Gene deficiency in activating Fcγ receptors influences the macrophage phenotypic balance and reduces atherosclerosis in mice

Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fcγ receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fcγ receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in γ-chain (the common signaling subunit of activating Fcγ receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fcγ receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fcγ receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fcγ receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-κB activity, and M1 macrophages at the lesion site, while increasing anti-inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fcγ receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2-associated genes in murine macrophages. Our study demonstrates that activating Fcγ receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fcγ receptor-mediated inflammatory responses could effectively suppress atherosclerosis

Yearly evolution of organ damage markers in diabetes or metabolic syndrome: data from the LOD-DIABETES study

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease morbidity-mortality is greater in people with type 2 diabetes mellitus or metabolic syndrome. The purpose of this study was to evaluate the yearly evolution of organ damage markers in diabetes or metabolic syndrome, and to analyze the associated factors.</p> <p>Methods</p> <p>An observational prospective study was carried out in the primary care setting, involving 112 patients: 68 diabetics and 44 subjects with metabolic syndrome, subjected to 12 months of follow-up. Measurements: traditional cardiovascular risk factors (blood pressure, blood glucose, lipids, smoking, body mass index (BMI) and) and non-traditional risk factors (waist circumference, hsC Reactive Protein and fibrinogen); subclinical vascular (carotid intima-media thickness, pulse wave velocity and ankle/brachial index), cardiac (Cornell voltage-duration product), renal organ damage (creatinine, glomerular filtration and albumin/creatinine index), and antihypertensive and lipid-lowering drugs.</p> <p>Results</p> <p>At baseline, the diabetics presented a mean age of 59.9 years, versus 55.2 years in the subjects with metabolic syndrome (p = 0.03). Diastolic blood pressure, total cholesterol and HDL-cholesterol were lower among the patients with diabetes, while blood glucose and HbA1c, as well as antihypertensive and lipid-lowering drug use, were greater. At evaluation after one year, the diabetics showed a decrease in BMI (-0.39), diastolic blood pressure (-3.59), and an increase in fibrinogen (30.23 mg/dL), ankle/brachial index (0.07) and the number of patients with ankle/brachial index pathologic decreased in 6. In turn, the patients with metabolic syndrome showed an increase in HDL-cholesterol (1-91 mg/dL), fibrinogen (25.54 mg/dL), Cornell voltage-duration product (184.22 mm/ms), ankle/brachial index (0.05) and the use of antihypertensive and lipid-lowering drugs, and a reduction in serum glucose (3.74 mg/dL), HOMA, systolic (-6.76 mmHg), diastolic blood pressure (-3.29 mmHg), and pulse wave velocity (-0.72 m/s). The variable that best predicted a decrease in pulse wave velocity in subjects with metabolic syndrome was seen to be an increase in antihypertensive drug use.</p> <p>Conclusions</p> <p>The annual assessment of cardiovascular risk factors and the decrease in pulse wave velocity was more favorable in the patients with metabolic syndrome, probably influenced by the increased percentage of subjects treated with antihypertensive and lipid lowering drugs in this group.</p

Stereodivergent addition of 4-Silyloxy-1,2-Allenes to aldehydes by hydroboration

We have established a new stereodivergent approach to 2-vinyl-1,3-diols based on a hydroboration of allene/addition of aldehyde tandem process. The stereocenter present next to the allenyl moiety (C1) in the starting allene effectively determines the configuration of the new formed carbinol (C3) whereas the relative configuration of C2 and C3 is determined by the configuration (E/Z) of the transient 2- alkenylborane intermediate. It should be noted that the order of mixing of the reagents and the kind of aldehyde used allowed us to obtain three out of the four possible diastereomers of the 1,3- diol

Geographical variation in relative risks associated with heat: Update of Spain's Heat Wave Prevention Plan

A decade after the implementation of prevention plans designed to minimise the impact of high temperatures on health, some countries have decided to update these plans in order to improve the weakness detected in these ten years of operation. In the case of Spain, this update has fundamentally consisted of changing the so-called "threshold" or "trigger" temperatures used to activate the plan, by switching from temperature values based on climatological criteria to others obtained by epidemiological studies conducted on a provincial scale. This study reports the results of these "trigger" temperatures for each of Spain's 52 provincial capitals, as well as the impact of heat on mortality by reference to the relative risks (RRs) and attributable risks (ARs) calculated for natural as well as circulatory and respiratory causes. The results obtained for threshold temperatures and RRs show a more uniform behaviour pattern than those obtained using temperature values based on climatological criteria; plus a clear decrease in RRs of heat-associated mortality due to the three causes considered, at both a provincial and regional level as well as for Spain as a whole. The updating of prevention plans is regarded as crucial for optimising the operation of these plans in terms of reducing the effect of high temperatures on population health.This study was supported by grants FIS ENPY 1001/13 & SEPY 1037/14 from Spain's Health Research Fund.S

Serum levels and removal by haemodialysis and haemodiafiltration of tryptophan-derived uremic toxins in ESKD patients

Tryptophan is an essential dietary amino acid that originates uremic toxins that contribute to end-stage kidney disease (ESKD) patient outcomes. We evaluated serum levels and removal during haemodialysis and haemodiafiltration of tryptophan and tryptophan-derived uremic toxins, indoxyl sulfate (IS) and indole acetic acid (IAA), in ESKD patients in different dialysis treatment settings. This prospective multicentre study in four European dialysis centres enrolled 78 patients with ESKD. Blood and spent dialysate samples obtained during dialysis were analysed with high-performance liquid chromatography to assess uremic solutes, their reduction ratio (RR) and total removed solute (TRS). Mean free serum tryptophan and IS concentrations increased, and concentration of IAA decreased over pre-dialysis levels (67%, 49%, -0.8%, respectively) during the first hour of dialysis. While mean serum total urea, IS and IAA concentrations decreased during dialysis (-72%, -39%, -43%, respectively), serum tryptophan levels increased, resulting in negative RR (-8%) towards the end of the dialysis session (p < 0.001), despite remarkable Trp losses in dialysate. RR and TRS values based on serum (total, free) and dialysate solute concentrations were lower for conventional low-flux dialysis (p < 0.001). High-efficiency haemodiafiltration resulted in 80% higher Trp losses than conventional low-flux dialysis, despite similar neutral Trp RR values. In conclusion, serum Trp concentrations and RR behave differently from uremic solutes IS, IAA and urea and Trp RR did not reflect dialysis Trp losses. Conventional low-flux dialysis may not adequately clear Trp-related uremic toxins while high efficiency haemodiafiltration increased Trp losses

The impact of a large object with Jupiter in July 2009

On 2009 July 19, we observed a single, large impact on Jupiter at a planetocentric latitude of 55^{\circ}S. This and the Shoemaker-Levy 9 (SL9) impacts on Jupiter in 1994 are the only planetary-scale impacts ever observed. The 2009 impact had an entry trajectory opposite and with a lower incidence angle than that of SL9. Comparison of the initial aerosol cloud debris properties, spanning 4,800 km east-west and 2,500 km north-south, with those produced by the SL9 fragments, and dynamical calculations of pre-impact orbit, indicate that the impactor was most probably an icy body with a size of 0.5-1 km. The collision rate of events of this magnitude may be five to ten times more frequent than previously thought. The search for unpredicted impacts, such as the current one, could be best performed in 890-nm and K (2.03-2.36 {\mu}m) filters in strong gaseous absorption, where the high-altitude aerosols are more reflective than Jupiter's primary cloud.Comment: 15 pages, 5 figure

A global transcriptional network connecting noncoding mutations to changes in tumor gene expression.

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer

Outbreak Of NDM-1-producing Klebsiella Pneumoniae In A Neonatal Unit In Colombia

Six multiresistant, NDM-1-producing Klebsiella pneumoniae strains were recovered from an outbreak that affected six neonatal patients in a Colombian hospital. Molecular analysis showed that all of the isolates harbored the blaNDM-1, qnrA, and intI1 genes and were clonally related. Multilocus sequence typing showed that the isolates belonged to a new sequence type (ST1043) that was different from the sequence types that had previously been reported. This is the first report of NDM-1-producing isolates in South America