susceptible individuals, and healthy controls and found miR-199a was overexpressed in patients’ plasma compared with healthy control. Because the miR-199a binding site in GLUT4 3′UTR is highly conserved among vertebrates, we detected the glucose uptake in rat L6 myoblast cells through gain- and loss-of-function of miR-199a. We found that miR-199a can repress glucose uptake in L6 cells, which was rescued by GLUT4 overexpression. These results indicate that T2DM patients may have a high level miR-199a that reduce GLUT4 expression and contribute to the insulin resistance. Hence, miR-199a may be a novel biomarker for risk estimation and classification in T2DM patients.