Role of <Emphasis Type="Italic">PPARG</Emphasis> (Pro12Ala) in Malaysian type 2 diabetes mellitus patients

Diabetes is one of the major lifestyle disorders in the world. Asian countries, including Malaysia, contribute with more than 60 % of the world’s diabetic population. The single nucleotide polymorphisms (SNPs) of the peroxisome proliferator-activated receptor gamma (PPARG) have been identified as one of the key regulators of glucose and lipid metabolism that controls the protein synthesis in multiple metabolic, biochemical, and molecular pathways. The aim of this study was to investigate the possible role of PPARG (Pro12Ala) gene polymorphism as a genetic risk factor for type 2 diabetes mellitus (T2DM) patients in Malaysian population. A total of 241 subjects between the age of 35 and 85 years were recruited in this study. Out of the total 241 subjects, 120 were T2DM patients and 121 were healthy individuals. SNP of PPARG (Pro12Ala) was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLPs). The frequencies of wild homozygote (WH), heterozygote (H), and mutant homozygote (MH) among the T2DM patients were (n?=?73) 60.8 %, (n?=?39) 32.5 %, and (n?=?3) 2.5 % compared to (n?=?57) 47 %, (n?=?46) 38 %, and (n?=?16) 13.2 % among the healthy subjects. The mean of Hba1C (%) among normal and diabetic patients with genotypes were different (5.36?±?0.54 vs 7.58?±?1.76), p?<?0.005. SNP of PPARG (Pro12Ala) gene could be a genetic risk factor for insulin resistance and T2DM among Malaysian population.     

MicroRNAs 103 and 107 link type 2 diabetes and post-menopausal breast cancer

Type 2 diabetes mellitus (T2DM) increases the incidence of post-menopausal breast cancer (PMBC). This study is intended to determine whether microRNA-103/107 (miR-103/107) should be regarded as a potential molecular link between T2DM and PMBC. Samples of serum from 90 patients with T2DM and/or PMBC were collected. Samples of serum from 20 non-diabetic post-menopausal women were used as the control. The body mass index (BMI) of patients with T2DM and PMBC was lower than the BMI of patients with only T2DM or PMBC (p?<?0.05). The expression of miR-103/107 was higher in the serum of T2DM patients compared with that in control samples (2.80?±?0.46/36.29?±?3.41 vs 0.88?±?0.25/8.59?±?1.91, p?<?0.05). The expression of miR-103/107 in the serum of PMBC patients was higher than that in T2DM patients (5.06?±?0.92/49.59?±?6.99 vs 2.80?±?0.46/36.29?±?3.41, p?<?0.05) but lower than that in patients diagnosed with both T2DM and PMBC (7.67?±?0.87/63.24?±?8.58, p?<?0.05). miR-103/107 was positively correlated with the homeostasis model assessment-insulin resistance (HOMA-IR) index (r?=?0.71, 0.685, p?<?0.01). The expression of miR-103/107 was an independent factor of the HOMA-IR index (β?=?0.638, 0.073, p?=?0.02, 0.01). There were higher levels of estradiol (E2) in patients with T2DM and/or PMBC than that in the control group. High expression of miR-103/107 results in insulin resistance and is associated with overweight or obese patients with T2DM and PMBC through elevated levels of E2. miR-103/107 may be a potential molecular link between T2DM and PMBC.     

CTLA-4 +49A/G gene polymorphism and type 1 diabetes mellitus in the Chinese population: a meta-analysis of 2238 subjects

Previous studies reported that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) +49A/G gene polymorphism is correlated with type 1 diabetes mellitus (T1DM) risk. However, their results remain disputable. This study aims to discuss the relationship between CTLA-4 +49A/G gene polymorphism and T1DM in a Chinese population. The current meta-analysis involved 2238 participants from seven individual studies. The pooled odds ratio (OR) and its corresponding 95 % confidence interval (95 % CI) were assessed by the random- or fixed-effects model. A significant relationship between CTLA-4 +49A/G gene polymorphism and T1DM was detected under allelic (OR: 1.84, 95 % CI: 1.62–2.10, P?<?0.00001), dominant (OR: 1.152, 95 % CI: 1.062–1.249, P?=?0.001), recessive (OR: 1.631, 95 % CI: 1.443–1.844, P?<?0.00001), and additive (OR: 1.292, 95 % CI: 1.224–1.363, P?<?0.00001) genetic models. A significant relationship exists between CTLA-4 +49A/G gene polymorphism and increased T1DM risk in the Chinese population. Individuals having the G allele of CTLA-4 +49A/G gene polymorphism have a higher risk for T1DM in the Chinese population.     

A study of paraoxonase1 (PON1) activities,HDL cholesterol and its association with vascular complication in type 2 diabetes mellitus

The aim of this study is to find out the clinical relevance of estimating serum paraoxonase1 (PON1) arylesterase and PON1 lactonase activity in type 2 diabetes mellitus patients in relation to the development of vascular complications. We have investigated the fasting blood glucose level, HDL cholesterol levels, PON1 arylesterase and PON1 lactonase activities in 80 type 2 diabetes mellitus (DM) patients (DM without complication n?=?40, DM with vascular complication n?=?40) and compared with 40 healthy age- and sex-matched controls. PON1 arylesterase (ARE) and lactonase (LACT) activities in DM patients with complications (ARE?=?60.615?±?15.510 KU/L, LACT?=?18.056?±?4.215 U/L) are decreased significantly than in DM without complications (ARE?=?93.507?±?21.813 KU/L, LACT?=?32.387?±?8.918 U/L) which are also decreased significantly as compared to controls (ARE?=?159.94?±?45.87 KU/L, LACT?=?50.625?±?6.973 U/L). Logistic regression analysis is applied for assessing predictive utility for diabetic complications demonstrated a significant contribution of PON1 lactonase (Naglekerke’s R ²?=?0.625, AUC?=?0.907) and arylesterase (Naglekerke’s R ²?=?0.427, AUC?=?0.853) activities. Decreased PON1 lactonase and arylesterase activities may be considered as an additional risk factor for the development of vascular complications in type 2 DM.     

A retrospective analysis of the impact of telephonic counseling on dietary and lifestyle modifications in Indian patients with type 2 diabetes mellitus

Dietary and lifestyle modifications are critical in the management of type 2 diabetes mellitus (T2DM). However, in a resource-constrained setting, providing physical counseling for dietary and lifestyle modifications is a challenge. Therefore, SPARSH, a call center based, telephonic counseling program was set up for patients with T2DM. In this study, effect of SPARSH services on dietary and lifestyle parameters of patients with T2DM was analyzed. Adult patients who received counseling regularly for at least 14 months were selected. At the end of 14 months, change from baseline in various dietary and lifestyle parameters was evaluated using t test and McNemar’s test at 5% significance level. Overall, 1283 patients were included. At the end of 14 months, change in dietary parameters was as follows: total calories, carbohydrates, and fat consumption decreased significantly by 169.1 kcal/day, 16.2 g/day, and 3.1 g/day, respectively (p?<?0.0001); proteins intake increased by 1.0 g/day (p?=?0.0043); cereals, alcohol, and junk food consumption decreased by 1.1 exchanges/day, 34.9 kcal/day, and 46.0 kcal/day, respectively (p?<?0.0001); fruits and vegetable consumption increased by 0.2 and 0.4 exchanges/day, respectively (p?<?0.0001); dietary fiber intake increased by 0.9 g/day (p?=?0.0207). Change in lifestyle parameters was as follows: increase in frequency and duration of exercise by 1.2 days/week and 1.3 h/week, respectively; self-inspection of feet and footwear by 1.5 and 1.0 times/week, respectively; and decrease in smoking by 2 cigarettes/day (p?<?0.0001). Regular telephonic counseling significantly improved dietary and lifestyle parameters in T2DM patients.     

Effect of vitamin D level on the immunogenicity to hepatitis B vaccination in dialysis patients

We undertook this study to assess the response of hepatitis B vaccination in dialysis patients and the effect of vitamin D level on the immunogenicity to hepatitis B vaccination. It was an observational study, which included 60 patients of end-stage renal disease on maintenance dialysis. Patients with anti-HBs antibody positive at baseline were excluded. All received intramuscular recombinant hepatitis B vaccination at 0, 1, 2, and 6 months 20 μg on each deltoid muscle bilateral. Anti-HBs antibody titers were measured at 4 and 7 months of vaccination and the titer ≥10 mIU/mL was considered as “positive”. Vitamin D levels were measured at baseline before starting the vaccination. The mean vitamin D level was 15.0?±?7.8 ng/mL. The vitamin D level <10 and <20 were 23.3% and 83.3 %, respectively. The patients on hemodialysis had relatively higher vitamin D level than on peritoneal dialysis patients, i.e. 16.3?±?8.5 and 11.5?±?3.1 ng/mL, respectively (p?=?0.03). Overall, 38 patients responded to the immunization (63.3 %) and 11 patients were non-responders (36.7 %) at 4 months. Difference of vitamin D level in responder (16.6?±?9.1 ng/mL) and non-responder (12.4?±?4.1 ng/mL) was not significant (p?=?0.16). At 7 months (1 month after completion of vaccination) 61.9 % were responders and 38.1 % were non-responders. The vitamin D level in responders and non-responders were statistically not significant (p?=?0.11). In responder, titer ≥100 mIU/mL was seen in 30 % at 4 months and in 42.9 % at 7 months (p?=?0.05). In the good and weak responders at 7 months, vitamin D levels were 21.5?±?10.8 and 10.1?±?3.7 ng/mL, respectively (p?=?0.37). The association of vitamin D level and anti-HBs antibody titer were not significant (r?=?0.03 and 95 % CI was ?0.43 to 0.48, p?=?0.89) in those who responded. Most patients on dialysis were vitamin D deficient. Vitamin D levels did not differ between responding and non-responding dialysis patients.     

Bachmann bundle pacing reduces atrial electromechanical delay in type 1 myotonic dystrophy patients

Background

Atrial electromechanical delay (AEMD) is an echocardiographic parameter correlated with the onset of supraventricular arrhythmias in several clinical conditions. Inter-atrial septal pacing in the region of Bachmann’s bundle (BB) has been shown to be safe and feasible in myotonic dystrophy type 1 (DM1) patients, with a low rate of sensing and pacing defects. The aim of this study was to assess the impact of temporary BB pacing compared with right atrial appendage (RAA) pacing on AEMD in DM1 patients undergoing pacemaker (PM) implantation for cardiac rhythm abnormalities.

Methods

The study enrolled 70 consecutive DM1 patients undergoing PM implantation for cardiac rhythm abnormalities in accordance with the current guidelines. Seventy age- and sex-matched non-DM1 patients undergoing dual-chamber PM implantation for cardiac rhythm abnormalities were used as controls. The atrial pacing lead was temporarily positioned in the RAA and on the right side of the inter-atrial septum in the region of Bachmann’s bundle. For each site (BB and RAA), temporary atrial pacing in the AAI mode was established at 10 beats per minute above the sinus rate and a detailed trans-thoracic echocardiogram with tissue Doppler (TDI) analysis was recorded after at least 10 min of atrial pacing to evaluate AEMD.

Results

Temporary RAA pacing did not show statistically significant differences in inter-AEMD (48.2?±?17.8 vs 50.5?±?16.5 ms; P?= 0.8), intra-left AEMD (43.3?±?15.5 vs 44.6?±?15.8 ms; P?= 0.1), or intra-right-AEMD (14.1?±?4.2 vs 15.4?±?5.8 ms; P?= 0.9), in comparison with sinus rhythm. Temporary BB pacing determined a significantly lower inter-AEMD (36.1?±?17.1 vs 50.5?±?16.5 ms; P?= 0.001) and intra-left AEMD (32.5?±?15.2 vs 44.6?±?15.8 ms; P?= 0.001) values in comparison with temporary RAA pacing. No statistically significant difference was found in intra-right AEMD (12.2?±?4.6 vs 15.4?±?5.8 ms; P?= 0.2). In the control group, neither temporary RAA pacing nor temporary BB pacing showed statistically significant differences in inter-AEMD, intra-left AEMD, or intra-right AEMD values in comparison with sinus rhythm.

Conclusions

In DM1 patients undergoing dual-chamber PM implantation, atrial pacing in the Bachmann bundle region is associated with significantly lower echocardiographic indices of atrial electromechanical delay (inter-AEMD and intra-left AEMD) in comparison with RAA pacing.

     

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes

Incretin hormones have been reported to have cytoprotective actions in addition to their glucose-lowering effects. We evaluated whether teneligliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, affects left ventricular (LV) function in patients with type 2 diabetes mellitus (T2DM). Twenty-nine T2DM patients not receiving any incretin-based drugs were enrolled and prescribed with teneligliptin for 3 months. Compared to baseline levels, hemoglobin A1c levels decreased (7.6 ± 1.0 % to 6.9 ± 0.7 %, p < 0.01) and 1,5-anhydro-d-glucitol levels increased (9.6 ± 7.2 μg/mL to 13.5 ± 8.7 μg/mL, p < 0.01) after treatment. Clinical parameters, including body mass index and blood pressure, did not show any difference before and after treatment. Three months after treatment, there were improvements in LV systolic and diastolic function [LV ejection fraction, 62.0 ± 6.5 % to 64.5 ± 5.0 %, p = 0.01; peak early diastolic velocity/basal septal diastolic velocity (E/e′) ratio, 13.3 ± 4.1 to 11.9 ± 3.3, p = 0.01]. Moreover, there was an improvement in endothelial function (reactive hyperemia peripheral arterial tonometry [RH-PAT] index; 1.58 ± 0.47 to 2.01 ± 0.72, p < 0.01). There was a significant negative correlation between changes in the E/e’ ratio and RH-PAT values. Furthermore, circulating adiponectin levels increased (27.0 ± 38.5 pg/mL to 42.7 ± 33.2 pg/mL, p < 0.01) without changes in patient body weight. Teneligliptin treatment was associated with improvements in LV function and endothelial functions, and an increase in serum adiponectin levels. These results support the cardio-protective effects of teneligliptin in T2DM patients and increase in serum adiponectin levels.     

Neutrophil extracellular traps may contribute to interstitial lung disease associated with anti-MDA5 autoantibody positive dermatomyositis

In dermatomyositis (DM), anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody (autoAb) marks a subtype with low grade or absent muscle inflammation but frequent and rapidly progressive interstitial lung disease (ILD). The pathogenesis of ILD remains poorly unknown. The aim of the study is to explore whether neutrophil extracellular traps (NETs) are involved in the development of ILD in DM patients with anti-MDA5 autoAb. Patients with clinically amyopathic dermatomyositis (CADM, n = 20), classic dermatomyositis (cDM, n = 30), polymyositis (PM, n = 20), and healthy controls (HC, n = 20) were enrolled. Anti-MDA5 autoantibody and Krebs von den Lungen-6 (KL-6) were detected by ELISA. Circulating levels of NETs were assessed by the quantification of both serum cell-free DNA (cfDNA) and LL-37 (cathelicidin LL-37). Immunofluorescent staining was used to visualize NETs ex vivo. The elevated circulating NETs level was detected in DM patients with ILD complication. Compared to anti-MDA5 Ab^? DM patients, anti-MDA5 Ab⁺ DM patients had the higher concentrations of serum cfDNA (293 ± 69 vs 252 ± 63 ng/ml; P = 0.035) and serum LL-37 (0.6 ± 1.0 vs 0.2 ± 0.2 ng/ml; P = 0.026). Positive correlations were established between serum levels of cfDNA and KL-6 in DM patients (r _s = 0.4422, P = 0.0003). anti-MDA5 Ab⁺ sera, other than anti-MDA5 Ab^? sera, could induce greater numbers of normal neutrophils to form NETs in vitro. These data suggest that aberrant NETs formation may be involved in the pathogenesis of ILD in DM patients with anti-MDA5 autoAb.     

Prevalence of type 2 diabetes–associated complications in Pakistan

The prevalence of type 2 diabetes (T2DM) is rapidly increasing in Pakistan. Various micro- and macro-vascular complications are associated with disease progression which increases the economic burden not only on patients but also on country. The aim of the present study was to determine the prevalence of micro- and macro-vascular complications among T2DM patients in Pakistan. A cross-sectional study was carried out on 692 T2DM patients during July 2011 to December 2012. The participants recruited in this study were clinically diagnosed by certified diabetologist and endocrinologists in the Pakistan Institute of Medical Sciences (PIMS) and Kahuta Research Laboratory (KRL) hospital of Islamabad. Demographic and clinical data was collected under supervision of a diabetologist and endocrinologist using a specially designed questionnaire. Clinical variables were statistically analyzed using SPSS version 16.0 and Graphpad prism 5 version 5.01. Of the 678 T2DM patients, 432 (63.62 %) were females with mean age of 51.81?±?11.43. Out of total patients, 0.56 % were diagnosed with retinopathy, 0.84 % with nephropathy, 0.28 % with neuropathy, 28.17 % with ischemic heart diseases, 8.45 % with stroke, and 5.35 % with peripheral vascular disease. Overall, 55.77 % of T2DM patients were hypertensive and 0.56 % experienced impotence. Significant association of hypertension (P?=?0.0072), ischemic heart disease (IHD; P?=?0.0001), and peripheral vascular disease (PVD; P?=?0.014) was observed at gender level in the study subjects. This study indicates high prevalence of macro-vascular complications along with high triglyceride level and hypertension among T2DM patients. A study with larger sample set is suggested to explore the relation of genetic and environmental factors on disease progression and sub-population variations.     

Left ventricular subclinical dysfunction associated with myocardial deformation changes in obstructive sleep apnea patients estimated by real-time 3D speckle-tracking echocardiography

Background

Previous studies have demonstrated that patients with obstructive sleep apnea (OSA) may develop left ventricular (LV) diastolic dysfunction. We aimed to study whether OSA patients have LV regional systolic dysfunction with myocardial deformation changes, despite a normal LV ejection fraction, using real-time 3D speckle-tracking echocardiography (Rt3D-STE).

Methods

Seventy-eight patients with OSA and no comorbidities were studied. They were divided into the following three groups according to the apnea–hypopnea index (AHI): 5~15/h as group I (mild OSA, 26 cases), 15~30/h as group II (moderate OSA, 29 cases), and ≥30/h as group III (severe OSA, 23 cases). Thirty gender–age-matched normal subjects were included as controls. The parameters of LV diastolic function were acquired with traditional echocardiography. The LV myocardial deformation parameters were obtained, including the longitudinal (LS), circumferential (CS), radial (RS), and area (AS) strains, with Rt3D-STE.

Results

LV global systolic function was normal in all patients, but diastolic function was impaired in groups II and III (E/E′ was 9.6?±?2.8 and 10.4?±?2.5, respectively, p?<?0.0001). The global LS and AS were significantly reduced in groups II and III compared with the controls and group I (LS 15.9?±?1.4 % and 14.8?±?1.5 % vs 18.2?±?1.7 % and 17.8?±?1.5 %; AS 27.4?±?1.8 % and 24.9?±?2.3 % vs 33.4?±?2.2 % and 32.7?±?2.9 %, respectively, p?<?0.0001), but the global CS and RS were significantly reduced only in group III (17.3?±?1.4 % and 43.1?±?6.5 % vs 19.6?±?1.6 % and 55.4?±?4.0 %, respectively, <0.0001). The severity of OSA was significantly associated with the LV global AS value (r?=??0.80, p?<?0.0001), LS (r?=??0.64, p?<?0.0001), CS (r?=??0.51, p?<?0.0001), and RS (r?=??0.62, p?<?0.0001).

Conclusions

Patients with moderate and severe OSA tended to have both LV diastolic dysfunction and abnormalities in regional systolic function with myocardial deformation changes, in spite of the normal LV ejection fraction. Myocardial strains of the LV were negatively correlated with the AHI. Rt-3DST had important clinical significance in the early evaluation of cardiac dysfunction in OSA patients.

     

Assessment of multimedia-supported intervention in Muslim diabetic patients treated with insulin

This study aimed to evaluate the effect on diabetic care of an educational DVD in Jawi, the primary spoken language of Muslims in the study area, and pharmacist intervention among Muslim patients with diabetes treated with insulin. Type 2 diabetes Muslim patients on insulin treatment and poor glycemic control (N?=?143) in one hospital in southern Thailand were recruited to participate in a 6-month-period pre- and post-intervention study. For the intervention, the pharmacist provided the patients with education using a DVD and then asked them to show how to use insulin injection. Afterward, the pharmacist would correct the techniques for patients individually. At 6 months after intervention, significant reductions in glycated hemoglobin (HbA_1c) (8.31?±?1.40 to 7.19?±?1.15 %, P?<?0.001), fasting blood glucose (FBG) (195.06?±?86.14 to 115.81?±?11.48 mg/dL, P?<?0.001), systolic blood pressure (130.62 to 126.57 mmHg, P?=?0.004), triglycerides (183.36?±?90.48 to 182.31?±?90.68 mg/dL, P?<?0.001), and total cholesterol (199.57?±?68.77 to 194.97?±?64.77 mg/dL, P?=?0.006) were detected in patients who received the intervention. Increased low-density lipoprotein cholesterol (LDL-C) level (P?=?0.028) but no significant change in high-density lipoprotein cholesterol (HDL-C) were found (P?=?0.900). Moreover, medication adherence, diabetes knowledge, and skill in using insulin injection improved at the end of the study (P?<?0.001). In conclusion, the combination of language-specific educational DVD and pharmacist intervention appears to improve the short-term outcomes of diabetes care in Muslim patients on correctional insulin therapy.     

Increased serum levels of adhesion molecules ICAM-1 and VCAM-1 in systemic sclerosis are not specific for pulmonary manifestations

Studies suggest elevated serum intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels may be markers of pulmonary arterial hypertension in systemic sclerosis (SSc-PAH). We sought to evaluate whether ICAM-1 and VCAM-1 levels are useful screening biomarkers for incident SSc-PAH. In this cross-sectional study, four groups were selected from the Australian Scleroderma Cohort Study: group 1 (n?=?15) had definite PAH; group 2 (n?=?19) had interstitial lung disease (ILD); group 3 (n?=?30) were SSc-controls; and group 4 (n?=?34) were healthy controls. Serum ICAM-1 and VCAM-1 levels were measured using the Millipore Milliplex MAP Human 2-Plex Panel. There were no differences in ICAM-1 levels in the PAH versus ILD group (263.0?±?85.4 vs 380.4?±?168.3 ng/mL, p?=?0.136), SSc-controls (263.0?±?85.4 vs 253.1?±?98.0 ng/mL, p?=?1.00), or healthy controls (263.0?±?85.4 vs 201.8?±?57.2 ng/mL, p?=?0.093). Similarly, there were no differences in VCAM-1 level in PAH versus ILD groups (1476.2?±?434.9 vs 1424.8?±?527.6 ng/mL, p?=?1.00) and SSc-controls (1476.2?±?434.9 vs 1409.5?±?341.1 ng/mL, p?=?1.00). SSc subjects had significantly higher levels of ICAM-1 (297.4?±?134.0 vs 201.8?±?57.2 ng/mL, p?<?0.0001) and VCAM-1 compared to healthy controls (1432.7?±?427.4 vs 1125.6?±?273.4 ng/mL, p?<?0.0001). Neither ICAM-1 nor VCAM-1 is a specific screening biomarker of SSc-PAH. Instead, increased levels of these adhesion molecules in SSc, irrespective of pulmonary complications, suggest that they may play a role in SSc pathogenesis.     

EphB4 mediates resistance to antiangiogenic therapy in experimental glioma

Introduction

Alterations in vascular morphogenesis are hallmarks of antiangiogenesis-resistant tumor vessels. Vascular morphogenesis is regulated by ephrinB2-EphB4 system which may induce different biological effects depending on the oncological and molecular contexts. It was the aim of the current study to characterize the influence of EphB4 on tumor microcirculation after antiangiogenic treatment using different SF126 glioma models.

Materials and methods

Using an ecotropic transfection system, empty vector (pLXSN) or EphB4 (EphB4^OE) overexpressing Phoenix-ECO cells were coimplanted with SF126 glioma cells subcutaneously (dorsal skinfold chamber, DSC) and orthotopically (cranial window, CW). Tumor volume was assessed by MRI. Intravital microscopy (IVM) allowed microcirculatory analysis (total {TVD} and functional vessel density {FVD}, diameter {D}, and permeability index {PI}) before and after antiangiogenic treatment (Sunitinib: DSC: 40 mg/kg BW, 6 days; CW: 80 mg/kg BW, 4 days). Immunohistochemistry included Pecam–Desmin, Ki67, TUNEL, and Caspase 3 stainings.

Results

EphB4^OE induced large and treatment-resistant tumor vessels (FVD: Control/Su: 110?±?23 cm/cm² vs. EphB4^OE/Su: 103?±?42 cm/cm²). Maintenance of pericyte–endothelial cell interactions (Control: 80?±?12 vs. Control/Su: 47?±?26%; EphB4^OE: 88?±?9 vs. EphB4^OE/Su: 74?±?25%) and reduced antiproliferative (Control: 637?±?80 vs. Control/Su: 110?±?22; EphB4^OE: 298?±?108 vs. EphB4^OE/Su: 213?±?80) and proapoptotic responses (Control: 196?±?25 vs. Control / Su: 404?±?60; EphB4^OE: 183?±?20 vs. EphB4^OE/Su: 270?±?66) were observed under EphB4 overexpression.

Conclusion

EphB4 overexpression leads to vascular resistance by altering vascular morphogenesis, pericyte coverage, and cellular proliferation/apoptosis in experimental SF126 glioma models.

     

Lipoprotein-associated phospholipase A2 activity in obese adolescents with and without type 2 diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) was identified as a strong predictor for cardiovascular events. Furthermore, it is highly associated with obesity. The role of Lp-PLA2 in diabetes mellitus is controversial and analyses, especially in adolescents with type 2 diabetes (T2D), are missing. Therefore, we compared Lp-PLA2 activity between two obese age-, sex-, and BMI-matched cohorts of adolescents with and without T2D. Relationships between Lp-PLA2 activity and age, BMI, hemoglobin A1c, lipids, and adipokines were evaluated. Lp-PLA2 activity was analyzed in serum of 72 obese adolescents without T2D (mean age 15.2 ± 1.6 years) and in 65 obese adolescents with T2D (mean age 15.5 ± 1.8 years). Clinical data were obtained from the Diabetes-Patienten-Verlaufsdokumentation (DPV) registry. Surprisingly, obese adolescents with T2D had lower levels of Lp-PLA2 activity than obese children without T2D (160.2 ± 45.0 versus 180.9 ± 35.6 nmol/min/ml, p = 0.003), but this decrease could only be detected in male (158.8 ± 45.3 versus 190.8 ± 31.3 nmol/min/ml, p < 0.001) and not in female adolescents (162.1 ± 45.5 versus 167.7 ± 37.1 nmol/min/ml, p = 0.60). In multiple linear regression analysis, differences in Lp-PLA2 activity between cohorts remained large and significant (ß-coefficient: ?31.60, 95% confidence interval [?49.27;?13.93], p < 0.001). Furthermore, Lp-PLA2 activity was positively associated with BMI (ß-coefficient: 2.04 [0.68;3.40], p = 0.004) and negatively associated with the adipokines leptin (ß-coefficient: ?0.53 [?0.89;?0.17], p = 0.004) and adiponectin (ß-coefficient: ?3.06, [?5.63;?0.48], p = 0.02). Elevated mean glucose concentrations in adolescents with T2D were not associated with an increase but with a decrease of Lp-PLA2 activity. Hence, in young patients with T2D the Lp-PLA2 activity as a risk predictor for cardiovascular events needs further investigation.     

Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology

Purpose

Mechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch.

Methods

Atrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n?=?28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3 μM).

Results

On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3 μM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3 μM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138 ± 26 ms vs 95 ± 9 ms; p?<?0.01), ventricular refractoriness (155 ± 18 ms vs 124 ± 16 ms; p?<?0.01) and increments in spectral concentration (23 ± 5% vs 17 ± 2%; p?<?0.01), the fifth percentile of ventricular activation intervals (46 ± 8 ms vs 31 ± 3 ms; p?<?0.05), and wavelength of ventricular fibrillation (2.5 ±0.5 cm vs 1.7 ± 0.3 cm; p?<?0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control?=?38%, 0.03 μM?=?33%, 0.1 μM?=?33%, 0.3 μM?=?14%; p?<?0.01) and the stretch-induced increments in arrhythmia complexity index (control?=?62%, 0.03μM?=?41%, 0.1 μM?=?32%, 0.3 μM?=?16%; p?<?0.05) progressively decreased on increasing the GS967 concentration.

Conclusions

GS967 attenuates stretch-induced changes in cardiac electrophysiology.

     

Effects of <Emphasis Type="Italic">S</Emphasis>-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback

Electromechanical coupling studies have described the intervention of nitric oxide and S-nitrosylation processes in Ca²⁺ release induced by stretch, with heterogeneous findings. On the other hand, ion channel function activated by stretch is influenced by nitric oxide, and concentration-dependent biphasic effects upon several cellular functions have been described. The present study uses isolated and perfused rabbit hearts to investigate the changes in mechanoelectric feedback produced by two different concentrations of the nitric oxide carrier S-nitrosoglutathione. Epicardial multielectrodes were used to record myocardial activation at baseline and during and after left ventricular free wall stretch using an intraventricular device. Three experimental series were studied: (a) control (n?=?10); (b) S-nitrosoglutathione 10 µM (n?=?11); and (c) S-nitrosoglutathione 50 µM (n?=?11). The changes in ventricular fibrillation (VF) pattern induced by stretch were analyzed and compared. S-nitrosoglutathione 10 µM did not modify VF at baseline, but attenuated acceleration of the arrhythmia (15.6?±?1.7 vs. 21.3?±?3.8 Hz; p?<?0.0001) and reduction of percentile 5 of the activation intervals (42?±?3 vs. 38?±?4 ms; p?<?0.05) induced by stretch. In contrast, at baseline using the 50 µM concentration, percentile 5 was shortened (38?±?6 vs. 52?±?10 ms; p?<?0.005) and the complexity index increased (1.77?±?0.18 vs. 1.27?±?0.13; p?<?0.0001). The greatest complexity indices (1.84?±?0.17; p?<?0.05) were obtained during stretch in this series. S-nitrosoglutathione 10 µM attenuates the effects of mechanoelectric feedback, while at a concentration of 50 µM the drug alters the baseline VF pattern and accentuates the increase in complexity of the arrhythmia induced by myocardial stretch.     

Hemodynamic impact of percutaneous left atrial appendage closure in patients with paroxysmal atrial fibrillation

Purpose

Percutaneous left atrial appendage (LAA) closure has become a valid alternative to anticoagulation therapy for the prevention of thromboembolic events in patients with atrial fibrillation (AF). However, scarce data exist on the impact of LAA closure on left atrial and ventricular function. We sought to assess the acute hemodynamic changes associated with percutaneous LAA closure in patients with paroxysmal AF.

Methods

The study population consisted of 31 patients (mean age 73?±?10 years; 49% women) with paroxysmal AF who underwent successful percutaneous LAA closure. All patients were in sinus rhythm and underwent 2D transthoracic echocardiography at baseline and the day after the procedure. A subset of 14 patients underwent preprocedural cardiac computed tomography (CT) with 3D LA and LAA reconstruction.

Results

Left ventricular systolic function parameters and LA volumetric indexes remained unchanged after the procedure. No significant changes in left ventricular stroke volume (72.4?±?16.0 vs. 73.3?±?15.7 mL, p?=?0.55) or LA stroke volume (total 15.6?±?4.2 vs. 14.6?±?4.2 mL, p?=?0.21; passive 9.0?±?2.8 vs. 8.3?±?2.6 mL, p?=?0.31; active 10.3?±?5.6 vs. 10.0?±?6.4 mL, p?=?0.72) occurred following LAA closure. Mean ratio of LAA to LA volume by 3D CT was 10.2?±?2.3%. No correlation was found between LAA/LA ratio and changes in LA stroke volume (r?=?0.35, p?=?0.22) or left ventricular stroke volume (r?=?0.28, p?=?0.33).

Conclusions

The LAA accounts for about 10% of the total LA volume, but percutaneous LAA closure did not translate into any significant changes in LA and left ventricular function.

     

Dual X-ray absorptiometry body composition and its associated factors in children and adolescence with type 1 diabetes mellitus in South of Iran,a case-control study

To date, limited studies have been conducted for evaluation of the body composition with the dual X-ray energy absorptiometry (DEXA) method in children with type 1 diabetes mellitus (T1DM). Also, there are lack of data about factors associated with body composition parameters in T1DM children. This case-control study was performed on T1DM children whom had referred to Diabetes Clinics of Shiraz University of Medical Sciences, 2013–2014. Weight, height, physical activity, sun exposure, insulin regimen, and the Tanner stage of children were recorded by a trained physician. Serum lipids and glycemic tests were assessed. Body composition was assessed by the DEXA Hologic system. Statistical analysis was carried out using SPSS 18.0 software. Eighty-seven T1DM children (39 male and 48 females) and 87 age- and sex-matched healthy controls with a mean age of 12.4 ± 4.2 years were enrolled in this study. Fat mass index was more in T1DM (P = 0.012), and lean mass index was more in non-diabetic children (P = 0.013). The android/gynecoid fat ratio in T1DM children was less than that of controls (P = 0.002). On multiple regression analysis, there was an independent effect of Tanner stage (P < 0.001) and FBS (P = 0.045) on total fat, an independent positive effect of age onset of T1DM (P < 0.001) on total lean mass. This study revealed an increase in the body fat index and a decrease in the lean mass index in T1DM children.