Oral DNA vaccination with a plasmid encoding soluble ICAM-1 modulates cytokine expression profiles in nonobese diabetic mice

Adhesion molecules are important for leukocyte extravasation and for the delivery of costimulatory signals in T cell activation. We therefore interfered in the immune process leading to islet inflammation in diabetes prone NOD mice by oral vaccination with plasmid DNA encoding soluble ICAM-1. Female NOD mice were treated orally with ICAM-1, TGF-beta, or control plasmid DNA and received a single injection of cyclophosphamide for synchronization and acceleration of the disease process in the pancreas. Quantitative RT-PCR analysis of pancreatic mRNA showed that cyclophosphamide induced the expression of Th1 cytokines (IFN-gamma and IL-12p40) in vehicle- or control plasmid-treated mice. Treatment with ICAM-1 and TGF-beta DNA resulted in increased levels of IL-10 mRNA in the pancreas, indicating an anti-inflammatory regulatory immune response. Histological analysis of pancreatic islets showed that the DNA treatment did not alter islet infiltration in response to cyclophosphamide. Hence vaccination with the ICAM-1 plasmid had not suppressed leukocyte migration but rather modulated lymphocyte activity, similarly as seen for the TGF-beta-encoding plasmid. Neither of the three plasmids caused recognizable changes in cytokine expression in the small intestine, Peyer's patches, or mesenteric lymph nodes. We conclude that oral vaccination with DNA encoding immunoregulatory molecules such as ICAM-1 and TGF-beta represents an approach for modulating the ongoing inflammatory process in the pancreas of diabetes prone NOD mice.     

Catheter ablation of ventricular tachycardias using remote magnetic navigation: a consecutive case-control study

Remote Magnetic Navigation for VT Ablation. Background: This study aimed to compare acute and late outcomes of VT ablation using the magnetic navigation system (MNS) to manual techniques (MAN) in patients with (SHD) and without (NSHD) structural heart disease. Methods: Ablation data of 113 consecutive patients (43 SHD, 70 NSHD) with ventricular tachycardia treated with catheter ablation at our center were analyzed. Success rate, complications, procedure, fluoroscopy, and ablation times, and recurrence rates were systematically recorded for all patients. Results: A total of 72 patients were included in the MNS group and 41 patients were included in the MAN group. Patient age, gender, and right ventricular and left ventricular VT were equally distributed. Acute success was achieved in 59 patients in the MNS group (82%) versus 27 (66%) patients in the MAN group (P = 0.046). Overall procedural time (177 ± 79 vs 232 ± 99 minutes, P < 0.01) and mean patient fluoroscopy time (27 ± 19 vs 56 ± 32 minutes, P < 0.001) were all significantly lower using MNS. In NSHD pts, higher acute success was achieved with MNS (83,7% vs 61.9%, P = 0.049), with shorter procedure times (151 ± 57 vs 210 ± 96, P = 0.011), whereas in SHD‐VT these were not significantly different. No major complications occurred in the MNS group (0%) versus 1 cardiac tamponade and 1 significantly damaged ICD lead in the MAN group (4.9%, NS). After follow‐up (20 ± 11 vs 20 ± 10 months, NS), VT recurred in 14 pts (23.7%) in the MNS group versus 12 pts (44.4%) in the MAN group (P = 0.047). Conclusions: The use of MNS offers advantages for ablation of NSHD‐VT, while it offers similar efficacy for SHD‐VT. ((J Cardiovasc Electrophysiol, Vol. 23, pp. 948‐954, September 2012)     

A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity

BACKGROUND: Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. METHODS: In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause. RESULTS: The AMH Ile(49)Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 -482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063). CONCLUSIONS: The observed association of the AMHR2 -482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.     

Circulating uncarboxylated matrix Gla protein,a marker of vitamin K status,as a risk factor of cardiovascular disease

Objectives

Vitamin K plays a pivotal role in the synthesis of Matrix Gla protein (MGP), a calcification inhibitor in vascular tissue. Vascular calcification has become an important predictor of cardiovascular disease. The aim of the current study was to examine the potential association of circulating desphospho-carboxylated and -uncarboxylated MGP (dp-cMGP and dp-ucMGP), reflecting vitamin K status, with the incidence of cardiovascular events and disease (CVD) in older individuals.

Study design

The study was conducted in 577 community-dwelling older men and women of the Longitudinal Aging Study Amsterdam (LASA), aged >55 year, who were free of cardiovascular disease at baseline. Multivariate Cox proportional hazards models were used to analyze the data.

Main outcome measures

Incidence of CVD.

Results

After a mean follow-up of 5.6 ± 1.2 year, we identified 40 incident cases of CVD. After adjustment for classical confounders and vitamin D status, we observed a more than 2-fold significantly higher risk of CVD for the highest tertile of dp-ucMGP with a HR of 2.69 (95% CI, 1.09–6.62) as compared with the lowest tertile. Plasma dp-cMGP was not associated with the risk of CVD.

Conclusions

Vitamin K insufficiency, as assessed by high plasma dp-ucMGP concentrations is associated with an increased risk for cardiovascular disease independent of classical risk factors and vitamin D status. Larger epidemiological studies on dp-ucMGP and CVD incidence are needed followed by clinical trials to test whether vitamin K-rich diets will lead to a decreased risk for cardiovascular events.     

Increased carotid wall thickening after radiotherapy on the neck

Patients treated for head and neck tumours with local radiotherapy (RT) on the neck harbour an increased risk of stroke. This may be due to accelerated atherosclerotic changes within the RT-field; however, the real impact of local RT on the carotid artery remains debatable. The aim of the present study was to assess the difference in carotid wall thickness (intima-media thickness) in 42 unilaterally irradiated parotid tumour patients by performing B-mode ultrasonography. A mean difference in intima-media thickness (IMT) of the irradiated compared with the non-irradiated carotid artery of 0.30 mm (P=0.031) was found. A significant correlation was established with a longer post-RT interval (P=0.008). RT on the neck is associated with increased thickening of carotid IMT. Screening and treatment of additional cerebrovascular risk factors which contribute to further IMT thickening and stroke development is recommended, especially in radiotherapy patients with a favourable prognosis.     

Reviewing the effort-reward imbalance model: drawing up the balance of 45 empirical studies

The present paper provides a review of 45 studies on the Effort-Reward Imbalance (ERI) Model published from 1986 to 2003 (inclusive). In 1986, the ERI Model was introduced by Siegrist et al. (Biological and Psychological Factors in Cardiovascular Disease, Springer, Berlin, 1986, pp. 104-126; Social Science & Medicine 22 (1986) 247). The central tenet of the ERI Model is that an imbalance between (high) efforts and (low) rewards leads to (sustained) strain reactions. Besides efforts and rewards, overcommitment (i.e., a personality characteristic) is a crucial aspect of the model. Essentially, the ERI Model contains three main assumptions, which could be labeled as (1) the extrinsic ERI hypothesis: high efforts in combination with low rewards increase the risk of poor health, (2) the intrinsic overcommitment hypothesis: a high level of overcommitment may increase the risk of poor health, and (3) the interaction hypothesis: employees reporting an extrinsic ERI and a high level of overcommitment have an even higher risk of poor health. The review showed that the extrinsic ERI hypothesis has gained considerable empirical support. Results for overcommitment remain inconsistent and the moderating effect of overcommitment on the relation between ERI and employee health has been scarcely examined. Based on these review results suggestions for future research are proposed.