Low YKL-40 in chronic heart failure may predict beneficial effects of statins: analysis from the controlled rosuvastatin multinational trial in heart failure (CORONA)

Context and objective: To evaluate if YKL-40 can provide prognostic information in patients with ischemic heart failure (HF) and identify patients who may benefit from statin therapy.

Materials and methods: The association between serum YKL-40 and predefined outcome was evaluated in 1344 HF patients assigned to rosuvastatin or placebo.

Results: YKL-40 was not associated with outcome in adjusted analysis. In YKL-40 tertile 1, an effect on the primary outcome (HR 0.50, p?=?0.006) and CV death (HR 0.54, p?=?0.040) was seen by rosuvastatin in adjusted analysis.

Conclusions: A beneficial modification of outcome was observed with statin therapy in patients with low YKL-40 levels.     

Benzo(a)pyrene metabolism by purified forms of rabbit liver microsomal cytochrome P-450, cytochrome b5 and epoxide hydrase in reconstituted phospholipid vesicles

The roles of rabbit liver cytochrome b₅, epoxide hydrase and various forms of cytochrome P-450 in the NADPH-dependent metabolism of benzo(a)pyrene were examined. After incorporation of the purified enzymes into phospholipid vesicles, using the cholate gel filtration technique, the various types of cytochrome P-450 did exhibit different stereospecificities in the oxygenation of the substrate. Cytochrome P-450_LM2 was found to efficiently convert benzo(a)pyrene in the presence of epoxide hydrase to 4,5-dihydroxy-4,5-dihydrobenzo(a)pyrene whereas cytochrome P-450_LM4 primarily participated in the formation of 9,10-dihydroxy-9,10-dihydrobenzo(a)pyrene. By contrast, benzo(a)pyrene was not metabolized by cytochrome P-450_LM3. Cytochrome b₅ enhanced cytochrome P-450_LM2-catalyzed oxygenations 5-fold, whereas cytochrome P-450_LM4-dependent oxygenations proceeded at a 3 times higher rate when cytochrome b₅ was present in the membrane.     

Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

Background

Atherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process.

Methods

Plasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50–69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined.

Results

Our major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality.

Conclusion

Our findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms.     

Expression of the AMBP gene transcript and its two protein products,alpha(1)-microglobulin and bikunin,in mouse embryogenesis

The expression pattern of the alpha(1)-microglobulin/bikunin precursor (AMBP) gene, and its two protein products were studied in mouse embryos of 8.5-15.5 days of embryonic development by in situ hybridization and immunohistochemistry. AMBP mRNA is strongly transcribed in liver parenchyma, pancreas, and intestine epithelium. Sites of weaker expression are the vessels of the umbilical cord, the developing vertebral bodies, and kidney. The alpha(1)-microglobulin and bikunin proteins are accordingly present in developing hepatocytes, pancreas, kidney, and gut. However, additional sites of protein distribution were found that do not correlate to mRNA localization: alpha(1)-microglobulin was found in myocytes and bikunin in cardiac muscle, nervous system microvasculature, and connective tissue. Both proteins were found in brain mesenchyme and meninges. Thus, a restricted expression of the AMBP mRNA in a few organs contrasts to a widespread and unique distribution of each of the two proteins.     

Isolation and characterization of three Mammalian orthoreoviruses from European bats

In recent years novel human respiratory disease agents have been described in South East Asia and Australia. The causative pathogens were classified as pteropine orthoreoviruses with strong phylogenetic relationship to orthoreoviruses of flying foxes inhabiting these regions. Subsequently, a zoonotic bat-to-human transmission has been assumed. We report the isolation of three novel mammalian orthoreoviruses (MRVs) from European bats, comprising bat-borne orthoreovirus outside of South East Asia and Australia and moreover detected in insectivorous bats (Microchiroptera). MRVs are well known to infect a broad range of mammals including man. Although they are associated with rather mild and clinically unapparent infections in their hosts, there is growing evidence of their ability to also induce more severe illness in dogs and man. In this study, eight out of 120 vespertilionid bats proved to be infected with one out of three novel MRV isolates, with a distinct organ tropism for the intestine. One isolate was analyzed by 454 genome sequencing. The obtained strain T3/Bat/Germany/342/08 had closest phylogenetic relationship to MRV strain T3D/04, isolated from a dog. These novel reoviruses provide a rare chance of gaining insight into possible transmission events and of tracing the evolution of bat viruses.     

The role of novelty and fat and sugar concentration in food selection by captive tufted capuchins (Sapajus apella)

Capuchins, like other primates, use feedback from sensory cues and digestion to make decisions about which foods to consume and which to avoid. However, little is known about how capuchins make consumption decisions when simultaneously presented with novel and familiar foods, or how food familiarity and macronutrient concentration together influence food choice, topics with potential implications for developmental and health research. In this study, we evaluated the role of familiarity, as well as fat and sugar concentration, in the food selections of captive tufted capuchins (Sapajus apella). In the first experiment, over 10 sessions, subjects were assigned to either a group that chose between one familiar and one novel food item both high in fat or sugar (high condition), or to a group that chose between one familiar and one novel food item both low in fat or sugar (low condition). In the second experiment, subjects were divided into three groups, familiarized with food over five feeding sessions, and then offered the familiarized food and a novel food that varied in fat or sugar for 10 sessions. When offered foods high in fat, capuchins showed no clear signs of neophobia, forming an initial preference for the novel food, rejecting foods less frequently, and selecting foods faster than when offered foods low in fat. These trends were generally not observed in response to foods with sugar. When presented with options that varied in macronutrient concentration, subjects showed an initial interest in the novel food irrespective of whether it was high in fat or sugar, yet formed a final preference for the higher-concentration item. Findings suggest that the concentration of fat or sugar in novel foods may be an important mediator of exploratory behavior and that capuchins rely on immediate feedback from taste and other sensory cues to make consumption decisions.     

3-(3-Aryloxyaryl)imidazo[1,2-a]pyridine sulfones as liver X receptor agonists

Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs.     

Cognitive Factors Mediate Placebo Responses in Patients with House Dust Mite Allergy

Background

Placebo effects have been reported in type I allergic reactions. However the neuropsychological mechanisms steering placebo responses in allergies are largely unknown. The study analyzed whether and to what extend a conditioned placebo response is affecting type I allergic reactions and whether this response can be reproduced at multiple occasions.

Methods

62 patients with house dust mite allergy were randomly allocated to either a conditioned (n = 25), sham-conditioned (n = 25) or natural history (n = 12) group. During the learning phase (acquisition), patients in the conditioned group received the H₁-receptor antagonist desloratadine (5mg) (unconditioned stimulus/US) together with a novel tasting gustatory stimulus (conditioned stimulus/CS). Patients in the sham-conditioned control group received the CS together with a placebo pill. After a wash out time of 9 days patients in the conditioned and sham-conditioned group received placebo pills together with the CS during evocation. Allergic responses documented by wheal size after skin prick test and symptom scores after nasal provocation were analyzed at baseline, after last desloratadine treatment and after the 1^st and 5^th CS re-exposure.

Results

Both conditioned and sham-conditioned patients showed significantly decreased wheal sizes after the 1^st CS-evocation and significantly decreased symptom scores after the 1^st as well as after the 5^th evocation compared to the natural history control group.

Conclusions

These results indicate that placebo responses in type I allergy are not primarily mediated by learning processes, but seemed to be induced by cognitive factors such as patients’ expectation, with these effects not restricted to a single evocation.     

Refinement of the MHC Risk Map in a Scandinavian Primary Sclerosing Cholangitis Population

Background

Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel.

Methodology/Principal Findings

A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10⁻¹¹).

Conclusions/Significance

Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.     

Mechanical integrin stress and magnetic forces induce biological responses in mesenchymal stem cells which depend on environmental factors

The control of mesenchymal stem cells (MSC) by physical cues is of great interest in regenerative medicine. Because integrin receptors function as mechanotransducers, we applied drag forces to β1 integrins on the apical surface of adherent human MSC. In addition to mechanical forces, the technique we used involved also the exposure of the cells to an inhomogeneous magnetic field. In order to assess the influence of the substrate on cell adhesion, cells were cultured on plain tissue culture polystyrene (TCP) or on coated well plates, which allowed only adhesion to embedded fibronectin or RGD peptides. We found that the expression of collagen I, which is involved in osteogenesis, and VEGF, a factor which stimulates angiogenesis, increased as a result of short-term mechanical integrin stress. Whereas, collagen I expression was stimulated by mechanical forces when the cells were cultured on fibronectin and RGD peptides but not on TCP, VEGF expression was enhanced by physical stimulation on TCP. The study further revealed that magnetic forces enhanced Sox 9 expression, a marker of chondrogenesis, and reduced the expression of ALP. Concerning the intracellular mechanisms involved, we found that the expression of VEGF induced by physical forces depended on Akt activation. Together, the results implicate that biological functions of MSC can be stimulated by integrin-mediated mechanical forces and a magnetic field. However, the responses of cells depend strongly on the substrate to which they adhere and on the cross-talk between integrin-mediated signals and soluble factors.