Changes in anti-heat shock protein 27 antibody and C-reactive protein levels following cardiac surgery and their association with cardiac function in patients with cardiovascular disease

The relationship between serum anti-heat shock protein (Hsp)27 antibody and high sensitive C-reactive protein (hs-CRP) levels and indices of cardiac function were investigated in patients undergoing coronary artery bypass grafting (CABG) or heart valve replacement. The changes in anti-Hsp27 antibody titers and hs-CRP levels were compared among patients undergoing off-pump and on-pump CABG or valvular heart replacement. Fifty-three patients underwent off-pump, on-pump CABG, and heart valvular replacement in each group. Serum anti-Hsp27 titers and hs-CRP values were measured 24 h before and after the operation and at discharge. Echocardiography was performed before surgery and before discharge. The results were compared with values from 83 healthy controls. hs-CRP levels increased and anti-Hsp27 antibody decreased following surgery (P < 0.001 and P < 0.05, respectively), although these changes were independent of operative procedure (P = 0.361 and P = 0.120, respectively). Anti-Hsp27 antibody levels were higher at the time of discharge (P = 0.016). Only in coronary patients were anti-Hsp27 antibody levels negatively associated with E/E′ (r = −0.268, P = 0.022), a marker of pulmonary capillary wedge pressure. In conclusions, anti-Hsp27 antibody levels are associated with indices of cardiac function in coronary patients. Cardiopulmonary bypass had no significant effect on the induction of changes in anti-Hsp27 levels. Moreover, anti-Hsp27 antibody levels fell in all groups postoperatively; this may be due to the formation of immune complexes of antigen–antibody, and antibody levels were higher at the time of discharge.

Electronic supplementary material

The online version of this article (doi:10.1007/s12192-012-0358-y) contains supplementary material, which is available to authorized users.     

Intercellular synchronization of diffusively coupled Ca2+ oscillators

We examine the synchrony in the dynamics of localized [Ca^2 +]_i oscillations among a group of cells exhibiting such complex Ca^2 + oscillations, connected in the form of long chain, via diffusing coupling where cytosolic Ca^2 + and inositol 1,4,5-triphosphate are coupling molecules. Based on our numerical results, we could able to identify three regimes, namely desynchronized, transition and synchronized regimes in the (T − k_e) (time period-coupling constant) and (A − k_e) (amplitude-coupling constant) spaces which are supported by phase plots (Δϕ verses time) and recurrence plots, respectively. We further show the increase of synchronization among the cells as the number of coupling molecules increases in the (T − k_e) and (A − k_e) spaces.     

The ethnicity-specific association of biomarkers with the angiographic severity of coronary artery disease

Background

Risk factor burden and clinical characteristics of patients with coronary artery disease (CAD) differ among ethnic groups. We related biomarkers to CAD severity in Caucasians, Chinese, Indians and Malays.

Methods

In the Dutch-Singaporean UNICORN coronary angiography cohort (n = 2033) we compared levels of five cardiovascular biomarkers: N-terminal pro-brain natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP), cystatin C (CysC), myeloperoxidase (MPO) and high-sensitivity troponin I (hsTnI). We assessed ethnicity-specific associations of biomarkers with CAD severity, quantified by the SYNTAX score.

Results

Adjusted for baseline differences, NTproBNP levels were significantly higher in Malays than in Chinese and Caucasians (72.1 vs. 34.4 and 41.1 pmol/l, p < 0.001 and p = 0.005, respectively). MPO levels were higher in Caucasians than in Indians (32.8 vs. 27.2 ng/ml, p = 0.026), hsTnI levels were higher in Malays than in Caucasians and Indians (33.3 vs. 16.4 and 17.8 ng/l, p < 0.001 and p = 0.029) and hsTnI levels were higher in Chinese than in Caucasians (23.3 vs. 16.4, p = 0.031). We found modifying effects of ethnicity on the association of biomarkers with SYNTAX score. NTproBNP associated more strongly with the SYNTAX score in Malays than Caucasians (β 0.132 vs. β 0.020 per 100 pmol/l increase in NTproBNP, p = 0.032). For MPO levels the association was stronger in Malays than Caucasians (β 1.146 vs. β 0.016 per 10 ng/ml increase, p = 0.017). Differing biomarker cut-off levels were found for the ethnic groups.

Conclusion

When corrected for possible confounders we observe ethnicity-specific differences in biomarker levels. Moreover, biomarkers associated differently with CAD severity, suggesting that ethnicity-specific cut-off values should be considered.     

Follow-up of implantable cardioverter-defibrillator therapy: comparison of coronary artery disease and dilated cardiomyopathy

Purpose

Since several large trials have proven the effectiveness of implantable cardioverter-defibrillators (ICDs) in patients with left ventricular dysfunction, disadvantages have become more apparent. As the prognosis of patients with cardiovascular diseases is improving, assessment of ICD patients and re-evaluation of the current guidelines is mandatory. We aimed to evaluate differences in mortality and occurrence of (in)appropriate shocks in ICD patients with coronary artery disease (CAD) or dilated cardiomyopathy (DCM).

Methods

In a large teaching hospital, all consecutive patients with systolic dysfunction due to CAD or DCM who received an ICD with and without resynchronisation therapy, were collected in a database.

Results

A total of 320 consecutive patients (age 67 ± 10 years) were classified as CAD patients and 178 (63 ± 11 years) as DCM patients. Median follow-up was 40 months (interquartile range [IQR] 23─57 months). All–cause mortality was 14 % (CAD 15 % vs DCM 13 %). Appropriate shocks occurred in 13 % of all patients (CAD 15 % vs DCM 11 %, p = 0.12) and inappropriate shocks occurred in 10 % (CAD 8 % vs DCM 12 %, p = 0.27). Multivariate analysis demonstrated impaired left ventricular ejection fraction, QRS >120, age ≥75 years and low estimated glomerular filtration rate as predictors for all-cause mortality. Predictors for inappropriate shocks were permanent and paroxysmal atrial fibrillation.

Conclusion

Mortality rates were similar in patients with CAD and DCM who received an ICD. Furthermore, no differences were found in the occurrence of appropriate and inappropriate ICD interventions between these patient groups.     

Vitamin k-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype

Background

Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE^−/− model of atherosclerosis.

Methodology/Principal Findings

A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE^−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K₁ (VK₁, 1.5 mg/g) or vitamin K₁ and warfarin (VK₁&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.

Conclusions/Significance

VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE^−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.     

Diagnostic and prognostic value of absence of coronary artery calcification in patients with stable chest symptoms

The aim of this study was to determine the prognostic value of a coronary artery calcium score (CACS) of 0 in patients with stable chest symptoms and to compare it as a first-line test with bicycle exercise testing (X-ECG). Altogether, 315 consecutive patients over 44 years of age, with stable chest symptoms and no previous diagnosis of coronary artery disease (CAD) visited the outpatient clinic of our community hospital and underwent both CACS and X-ECG. The mean age was 60.54 years (SD 9.7; range 45–88 years). Of these patients, 141 had no detectable coronary calcium (44.8%) We excluded patients who did not sign informed consent (n = 4). Three patients were lost to follow-up. The follow-up group therefore consisted of 134 patients. The mean follow-up period was 44.6 months (25th–75th percentile: 35.5–54.3 months), during which no major adverse cardiac events (MACE) occurred. The negative predictive value (NPV) was 100%. X-ECG was negative in only 89 patients, equivocal in 39 patients and false-positive in 6 patients requiring additional stress myocardial imaging in 45 patients. NPV as a first-line test was therefore 66.4%. In conclusion: patients over 44 years with stable chest symptoms and no detectable coronary calcium have an excellent prognosis. CACS performs better compared with X-ECG as an initial test in patients with stable chest symptoms.     

The IL-33-ST2L Pathway Is Associated with Coronary Artery Disease in a Chinese Han Population

The effects of interleukin-33 (IL-33) on the immune system have been clearly demonstrated; however, in cardiovascular diseases, especially in coronary artery disease (CAD), these effects have not yet been clarified. In this study, we investigate the genetic role of the IL-33-ST2L pathway in CAD. We performed three-stage case-control association analyses on a total of 4,521 individuals with CAD and 4,809 controls via tag SNPs in the genes encoding IL-33 and ST2L-IL-1RL1. One tag SNP in each gene was significantly associated with CAD (rs7025417^T in IL33, p_adj = 1.19 × 10⁻²⁸, OR = 1.39, 95% CI: 1.31–1.47; rs11685424^G in IL1RL1, p_adj = 6.93 × 10⁻³⁰, OR = 1.40, 95% CI: 1.32–1.48). Combining significant variants in two genes, the risk for CAD increased nearly 5-fold (p_adj = 8.90 × 10⁻²¹, OR = 4.98, 95% CI: 3.56–6.97). Traditional risk factors for CAD were adjusted for the association studies by SPSS with logistic regression analysis. With the two variants above, both located within the gene promoter regions, reporter gene analysis indicated that the rs7025417 C>T and rs11685424 A>G changes resulted in altered regulation of IL33 and IL1RL1 gene expression, respectively (p < 0.005). Further studies revealed that the rs7025417 genotype was significantly associated with plasma IL-33 levels in the detectable subjects (n = 227, R² = 0.276, p = 1.77 × 10⁻¹⁷): the level of IL-33 protein increased with the number of rs7025417 risk (T) alleles. Based on genetic evidence in humans, the IL-33-ST2L pathway appears to have a causal role in the development of CAD, highlighting this pathway as a valuable target for the prevention and treatment of CAD.     

Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study

The risk for cardiovascular (CV) disease is increased in rheumatoid arthritis (RA) but data on the burden of coronary atherosclerosis in patients with RA are lacking. We conducted a retrospective case-control study of Olmsted County (MN, USA) residents with RA and new-onset coronary artery disease (CAD) (n = 75) in comparison with age-and sex-matched controls with newly diagnosed CAD (n = 128). Angiographic scores of the first coronary angiogram and data on CV risk factors and CV events on follow-up were obtained by chart abstraction. Patients with RA were more likely to have multi-vessel coronary involvement at first coronary angiogram compared with controls (P = 0.002). Risk factors for CAD including diabetes, hypertension, hyperlipidemia, and smoking history were not significantly different in the two cohorts. RA remained a significant risk factor for multi-vessel disease after adjustment for age, sex and history of hyperlipidemia. The overall rate of CV events was similar in RA patients and controls; however, there was a trend for increased CV death in patients with RA. In a nested cohort of patients with RA and CAD (n = 27), we measured levels of pro-inflammatory CD4⁺CD28^null T cells by flow cytometry. These T cells have been previously implicated in the pathogenesis of CAD and RA. Indeed, CD4⁺CD28^null T cells were significantly higher in patients with CAD and co-existent RA than in controls with stable angina (P = 0.001) and reached levels found in patients with acute coronary syndromes. Patients with RA are at increased risk for multi-vessel CAD, although the risk of CV events was not increased in our study population. Expansion of CD4⁺CD28^null T cells in these patients may contribute to the progression of atherosclerosis.     

In vitro propagation of female Ephedra foliata Boiss. & Kotschy ex Boiss.: an endemic and threatened Gymnosperm of the Thar Desert

Ephedra foliata Boiss. & Kotschy ex Boiss., (family – Ephedraceae), is an ecologically and economically important threatened Gymnosperm of the Indian Thar Desert. A method for micropropagation of E. foliata using nodal explant of mature female plant has been developed. Maximum bud-break (90 %) of the explant was obtained on MS medium supplemented with 1.5 mg l⁻¹ of benzyl adenine (BA) + additives. Explant produces 5.3 ± 0.40 shoots from single node with 3.25 ± 0.29 cm length. The multiplication of shoots in culture was affected by salt composition of media, types and concentrations of plant growth regulators (PGR’s) and their interactions, time of transfer of the cultures. Maximum number of shoots (26.3 ± 0.82 per culture vessel) were regenerated on MS medium modified by reducing the concentration of nitrates to half supplemented with 200 mg l⁻¹ ammonium sulphate {(NH₄) ₂SO₄} (MMS3) + BA (0.25 mg l⁻¹), Kinetin (Kin; 0.25 mg l⁻¹), Indole-3-acetic acid (IAA; 0.1 mg l⁻¹) and additives. The in vitro produced shoots rooted under ex vitro on soilrite moistened with one-fourth strength of MS macro salts in screw cap bottles by treating the shoot base (s) with 500 mg l⁻¹ of Indole-3-butyric acid (IBA) for 5 min. The micropropagated plants were hardened in the green house. The described protocol can be applicable for (i) large scale plant production (ii) establishment of plants in natural habitat and (iii) germplasm conservation of this endemic Gymnosperm of arid regions.     

Right ventricular function in dilated cardiomyopathy and ischemic heart disease: assessment with non-invasive imaging

Background

Dilated cardiomyopathy and ischaemic heart disease can both lead to right ventricular (RV) dysfunction. Direct comparisons of the two entities regarding RV size and function using state-of-the-art imaging techniques have not yet been performed. We aimed to determine RV function and volume in dilated cardiomyopathy and ischaemic heart disease in relation to left ventricular (LV) systolic and diastolic function and systolic pulmonary artery pressure.

Methods and results

A well-characterised group (cardiac magnetic resonance imaging, echocardiography, coronary angiography and endomyocardial biopsy) of 46 patients with dilated cardiomyopathy was compared with LV ejection fraction (EF)-matched patients (n = 23) with ischaemic heart disease. Volumes and EF were determined with magnetic resonance imaging, diastolic LV function and pulmonary artery pressure with echocardiography.After multivariable linear regression, four factors independently influenced RVEF (R² = 0.51, p < 0.001): LVEF (r = 0.54, p < 0.001), ratio of peak early and peak atrial transmitral Doppler flow velocity as measure of LV filling pressure (r = − 0.52, p < 0.001) and tricuspid regurgitation flow velocity as measure of pulmonary artery pressure (r = − 0.38, p = 0.001). RVEF was significantly worse in patients with dilated cardiomyopathy compared with ischaemic heart disease: median 48 % (interquartile range (IQR) 37–55 %) versus 56 % (IQR 48–63 %), p < 0.05.

Conclusions

In patients with dilated cardiomyopathy and ischaemic heart disease, RV function is determined by LV systolic and diastolic function, the underlying cause of LV dysfunction, and pulmonary artery pressure. It was demonstrated that RV function is more impaired in dilated cardiomyopathy.     

Small-Size Circulating Endothelial Microparticles in Coronary Artery Disease

Objectives

Several recent lines of evidence indicate that endothelial microparticles are a new biomarker that can be used to monitor endothelial dysfunction in coronary artery disease (CAD). However, data concerning the detection of small microparticles (diameter <0.5 µm) are lacking. The aim of this study was to detect small-size endothelial microparticles (SEMPs) in CAD patients to monitor endothelial dysfunction.

Methods

In total, 19 CAD patients and 14 healthy subjects were recruited. The absolute numbers and percentages of CD31⁺/CD42b⁻ SEMPs and CD62E⁺ SEMPs were determined by flow cytometry. Clinical parameters were also recorded.

Results

The mean percentage of CD62E⁺ SEMPs was higher in the CAD patient group than in the healthy subject group. The area under the receiver operating characteristic curve of the percentage of CD62E⁺ SEMPs was 0.795, and the cut-off value was 1.35. There was no correlation between the percentage of CD62E⁺ SEMPs and various clinical parameters.

Conclusion

The percentage of CD62E⁺ SEMPs is a potential biomarker for monitoring endothelial function in CAD.     

Microscopic Modeling of País Grape Seed Extract Absorption in the Small Intestine

The concentration profiles and the absorbed fraction (F) of the País grape seed extract in the human small intestine were obtained using a microscopic model simulation that accounts for the extracts'' dissolution and absorption. To apply this model, the physical and chemical parameters of the grape seed extract solubility (C_s), density (ρ), global mass transfer coefficient between the intestinal and blood content (k) (effective permeability), and diffusion coefficient (D) were experimentally evaluated. The diffusion coefficient (D = 3.45 × 10⁻⁶ ± 5 × 10⁻⁸ cm²/s) was approximately on the same order of magnitude as the coefficients of the relevant constituents. These results were chemically validated to discover that only the compounds with low molecular weights diffused across the membrane (mainly the (+)-catechin and (−)-epicatechin compounds). The model demonstrated that for the País grape seed extract, the dissolution process would proceed at a faster rate than the convective process. In addition, the absorbed fraction was elevated (F = 85.3%). The global mass transfer coefficient (k = 1.53 × 10⁻⁴ ± 5 × 10⁻⁶ cm/s) was a critical parameter in the absorption process, and minor changes drastically modified the prediction of the extract absorption. The simulation and experimental results show that the grape seed extract possesses the qualities of a potential phytodrug.KEY WORDS: dose absorption, mathematical modeling, País grape seed extract, simulation     

Circulating stem cell vary with NYHA stage in heart failure patients

We have investigated the blood levels of sub-classes of stem cells (SCs) [mesenchymal stem cells (MSCs), haematopoietic stem cells (HSCs), endothelial progenitor cells/circulating endothelial cells (EPCs/CECs) and tissue-committed stem cells (TCSCs)] in heart failure (HF) patients at different stage of pathology and correlated it with plasmatic levels of proangiogenic cytokines. Peripheral blood level of SCs were analysed in 97 HF patients (24 in NYHA class I, 41 in class II, 17 in class III and 15 in class IV) and in 23 healthy controls. Plasmatic levels of PDGF-BB, bFGF, HGF, vascular endothelial growth factor (VEGF), SDF-1α, TNF-α and NTproBNP were also measured. Compared with healthy individuals, MSC, and in particular the sub-classes CD45⁻CD34⁻CD90⁺, CD45⁻CD34⁻CD105⁺ and CD45⁻CD34⁻CXCR4⁺ were significantly enhanced in NYHA class IV patients (16.8-, 6.4- and 2.7-fold, respectively). Level of CD45⁻CD34⁻CD90⁺CXCR4⁺cells progressively increased from class II to class IV (fold increases compared with controls: 8.5, 12 and 21.5, respectively). A significant involvement of CXCR4⁺ subpopulation of HSC (CD45⁺CD34⁺CD90⁺CXCR4⁺, 1.4 versus 13.3 cells/μl in controls and NYHA class III patients, respectively) and TCSC (CD45⁻CD34⁺CXCR4⁺, 1.5 cells/ μl in controls versus 12.4 and 28.6 cells/μl in NYHA classes II and IV, respectively) were also observed. All tested cytokines were enhanced in HF patients. In particular, for PDGF-BB and SDF-1α we studied specific ligand/receptors pairs. Interestingly, the first one positively correlated with TCSCs expressing PDGFR (r = 0.52, P = 0.001), whereas the second one correlated with TCSCs (r = 0.34, P = 0.005) and with MSCs CD90⁺ expressing CXCR4 (r = 0.39, P = 0.001). HF is characterized by the increase in the circulating levels of different MSC, HSC, EPC and TCSC subsets. Both the entity and kinetic of this process varied in distinct cell subsets. Specifically, differently from HSCs and EPCs/CECs, MSCs and TCSCs significantly increased with the progression of the disease, suggesting a possible distinct role of these cells in the pathophysiology of HF.     

Heat-shock protein 60 kDa and atherogenic dyslipidemia in patients with untreated mild periodontitis: a pilot study

Identification of predictors of cardiovascular risk can help in the prevention of pathologic episodes and the management of patients at all stages of illness. Here, we investigated the relationships between serum levels of Hsp60 and dyslipidemia in patients with periodontitis by performing a cross-sectional study of 22 patients with mild periodontitis without any prior treatment for it (i.e., drug naïve) and 22 healthy controls, matched for age and body mass index (BMI). All subjects were evaluated for periodontal status, gingival inflammation, and oral hygiene. Levels of circulating Hsp60, C-reactive protein (CRP), and plasma lipids were measured, and small, dense low-density lipoproteins (LDL) were indirectly assessed by determining the triglycerides/high-density lipoproteins (HDL) cholesterol ratio. We also assessed by immunohistochemistry Hsp60 levels in oral mucosa of patients and controls. No difference was found in CRP levels or plasma lipids between the two groups, but subjects with periodontitis showed, in comparison to controls, higher levels of small, dense LDL (p  = 0.0355) and circulating Hsp60 concentrations (p < 0.0001). However, levels of mucosal Hsp60 did not change significantly between groups. Correlation analysis revealed that circulating Hsp60 inversely correlated with HDL-cholesterol (r  = −0.589, p  = 0.0039), and positively with triglycerides (r  = +0.877, p < 0.0001), and small, dense LDL (r  = +0.925, p < 0.0001). Serum Hsp60 significantly correlated with the degree of periodontal disease (r  = +0.403, p  = 0.0434). In brief, untreated patients with mild periodontitis had increased small, dense LDL and serum Hsp60 concentrations, in comparison to age- and BMI-matched controls and both parameters showed a strong positive correlation. Our data indicate that atherogenic dyslipidemia and elevated circulating Hsp60 tend to be linked and associated to periodontal pathology. Thus, the road is open to investigate the potential value of elevated levels of circulating Hsp60 as predictor of risk for cardiovascular disease when associated to dyslipidemia in periodontitis patients.     

Predicting translational diffusion of evolutionary conserved RNA structures by the nucleotide number

Ribonucleic acids are highly conserved essential parts of cellular life. RNA function is determined to a large extent by its hydrodynamic behaviour. The presented study proposes a strategy to predict the hydrodynamic behaviour of RNA single strands on the basis of the polymer size. By atom-level shell-modelling of high-resolution structures, hydrodynamic radius and diffusion coefficient of evolutionary conserved RNA single strands (ssRNA) were calculated. The diffusion coefficients D of 17–174 nucleotides (nt) containing ssRNA depended on the number of nucleotides N with D = 4.56 × 10⁻¹⁰ N^−0.39 m² s⁻¹. The hydrodynamic radius R_H depended on N with R_H = 5.00 × 10⁻¹⁰ N^0.38 m. An average ratio of the radius of gyration and the hydrodynamic radius of 0.98 ± 0.08 was calculated in solution. The empirical law was tested by in solution measured hydrodynamic radii and radii of gyration and was found to be highly consistent with experimental data of evolutionary conserved ssRNA. Furthermore, the hydrodynamic behaviour of several evolutionary unevolved ribonucleic acids could be predicted. Based on atom-level shell-modelling of high-resolution structures and experimental hydrodynamic data, empirical models are proposed, which enable to predict the translational diffusion coefficient and molecular size of short RNA single strands solely on the basis of the polymer size.     

Evidence for a role of autoantibodies to heat shock protein 60, 70, and 90 in patients with dermatitis herpetiformis

Heat shock proteins (Hsp) are highly conserved immunomodulatory molecules upregulated when cells are exposed to stressful stimuli, such as inflammation. Their involvement in various autoimmune diseases, including autoimmune bullous diseases and celiac disease, has been increasingly recognized. To further study the role of Hsp in autoimmune bullous diseases, we have investigated for the first time the humoral autoimmune response to Hsp40, Hsp60, Hsp70, and Hsp90 in patients with dermatitis herpetiformis (DH; n = 26), bullous pemphigoid (BP; n = 23), and pemphigus vulgaris (PV; n = 16), the first representing a cutaneous manifestation of celiac disease. While in patients with active BP and PV, serum levels of autoantibodies against these Hsp did not differ from the corresponding age- and gender-matched healthy controls (n = 9–14); circulating autoantibodies against Hsp60, Hsp70, and Hsp90 were found to be increased at the active disease stage of DH. Further analysis of this latter patient subgroup showed that these anti-Hsp autoantibodies decreased in parallel with serum autoantibodies against epidermal and tissue transglutaminase during remission of skin lesions following a gluten-free diet, revealing significantly positive correlations. Although further studies on larger groups of patients will be needed to confirm the present data, our results support the notion that autoantibodies against Hsp60, Hsp70, and Hsp90 deserve attention in the study of the mechanisms that promote the development and maintenance of DH and possibly also the underlying celiac disease as well as potential novel disease biomarkers.     

CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration

We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study cohort (p = 7.66 × 10⁻³, 7.83 × 10⁻³, respectively). VEGF-rs699947 was also associated with vision changes at 1 month and PEDF-rs1136287 at 3 months (p = 5.11 × 10⁻³, 2.05 × 10⁻², respectively). These variants may be utilized for genetic biomarkers to estimate visual outcomes in the response to intravitreal bevacizumab treatment for AMD.     

Characterization of the kinetic and thermodynamic landscape of RNA folding using a novel application of isothermal titration calorimetry

A novel isothermal titration calorimetry (ITC) method was applied to investigate RNA helical packing driven by the GAAA tetraloop–receptor interaction in magnesium and potassium solutions. Both the kinetics and thermodynamics were obtained in individual ITC experiments, and analysis of the kinetic data over a range of temperatures provided Arrhenius activation energies (ΔH^‡) and Eyring transition state entropies (ΔS^‡). The resulting rich dataset reveals strongly contrasting kinetic and thermodynamic profiles for this RNA folding system when stabilized by potassium versus magnesium. In potassium, association is highly exothermic (ΔH_25°C = −41.6 ± 1.2 kcal/mol in 150 mM KCl) and the transition state is enthalpically barrierless (ΔH^‡ = −0.6 ± 0.5). These parameters are sigificantly positively shifted in magnesium (ΔH_25°C = −20.5 ± 2.1 kcal/mol, ΔH^‡ = 7.3 ± 2.2 kcal/mol in 0.5 mM MgCl₂). Mixed salt solutions approximating physiological conditions exhibit an intermediate thermodynamic character. The cation-dependent thermodynamic landscape may reflect either a salt-dependent unbound receptor conformation, or alternatively and more generally, it may reflect a small per-cation enthalpic penalty associated with folding-coupled magnesium uptake.     

Peripheral arterial tonometry cannot detect patients at low risk of coronary artery disease

Background

Endothelial dysfunction precedes coronary artery disease (CAD) and can be measured by peripheral arterial tonometry (PAT). We examined the applicability of PAT to detect a low risk of CAD in a chest pain clinic.

Methods

In 93 patients, PAT was performed resulting in reactive hyperaemia (RHI) and augmentation (AIx) indices. Patients were risk classified according to HeartScore, Diamond and Forrester pretest probability (DF), exercise testing (X-ECG), and computed tomography calcium scoring (CCS) and angiography (CTA). Correlations, risk group differences and prediction of revascularisation within 1 year were calculated.

Results

RHI correlated with HeartScore (r = − 0.21, p = 0.05), AIx with DF (r = 0.26, p = 0.01). However, both were not significantly different between normal and ischaemic X-ECG groups. In addition RHI and AIx were similar between low risk as compared with intermediate-to-high risk, based on risk algorithms (RHI: 1.98 (0.67) vs 1.94 (0.78); AIx: 0.0 (21) vs 5.0 (25); p = NS), or CCS and CTA (RHI: 1.99 (0.58) vs 1.89 (0.82); AIx: − 2.0 (24) vs 4.0 (25); p = NS). Finally, RHI and AIx failed to predict revascularisation (RHI: OR 1.42, CI 0.65–3.1; AIx: OR 1.02, CI 0.98–1.05).

Conclusions

PAT cannot detect a low risk of CAD, possibly because RHI and AIx versus X-ECG, CCS and CTA represent independent processes.