Intraskeletal variation in human cortical osteocyte lacunar density: Implications for bone quality assessment

AbstractOsteocytes and their lacunocanalicular network have been identified as the regulator of bone quality and function by exerting extensive influence over metabolic processes, mechanical adaptation, and mineral homeostasis. Recent research has shown that osteocyte apoptosis leads to a decrease in bone quality and increase in bone fragility mediated through its effects on remodeling. The purpose of this study is to investigate variation in cortical bone osteocyte lacunar density with respect to major factors including sex, age, and intracortical porosity to establish both regional and systemic trends. Samples from the midshaft femur, midshaft rib and distal one-third diaphysis of the radius were recovered from 30 modern cadaveric individuals (15 males and 15 females) ranging from 49 to 100years old. Thick ground undecalcified histological (80μm) cross-sections were made and imaged under bright field microscopy. Osteocyte lacunar density (Ot.Lc.N/B.Ar) and intracortical porosity (%Po.Ar) were quantified. No significant sex differences in Ot.Lc.N/B.Ar or %Po.Ar were found in any element. Linear regressions demonstrated a significant decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar) and increase in intracortical porosity (%Po.Ar) with age for the sex-pooled sample in the femur (R2=0.208, 0.297 respectively) and radius (R2=0.108, 0.545 respectively). Age was unable to significantly predict osteocyte lacunar density or intracortical porosity in the rib (R2=0.058, 0.114 respectively). Comparisons of regression coefficients demonstrated a systemic trend in the decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar) and increase in intracortical porosity (%Po.Ar) with age. In each element, intracortical porosity was significantly negatively correlated with lacunar density for which the radius demonstrated the strongest relationship (r=−0.746). Using pore number (Po.N) as a proxy for available vascularity to support the osteocyte population, Po.N was able to predict 61.8% of variation in osteocyte lacunar number (Ot.Lc.N) in the rib. The femur and radius also demonstrated significant relationships between these variables (R2=0.560 and 0.397 respectively). The results from this study indicate that although the femur, radius and rib may be experiencing systemically influenced declines in osteocyte lacunar density, there may be differential effects at each anatomical site potentially due to age related changes in mechanical loading. With decreasing osteocyte lacunar density in each element, intracortical porosity increased with likely direct impacts on gross bone strength. This study provides a foundation upon which to build interpretations of osteocyte lacunar density values and their effect on differential fracture risk for aging individuals

Wildlife Management Practices Associated with Pathogen Exposure in Non-NativeWild Pigs in Florida, U.S.

Land use influences disease emergence by changing the ecological dynamics of humans, wildlife, domestic animals, and pathogens. This is a central tenet of One Health, and one that is gaining momentum in wildlife management decision-making in the United States. Using almost 2000 serological samples collected from non-native wild pigs (Sus scrofa) throughout Florida (U.S.), we compared the prevalence and exposure risk of two directly transmitted pathogens, pseudorabies virus (PrV) and Brucella spp., to test the hypothesis that disease emergence would be positively correlated with one of the most basic wildlife management operations: Hunting. The seroprevalence of PrV-Brucella spp. coinfection or PrV alone was higher for wild pigs in land management areas that allowed hunting with dogs than in areas that culled animals using other harvest methods. This pattern did not hold for Brucella alone. The likelihood of exposure to PrV, but not Brucella spp., was also significantly higher among wild pigs at hunted sites than at sites where animals were culled. By failing to consider the impact of dog hunting on the emergence of non-native pathogens, current animal management practices have the potential to affect public health, the commercial livestock industry, and wildlife conservation

Wildlife Management Practices Associated with Pathogen Exposure in Non-NativeWild Pigs in Florida, U.S.

Land use influences disease emergence by changing the ecological dynamics of humans, wildlife, domestic animals, and pathogens. This is a central tenet of One Health, and one that is gaining momentum in wildlife management decision-making in the United States. Using almost 2000 serological samples collected from non-native wild pigs (Sus scrofa) throughout Florida (U.S.), we compared the prevalence and exposure risk of two directly transmitted pathogens, pseudorabies virus (PrV) and Brucella spp., to test the hypothesis that disease emergence would be positively correlated with one of the most basic wildlife management operations: Hunting. The seroprevalence of PrV-Brucella spp. coinfection or PrV alone was higher for wild pigs in land management areas that allowed hunting with dogs than in areas that culled animals using other harvest methods. This pattern did not hold for Brucella alone. The likelihood of exposure to PrV, but not Brucella spp., was also significantly higher among wild pigs at hunted sites than at sites where animals were culled. By failing to consider the impact of dog hunting on the emergence of non-native pathogens, current animal management practices have the potential to affect public health, the commercial livestock industry, and wildlife conservation

Global association of air pollution and heart failure:a systematic review and meta-analysis

BACKGROUND: Acute exposure to air pollution has been linked to myocardial infarction, but its effect on heart failure is uncertain. We did a systematic review and meta-analysis to assess the association between air pollution and acute decompensated heart failure including hospitalisation and heart failure mortality. METHODS: Five databases were searched for studies investigating the association between daily increases in gaseous (carbon monoxide, sulphur dioxide, nitrogen dioxide, ozone) and particulate (diameter <2·5 μm [PM(2·5)] or <10 μm [PM(10)]) air pollutants, and heart failure hospitalisations or heart failure mortality. We used a random-effects model to derive overall risk estimates per pollutant. FINDINGS: Of 1146 identified articles, 195 were reviewed in-depth with 35 satisfying inclusion criteria. Heart failure hospitalisation or death was associated with increases in carbon monoxide (3·52% per 1 part per million; 95% CI 2·52–4·54), sulphur dioxide (2·36% per 10 parts per billion; 1·35–3·38), and nitrogen dioxide (1·70% per 10 parts per billion; 1·25–2·16), but not ozone (0·46% per 10 parts per billion; −0·10 to 1·02) concentrations. Increases in particulate matter concentration were associated with heart failure hospitalisation or death (PM(2·5) 2·12% per 10 μg/m(3), 95% CI 1·42–2·82; PM(10) 1·63% per 10 μg/m(3), 95% CI 1·20–2·07). Strongest associations were seen on the day of exposure, with more persistent effects for PM(2·5). In the USA, we estimate that a mean reduction in PM(2·5) of 3·9 μg/m(3) would prevent 7978 heart failure hospitalisations and save a third of a billion US dollars a year. INTERPRETATION: Air pollution has a close temporal association with heart failure hospitalisation and heart failure mortality. Although more studies from developing nations are required, air pollution is a pervasive public health issue with major cardiovascular and health economic consequences, and it should remain a key target for global health policy. FUNDING: British Heart Foundation

Dispersal and Land Cover Contribute to Pseudorabies Virus Exposure in Invasive Wild Pigs

We investigated the landscape epidemiology of a globally distributed mammal, the wild pig (Sus scrofa), in Florida (U.S.), where it is considered an invasive species and reservoir to pathogens that impact the health of people, domestic animals, and wildlife. Specifically, we tested the hypothesis that two commonly cited factors in disease transmission, connectivity among populations and abundant resources, would increase the likelihood of exposure to both pseudorabies virus (PrV) and Brucella spp. (bacterial agent of brucellosis) in wild pigs across the Kissimmee Valley of Florida. Using DNA from 348 wild pigs and sera from 320 individuals at 24 sites, we employed population genetic techniques to infer individual dispersal, and an Akaike information criterion framework to compare candidate logistic regression models that incorporated both dispersal and land cover composition. Our findings suggested that recent dispersal conferred higher odds of exposure to PrV, but not Brucella spp., among wild pigs throughout the Kissimmee Valley region. Odds of exposure also increased in association with agriculture and open canopy pine, prairie, and scrub habitats, likely because of highly localized resources within those land cover types. Because the effect of open canopy on PrV exposure reversed when agricultural cover was available, we suggest that small-scale resource distribution may be more important than overall resource abundance. Our results underscore the importance of studying and managing disease dynamics through multiple processes and spatial scales, particularly for non-native pathogens that threaten wildlife conservation, economy, and public health

High Energy Neutrino Astronomy: Towards Kilometer-Scale Detectors

Of all high-energy particles, only neutrinos can directly convey astronomical information from the edge of the universe---and from deep inside the most cataclysmic high-energy processes. Copiously produced in high-energy collisions, travelling at the velocity of light, and not deflected by magnetic fields, neutrinos meet the basic requirements for astronomy. Their unique advantage arises from a fundamental property: they are affected only by the weakest of nature's forces (but for gravity) and are therefore essentially unabsorbed as they travel cosmological distances between their origin and us. Many of the outstanding mysteries of astrophysics may be hidden from our sight at all wavelengths of the electromagnetic spectrum because of absorption by matter and radiation between us and the source. For example, the hot dense regions that form the central engines of stars and galaxies are opaque to photons. In other cases, such as supernova remnants, gamma ray bursters, and active galaxies, all of which may involve compact objects or black holes at their cores, the precise origin of the high-energy photons emerging from their surface regions is uncertain. Therefore, data obtained through a variety of observational windows---and especially through direct observations with neutrinos---may be of cardinal importance. In this talk, the scientific goals of high energy neutrino astronomy and the technical aspects of water and ice Cherenkov detectors are examined, and future experimental possibilities, including a kilometer-square deep ice neutrino telescope, are explored.Comment: 13 pages, Latex, 6 postscript figures, uses aipproc.sty and epsf.sty. Talk presented at the International Symposium on High Energy Gamma Ray Astronomy, Heidelberg, June 200

A Role for the Long Noncoding RNA SENCR in Commitment and Function of Endothelial Cells

Despite the increasing importance of long non-coding RNA in physiology and disease, their role in endothelial biology remains poorly understood. Growing evidence has highlighted them to be essential regulators of human embryonic stem cell differentiation. SENCR, a vascular-enriched long non-coding RNA, overlaps the Friend Leukemia Integration virus 1 (FLI1) gene, a regulator of endothelial development. Therefore, we wanted to test the hypothesis that SENCR may contribute to mesodermal and endothelial commitment as well as in endothelial function. We thus developed new differentiation protocols allowing generation of endothelial cells from human embryonic stem cells using both directed and haemogenic routes. The expression of SENCR was markedly regulated during endothelial commitment using both protocols. SENCR did not control the pluripotency of pluripotent cells; however its overexpression significantly potentiated early mesodermal and endothelial commitment. In HUVEC, SENCR induced proliferation, migration and angiogenesis. SENCR expression was altered in vascular tissue and cells derived from patients with critical limb ischemia and premature coronary artery disease compared to controls. Here, we showed that SENCR contributes to the regulation of endothelial differentiation from pluripotent cells and controls the angiogenic capacity of HUVEC. These data give novel insight into the regulatory processes involved in endothelial development and function

Asthma Discordance in Twins Is Linked to Epigenetic Modifications of T Cells

T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma

Coronary CT Angiography and 5-Year Risk of Myocardial Infarction.

BACKGROUND: Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5-year clinical outcomes is unknown. METHODS: In an open-label, multicenter, parallel-group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow-up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years. RESULTS: The median duration of follow-up was 4.8 years, which yielded 20,254 patient-years of follow-up. The 5-year rate of the primary end point was lower in the CTA group than in the standard-care group (2.3% [48 patients] vs. 3.9% [81 patients]; hazard ratio, 0.59; 95% confidence interval [CI], 0.41 to 0.84; P=0.004). Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard-care group in the first few months of follow-up, overall rates were similar at 5 years: invasive coronary angiography was performed in 491 patients in the CTA group and in 502 patients in the standard-care group (hazard ratio, 1.00; 95% CI, 0.88 to 1.13), and coronary revascularization was performed in 279 patients in the CTA group and in 267 in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91 to 1.27). However, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). There were no significant between-group differences in the rates of cardiovascular or noncardiovascular deaths or deaths from any cause. CONCLUSIONS: In this trial, the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization. (Funded by the Scottish Government Chief Scientist Office and others; SCOT-HEART ClinicalTrials.gov number, NCT01149590 .)