Endothelial Dysfunction and Brachial Intima-Media Thickness: Long Term Cardiovascular Risk with Claudication Related to Peripheral Arterial Disease: A Prospective Analysis

Objective

Endothelial dysfunction plays a key role in the development, progression, and clinical manifestation of atherosclerosis, and in symptomatic peripheral arterial disease, endothelial dysfunction and enlarged intima-media thickness might be associated with increased cardiovascular risk. Flow-mediated dilatation and serologic parameters are used to evaluate individual endothelial function. Brachial intima-media thickness, a less recognized parameter of cardiovascular risk, is independently associated with coronary artery disease. The aim of this study was to evaluate the prognostic value of ultrasound and serologic parameters of endothelial function in relation to cardiovascular mortality in peripheral arterial disease.

Design

monocentric, prospective cohort study.

Methods

Flow mediated dilatation and brachial intima-media thickness were assessed in 184 (124 male) patients with peripheral arterial disease (Rutherford stages 2–3). Serologic parameters of endothelial function included asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-homoarginine. Cardiovascular events were recorded during a follow-up of 99.1±11.1 months. Subjects who died of noncardiovascular causes were excluded from further analysis.

Results

Eighty-two patients (44.6%) died during follow-up after a mean duration of 49.7±28.3 months. There were 49 cardiovascular deaths (59.8%) and 33 other deaths (40.2%). Flow mediated dilatation was associated with cardiovascular death [1.17% (0.0, 4.3) vs. 4.1% (1.2, 6.4), p<0.001]. Intima-media thickness was greater in patients who succumbed to cardiovascular disease [0.37 mm (0.30, 0.41)] than in survivors [0.21 mm (0.15, 0.38), p<0.001]. Brachial intima-media thickness above 0.345 mm was most predictive of cardiovascular death, with sensitivity and specificity values of 0.714 and 0.657, respectively (p<0.001). Furthermore, ADMA levels above 0.745 µmol/l and SDMA levels above 0.825 µmol/l were significantly associated with cardiovascular death (p<0.001 and 0.030).

Conclusion

In symptomatic peripheral arterial disease, decreased flow mediated dilatation, enlarged intima-media thickness, and elevated levels of ADMA and SDMA were associated with increased cardiovascular risk.     

Meta-Regression Analyses to Explain Statistical Heterogeneity in a Systematic Review of Strategies for Guideline Implementation in Primary Health Care

This study is an in-depth-analysis to explain statistical heterogeneity in a systematic review of implementation strategies to improve guideline adherence of primary care physicians in the treatment of patients with cardiovascular diseases. The systematic review included randomized controlled trials from a systematic search in MEDLINE, EMBASE, CENTRAL, conference proceedings and registers of ongoing studies. Implementation strategies were shown to be effective with substantial heterogeneity of treatment effects across all investigated strategies. Primary aim of this study was to explain different effects of eligible trials and to identify methodological and clinical effect modifiers. Random effects meta-regression models were used to simultaneously assess the influence of multimodal implementation strategies and effect modifiers on physician adherence. Effect modifiers included the staff responsible for implementation, level of prevention and definition pf the primary outcome, unit of randomization, duration of follow-up and risk of bias. Six clinical and methodological factors were investigated as potential effect modifiers of the efficacy of different implementation strategies on guideline adherence in primary care practices on the basis of information from 75 eligible trials. Five effect modifiers were able to explain a substantial amount of statistical heterogeneity. Physician adherence was improved by 62% (95% confidence interval (95% CI) 29 to 104%) or 29% (95% CI 5 to 60%) in trials where other non-medical professionals or nurses were included in the implementation process. Improvement of physician adherence was more successful in primary and secondary prevention of cardiovascular diseases by around 30% (30%; 95% CI -2 to 71% and 31%; 95% CI 9 to 57%, respectively) compared to tertiary prevention. This study aimed to identify effect modifiers of implementation strategies on physician adherence. Especially the cooperation of different health professionals in primary care practices might increase efficacy and guideline implementation seems to be more difficult in tertiary prevention of cardiovascular diseases.     

Magnetic resonance imaging, computed tomography, and conventional X-ray in 3 cases of symmelia

BACKGROUND: Symmelia is a rare birth defect, often combined with severe malformations of the urogenital system and the lower gastrointestinal tract. Additionally, a deformed pelvis and various degrees of separation of the lower limbs are present. CASES: We report the examination findings of 3 autopsy specimens of symmelia using magnetic resonance imaging (MRI) and computed tomography (CT) with 3-dimensional (3D) reconstructions, and conventional X-ray. CONCLUSIONS: MRI and CT with the addition of 3D visualization can be used additionally with autopsy and conventional X-ray images in the investigation of such complex anatomical abnormalities.     

Poly(carbamoylsulfonate), a material for immobilization: Synthesis,diffusion- and mechanical properties

Summary A simple method is described for the synthesis of a material for immobilization, Poly(carbamoylsulfonate) (PCS). PCS is based on the synthesis of a hydrophilic polyether polyol and a polyisocyanate to the isocyanate-pre-polymer. The real diffusion coefficients of the PCS hydrogel are comparable with the values of Ca-alginate, the molecular weight cut-off can be found between myoglobine (MW 17000 g/mol) and albumine (MW 67000 g/mol). PCS hydrogels have optimal elastic properties (higher elongation at break and lower modulus of elasticity than other natural hydrogels) and therefore can be used for a matrix of biocatalysts in an agitated reactor as well as in a fluid-bed reactor.     

Unique and Overlapping Functions of Formins Frl and DAAM During Ommatidial Rotation and Neuronal Development in Drosophila

The noncanonical Frizzled/planar cell polarity (PCP) pathway regulates establishment of polarity within the plane of an epithelium to generate diversity of cell fates, asymmetric, but highly aligned structures, or to orchestrate the directional migration of cells during convergent extension during vertebrate gastrulation. In Drosophila, PCP signaling is essential to orient actin wing hairs and to align ommatidia in the eye, in part by coordinating the movement of groups of photoreceptor cells during ommatidial rotation. Importantly, the coordination of PCP signaling with changes in the cytoskeleton is essential for proper epithelial polarity. Formins polymerize linear actin filaments and are key regulators of the actin cytoskeleton. Here, we show that the diaphanous-related formin, Frl, the single fly member of the FMNL (formin related in leukocytes/formin-like) formin subfamily affects ommatidial rotation in the Drosophila eye and is controlled by the Rho family GTPase Cdc42. Interestingly, we also found that frl mutants exhibit an axon growth phenotype in the mushroom body, a center for olfactory learning in the Drosophila brain, which is also affected in a subset of PCP genes. Significantly, Frl cooperates with Cdc42 and another formin, DAAM, during mushroom body formation. This study thus suggests that different formins can cooperate or act independently in distinct tissues, likely integrating various signaling inputs with the regulation of the cytoskeleton. It furthermore highlights the importance and complexity of formin-dependent cytoskeletal regulation in multiple organs and developmental contexts.     

Widespread occurrence and genomic context of unusually small polyketide synthase genes in microbial consortia associated with marine sponges

Numerous marine sponges harbor enormous amounts of as-yet-uncultivated bacteria in their tissues. There is increasing evidence that these symbionts play an important role in the synthesis of protective metabolites, many of which are of great pharmacological interest. In this study, genes for the biosynthesis of polyketides, one of the most important classes of bioactive natural products, were systematically investigated in 20 demosponge species from different oceans. Unexpectedly, the sponge metagenomes were dominated by a ubiquitously present, evolutionarily distinct, and highly sponge-specific group of polyketide synthases (PKSs). Open reading frames resembling animal fatty acid genes were found on three corresponding DNA regions isolated from the metagenomes of Theonella swinhoei and Aplysina aerophoba. Their architecture suggests that methyl-branched fatty acids are the metabolic product. According to a phylogenetic analysis of housekeeping genes, at least one of the PKSs belongs to a bacterium of the Deinococcus-Thermus phylum. The results provide new insights into the chemistry of sponge symbionts and allow inference of a detailed phylogeny of the diverse functional PKS types present in sponge metagenomes. Based on these qualitative and quantitative data, we propose a significantly simplified strategy for the targeted isolation of biomedically relevant PKS genes from complex sponge-symbiont associations.