Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes

BACKGROUND: Elevated white blood cell counts (WBC) in acute coronary syndromes (ACS) increase the risk of recurrent events, but it is not known if this is exacerbated by pro-inflammatory factors. We sought to identify whether pro-inflammatory genetic variants contributed to alterations in WBC and C-reactive protein (CRP) in an ACS population. METHODS: WBC and genotype of interleukin 6 (IL-6 G-174C) and of interleukin-1 receptor antagonist (IL1RN intronic repeat polymorphism) were investigated in 732 Caucasian patients with ACS in the OPUS-TIMI-16 trial. Samples for measurement of WBC and inflammatory factors were taken at baseline, i.e. Within 72 hours of an acute myocardial infarction or an unstable angina event. RESULTS: An increased white blood cell count (WBC) was associated with an increased C-reactive protein (r = 0.23, p < 0.001) and there was also a positive correlation between levels of β-fibrinogen and C-reactive protein (r = 0.42, p < 0.0001). IL1RN and IL6 genotypes had no significant impact upon WBC. The difference in median WBC between the two homozygote IL6 genotypes was 0.21/mm(3 )(95% CI = -0.41, 0.77), and -0.03/mm(3 )(95% CI = -0.55, 0.86) for IL1RN. Moreover, the composite endpoint was not significantly affected by an interaction between WBC and the IL1 (p = 0.61) or IL6 (p = 0.48) genotype. CONCLUSIONS: Cytokine pro-inflammatory genetic variants do not influence the increased inflammatory profile of ACS patients

Association study of functional genetic variants of innate immunity related genes in celiac disease

BACKGROUND: Recent evidence suggest that the innate immune system is implicated in the early events of celiac disease (CD) pathogenesis. In this work for the first time we have assessed the relevance of different proinflammatory mediators typically related to innate immunity in CD predisposition. METHODS: We performed a familial study in which 105 celiac families characterized by the presence of an affected child with CD were genotyped for functional polymorphisms located at regulatory regions of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes. Familial data was analysed with a transmission disequilibrium test (TDT) that revealed no statistically significant differences in the transmission pattern of the different genetic markers considered. RESULTS: The TDT analysis for IL-1α, IL-1β, IL-1RN, IL-18, and MCP-1 genes genetic variants did not reveal biased transmission to the affected offspring. Only a borderline association of RANTES promoter genetic variants with CD predisposition was observed. CONCLUSION: Our results suggest that the analysed polymorphisms of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes do not seem to play a major role in CD genetic predisposition in our population

Stressful conditions reveal decrease in size, modification of shape but relatively stable asymmetry in bumblebee wings

Human activities can generate a wide variety of direct and indirect effects on animals, which can manifest as environmental and genetic stressors. Several phenotypic markers have been proposed as indicators of these stressful conditions but have displayed contrasting results, depending, among others, on the phenotypic trait measured. Knowing the worldwide decline of multiple bumblebee species, it is important to understand these stressors and link them with the drivers of decline. We assessed the impact of several stressors (i.e. natural toxin-, parasite-, thermic- and inbreeding-stress) on both wing shape and size and their variability as well as their directional and fluctuating asymmetries. The total data set includes 650 individuals of Bombus terrestris (Hymenoptera: Apidae). Overall wing size and shape were affected by all the tested stressors. Except for the sinigrin (e.g. glucosinolate) stress, each stress implies a decrease of wing size. Size variance was affected by several stressors, contrary to shape variance that was affected by none of them. Although wing size directional and fluctuating asymmetries were significantly affected by sinigrin, parasites and high temperatures, neither directional nor fluctuating shape asymmetry was significantly affected by any tested stressor. Parasites and high temperatures led to the strongest phenotype modifications. Overall size and shape were the most sensitive morphological traits, which contrasts with the common view that fluctuating asymmetry is the major phenotypic marker of stress

Variable number of tandem repeat polymorphisms of the interleukin-1 receptor antagonist gene IL-1RN: a novel association with the athlete status

<p>Abstract</p> <p>Background</p> <p>The interleukin-1 (IL-1) family of cytokines is involved in the inflammatory and repair reactions of skeletal muscle during and after exercise. Specifically, plasma levels of the IL-1 receptor antagonist (IL-1ra) increase dramatically after intense exercise, and accumulating evidence points to an effect of genetic polymorphisms on athletic phenotypes. Therefore, the IL-1 family cytokine genes are plausible candidate genes for athleticism. We explored whether IL-1 polymorphisms are associated with athlete status in European subjects.</p> <p>Methods</p> <p>Genomic DNA was obtained from 205 (53 professional and 152 competitive non-professional) Italian athletes and 458 non-athlete controls. Two diallelic polymorphisms in the IL-1β gene (<it>IL-1B</it>) at -511 and +3954 positions, and a variable number tandem repeats (VNTR) in intron 2 of the IL-1ra gene (<it>IL-1RN</it>) were assessed.</p> <p>Results</p> <p>We found a 2-fold higher frequency of the <it>IL-1RN </it>1/2 genotype in athletes compared to non-athlete controls (OR = 1.93, 95% CI = 1.37-2.74, 41.0% vs. 26.4%), and a lower frequency of the 1/1 genotype (OR = 0.55, 95% CI = 0.40-0.77, 43.9% vs. 58.5%). Frequency of the <it>IL-1RN </it>2/2 genotype did not differ between groups. No significant differences between athletes and controls were found for either -511 or +3954 <it>IL-1B </it>polymorphisms. However, the haplotype (-511)C-(+3954)T-(VNTR)2 was 3-fold more frequent in athletes than in non-athletes (OR = 3.02, 95% CI = 1.16-7.87). Interestingly, the <it>IL-1RN </it>1/2 genotype was more frequent in professional than in non-professional athletes (OR = 1.92, 95% CI = 1.02-3.61, 52.8% vs. 36.8%).</p> <p>Conclusions</p> <p>Our study found that variants at the IL-1ra gene associate with athletic status. This confirms the crucial role that cytokine IL-1ra plays in human physical exercise. The VNTR <it>IL-1RN </it>polymorphism may have implications for muscle health, performance, and/or recovery capacities. Further studies are needed to assess these specific issues. As VNTR <it>IL-1RN </it>polymorphism is implicated in several disease conditions, athlete status may constitute a confounding variable that will need to be accounted for when examining associations of this polymorphism with disease risk.</p

Behaviour of Solitary Adult Scandinavian Brown Bears (Ursus arctos) when Approached by Humans on Foot

Successful management has brought the Scandinavian brown bear (Ursus arctos L.) back from the brink of extinction, but as the population grows and expands the probability of bear-human encounters increases. More people express concerns about spending time in the forest, because of the possibility of encountering bears, and acceptance for the bear is decreasing. In this context, reliable information about the bear's normal behaviour during bear-human encounters is important. Here we describe the behaviour of brown bears when encountering humans on foot. During 2006–2009, we approached 30 adult (21 females, 9 males) GPS-collared bears 169 times during midday, using 1-minute positioning before, during and after the approach. Observer movements were registered with a handheld GPS. The approaches started 869±348 m from the bears, with the wind towards the bear when passing it at approximately 50 m. The bears were detected in 15% of the approaches, and none of the bears displayed any aggressive behaviour. Most bears (80%) left the initial site during the approach, going away from the observers, whereas some remained at the initial site after being approached (20%). Young bears left more often than older bears, possibly due to differences in experience, but the difference between ages decreased during the berry season compared to the pre-berry season. The flight initiation distance was longer for active bears (115±94 m) than passive bears (69±47 m), and was further affected by horizontal vegetation cover and the bear's age. Our findings show that bears try to avoid confrontations with humans on foot, and support the conclusions of earlier studies that the Scandinavian brown bear is normally not aggressive during encounters with humans

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration.

Following severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. We recently showed that ductal cells clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells. However, the molecular mechanisms by which adult ductal-committed cells acquire cellular plasticity, initiate organoids and regenerate the damaged tissue remain largely unknown. Here, we describe that ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licences differentiated ductal cells to initiate organoids and activate the regenerative programme through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signalling. Our results argue in favour of the remodelling of genomic methylome/hydroxymethylome landscapes as a general mechanism by which differentiated cells exit a committed state in response to tissue damage.RCUK Cancer Research UK ERC H2020 Wellcome Trus

Ape Conservation Physiology: Fecal Glucocorticoid Responses in Wild Pongo pygmaeus morio following Human Visitation

Nature-based tourism can generate important revenue to support conservation of biodiversity. However, constant exposure to tourists and subsequent chronic activation of stress responses can produce pathological effects, including impaired cognition, growth, reproduction, and immunity in the same animals we are interested in protecting. Utilizing fecal samples (N = 53) from 2 wild habituated orangutans (Pongo pygmaeus morio) (in addition to 26 fecal samples from 4 wild unhabituated orangutans) in the Lower Kinabatangan Wildlife Sanctuary of Sabah, Malaysian Borneo, we predicted that i) fecal glucocorticoid metabolite concentrations would be elevated on the day after tourist visitation (indicative of normal stress response to exposure to tourists on the previous day) compared to samples taken before or during tourist visitation in wild, habituated orangutans, and ii) that samples collected from habituated animals would have lower fecal glucocorticoid metabolites than unhabituated animals not used for tourism. Among the habituated animals used for tourism, fecal glucocorticoid metabolite levels were significantly elevated in samples collected the day after tourist visitation (indicative of elevated cortisol production on the previous day during tourist visitation). Fecal glucocorticoid metabolite levels were also lower in the habituated animals compared to their age-matched unhabituated counterparts. We conclude that the habituated animals used for this singular ecotourism project are not chronically stressed, unlike other species/populations with documented permanent alterations in stress responses. Animal temperament, species, the presence of coping/escape mechanisms, social confounders, and variation in amount of tourism may explain differences among previous experiments. Acute alterations in glucocorticoid measures in wildlife exposed to tourism must be interpreted conservatively. While permanently altered stress responses can be detrimental, preliminary results in these wild habituated orangutans suggest that low levels of predictable disturbance can likely result in low physiological impact on these animals

Liver cell therapy: is this the end of the beginning?

The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration

Satellite Tagging and Biopsy Sampling of Killer Whales at Subantarctic Marion Island: Effectiveness, Immediate Reactions and Long-Term Responses

Remote tissue biopsy sampling and satellite tagging are becoming widely used in large marine vertebrate studies because they allow the collection of a diverse suite of otherwise difficult-to-obtain data which are critical in understanding the ecology of these species and to their conservation and management. Researchers must carefully consider their methods not only from an animal welfare perspective, but also to ensure the scientific rigour and validity of their results. We report methods for shore-based, remote biopsy sampling and satellite tagging of killer whales Orcinus orca at Subantarctic Marion Island. The performance of these methods is critically assessed using 1) the attachment duration of low-impact minimally percutaneous satellite tags; 2) the immediate behavioural reactions of animals to biopsy sampling and satellite tagging; 3) the effect of researcher experience on biopsy sampling and satellite tagging; and 4) the mid- (1 month) and long- (24 month) term behavioural consequences. To study mid- and long-term behavioural changes we used multievent capture-recapture models that accommodate imperfect detection and individual heterogeneity. We made 72 biopsy sampling attempts (resulting in 32 tissue samples) and 37 satellite tagging attempts (deploying 19 tags). Biopsy sampling success rates were low (43%), but tagging rates were high with improved tag designs (86%). The improved tags remained attached for 26±14 days (mean ± SD). Individuals most often showed no reaction when attempts missed (66%) and a slight reaction-defined as a slight flinch, slight shake, short acceleration, or immediate dive-when hit (54%). Severe immediate reactions were never observed. Hit or miss and age-sex class were important predictors of the reaction, but the method (tag or biopsy) was unimportant. Multievent trap-dependence modelling revealed considerable variation in individual sighting patterns; however, there were no significant mid- or long-term changes following biopsy sampling or tagging