Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation

Gln27Glu polymorphism in the beta2 adrenergic receptor gene and lipid metabolism during exercise in obese women

BACKGROUND: The Glu27Glu genotype in the beta-2-adrenergic receptor (ADRB2) is associated with fat mass, body mass index and obesity in females. In our population, we previously found an association of higher body mass index (BMI) among women who reported more physical activity and carried the Glu27 allele as compared to non carriers with the same level of activity. OBJECTIVE: To examine the lipid metabolism differences, both at rest and during submaximal exercise in ADRB2 Glu27Glu vs Gln27Gln obese women. SUBJECTS: Eight obese women with the Glu27Glu genotype (age, 43±5 y; body mass index (BMI), 31.7±0.9 kg/m2; percentage fat mass, 42.0±1.3; WHR, 0.83±0.02; and VO2max, 21.6±0.9 ml/kg/min) were compared with seven obese women with the Gln27Gln genotype (age, 43±5 y; BMI, 33.9±1.3 kg/m2; percentage fat mass, 41.6±1.2; WHR, 0.83±0.02; and VO2max, 20.6±0.8 ml/kg/min). MEASUREMENTS: The ADRB2 polymorphism was identified by PCR-RFLP. Respiratory quotient was determined by indirect calorimetry at baseline, during 1 h of walking on a treadmill and 1 h after the exercise. Plasma triglycerides, glycerol, FFA, hydroxybutyrate, glucose and lactate were assayed by spectrophotometric methods. Insulin, leptin and progesterone were measured by radioimmunoassay. Adrenaline and noradrenaline were quantified by high performance liquid chromatography. RESULTS: The ADRB2 Glu27Glu subjects had lower plasma glycerol (P=0.047) and lower hydroxybutyrate (P=0.001) throughout the study than the Gln27Gln group. Plasma triglycerides (P=0.001), lactate (P<0.05) and serum insulin (P<0.05) remained higher in the Glu27Glu group vs the Gln27Gln group. The respiratory quotient (RQ) was higher in the Glu27Glu obese women along the study (P=0.046), and fat oxidation was significantly lower in this group during the recovery (P=0.048). The other variables did not differ statistically between groups. CONCLUSION: These data suggest that both lipolysis and fat oxidation promoted by an acute submaximal exercise intervention could be blunted in the polymorphic ADRB2 Glu27Glu group of our female obese population

Clash of Titans: The Impact of Cluster Mergers in the Galaxy Cluster Red Sequence

Merging of galaxy clusters are some of the most energetic events in the Universe, and they provide a unique environment to study galaxy evolution. We use a sample of 84 merging and relaxed SPT galaxy clusters candidates, observed with the Dark Energy Camera in the $0.11<z<0.88$ redshift range, to build colour-magnitude diagrams to characterize the impact of cluster mergers on the galaxy population. We divided the sample between relaxed and disturbed, and in two redshifts bin at $z = 0.55$. When comparing the high-z to low-z clusters we find the high-z sample is richer in blue galaxies, independently of the cluster dynamical state. In the high-z bin we find that disturbed clusters exhibit a larger scatter in the Red Sequence, with wider distribution and an excess of bluer galaxies compared to relaxed clusters, while in the low-z bin we find a complete agreement between the relaxed and disturbed clusters. Our results support the scenario in which massive cluster halos at $z<0.55$ galaxies are quenched as satellites of another structure, i.e. outside the cluster, while at $z \geq 0.55$ the quenching is dominated by in-situ processes.Comment: 9 pages, 5 figures, paper accepted in MNRA

Novel association of high C-reactive protein levels and A69S at risk alleles in wet age-related macular degeneration women

Purpose: To explore the relationship between plasma C-reactive protein (CRP) levels, the main ARMS2 gene single nucleotide polymorphism (SNP), and gender in patients with neovascular age-related macular degeneration (wet AMD). Methods: Our study included 131 patients with wetAMD [age-related eye disease study (AREDS) category 4] and 153 control participants (AREDS category 1) from two Spanish retinal units. CRP levels were determined on blood samples by high-sensitivity ELISA assay. According to their CRP level, subjects were categorized into three well-established CRP categories: low (3.00 mg/L, H-CRP). Genomic DNA was extracted from oral swabs using QIAcube (Qiagen, Hilden, Germany) and the A69S; rs10490924 of ARMS2 gene was genotyped by allelic discrimination with validated TaqMan assays (Applied Biosystems, Foster City, CA, USA). Univariate and multivariate logistic regression adjusted for age was used to analyze the genomic frequencies and to calculate odds ratio (OR) using SNPStats software. Results: Considering CRP risk categories, H-CRP group showed a significant [OR 4.0 (1.9-8.3)] association with wetAMD compared to L-CRP group. The risk genotypes of A69S (TT) SNPs showed an association with wetAMD risk [OR 14.0 (4.8-40.8)]. Interestingly, the gender stratification of the CRP categories showed a significant increase in CRP levels in wetAMD women compared with control women [OR 6.9 (2.2-22.3)] and with wetAMD men [OR 4.6 (1.3-16.9)]. In addition, the subgroup analysis of CRP within A69S genotype and gender showed a link in women between the A69S and CRP levels in the AMD group compared to controls [OR 4.2 (1.4-12.6)]. Conclusion: Our study shows, for the first time, that a different genetic association related with gender could contribute to AMD risk. As a consequence, the risk of female gender in the different CRP levels and A69S SNP frequencies could be taken into consideration to the established risk relationship of high levels of CRP and its association with risk A69S genotype

Relationship between lactose digestion, gastrointestinal transit time and symptoms in lactose malabsorbers after dairy consumption

Background: The relationship of symptoms with objective measurements, as well as some of the mechanisms involved in lactose tolerance after yoghurt consumption, remain unclear. Methods: The trial had a double-blind design in which 22 lactose malabsorbers received 25 g daily lactose in fresh (living bacteria > 108 cfu/g) yoghurt or heated (< 102 cfu/g) yoghurt for 15 days, followed by a crossover (15 days) after a wash-out period (14 days). The lactose digestion was determined by the breath H2 test, the gastric emptying (GE) with a 13C-acetate breath test and the revealed transit time (OCTT) by 15N-lactoseureide test. Subjects reported their gastrointestinal symptoms (GIS) in a validated questionnaire. Results: Breath H2 test indicated more effective lactose digestion after fresh yoghurt intake. The OCTT was shorter after heated yoghurt ingestion as compared with the fresh. There was lower severity of GIS (P < 0.05) after fresh yoghurt intake, and this showed an inverse correlation with OCTT (P < 0.05). Conclusions: Delayed orocoecal transit time was associated with fewer gastrointestinal symptoms. The improved lactose digestion and tolerance of fresh yoghurt should be mainly attributed to the presence of living bacteria

Vitamin D protects against oxidative stress and inflammation in human retinal cells

Diabetic retinopathy is a vision-threatening microvascular complication of diabetes and is one of the leading causes of blindness. Oxidative stress and inflammation play a major role in its pathogenesis, and new therapies counteracting these contributors could be of great interest. In the current study, we investigated the role of vitamin D against oxidative stress and inflammation in human retinal pigment epithelium (RPE) and human retinal endothelial cell lines. We demonstrate that vitamin D effectively counteracts the oxidative stress induced by hydrogen peroxide (H2O2). In addition, the increased levels of proinflammatory proteins such as Interleukin (IL)-6, IL-8, Monocyte chemoattractant protein (MCP)-1, Interferon (IFN)-γ, and tumor necrosis factor (TNF)-α triggered by lipopolysaccharide (LPS) exposure were significantly decreased by vitamin D addition. Interestingly, the increased IL-18 only decreased by vitamin D addition in endothelial cells but not in RPE cells, suggesting a main antiangiogenic role under inflammatory conditions. Moreover, H2O2 and LPS induced the alteration and morphological damage of tight junctions in adult retinal pigment epithelium (ARPE-19) cells that were restored under oxidative and inflammatory conditions by the addition of vitamin D to the media. In conclusion, our data suggest that vitamin D could protect the retina by enhancing antioxidant defense and through exhibiting anti-inflammatory properties

Mediterranean alcohol-drinking pattern and the incidence of cardiovascular disease and cardiovascular Mortality: the SUN project

Background: We assessed the still unclear effect of the overall alcohol-drinking pattern, beyond the amount of alcohol consumed, on the incidence of cardiovascular clinical disease (CVD). Methods: We followed 14,651 participants during up to 14 years. We built a score assessing simultaneously seven dimensions of alcohol consumption to capture the conformity to a traditional Mediterranean alcohol-drinking pattern (MADP). It positively scored moderate alcohol intake, alcohol intake spread out over the week, low spirit consumption, preference for wine, red wine consumption, wine consumed during meals and avoidance of binge drinking. Results: During 142,177 person-years of follow-up, 127 incident cases of CVD (myocardial infarction, stroke or cardiovascular mortality) were identified. Compared with the category of better conformity with the MADP, the low-adherence group exhibited a non-significantly higher risk (HR) of total CVD ((95% CI) = 1.55 (0.58–4.16)). This direct association with a departure from the traditional MADP was even stronger for cardiovascular mortality (HR (95% CI) = 3.35 (0.77–14.5)). Nevertheless, all these associations were statistically non-significant. Conclusion: Better conformity with the MADP seemed to be associated with lower cardiovascular risk in most point estimates; however, no significant results were found and more powered studies are needed to clarify the role of the MADP on CVD