Hostility, Race, and Glucose Metabolism in Nondiabetic Individuals

OBJECTIVE— The present study was designed to determine whether hostility is differentially related to measures of glucose metabolism in African-Americans and Caucasians. RESEARCH DESIGN AND METHODS— The relationship of hostility, as measured by a subset of the Cook-Medley hostility scale (CMHOST) inventory items, to various parameters of glucose metabolism were examined in a young, healthy sample of male and female African-American and Caucasian volunteers. Fasting blood samples were collected during an inpatient admission, at which time the CMHOST was also administered. RESULTS— In the entire sample, the CMHOST was found to be significantly correlated with fasting glucose and insulin sensitivity, as measured by the homeostatic model assessment (HOMA). However, the relationship of hostility to these parameters of glucose metabolism was different in African-American and Caucasian subjects. Hostility was significantly related to fasting glucose in African-Americans and to insulin sensitivity and fasting insulin in Caucasian subjects. The relationship of hostility to insulin sensitivity and fasting insulin was partially dependent on BMI in Caucasians, but the relationship of hostility to fasting glucose was unrelated to BMI in African-Americans. CONCLUSIONS— Our data suggest that the relationship of hostility to measures of glucose metabolism is mediated differently in these two ethnic groups. Therefore, hostility seems to be part of a constellation of risk-related behaviors related to BMI in Caucasians but independently related to fasting glucose in African-Americans

Dissolved organic carbon transformations and microbial community response to variations in recharge waters in a shallow carbonate aquifer

© 2016, The Author(s). In carbonate aquifers, dissolved organic carbon from the surface drives heterotrophic metabolism, generating CO2 in the subsurface. Although this has been a proposed mechanism for enhanced dissolution at the water table, respiration rates and their controlling factors have not been widely evaluated. This study investigates the composition and concentration of dissolved organic carbon (DOC) reaching the water table from different recharge pathways on a subtropical carbonate island using a combination of DOC concentration measurements, fluorescence and absorption characterisation. In addition, direct measurements of the microbial response to the differing water types were made. Interactions of rainfall with the vegetation, via throughfall and stemflow, increase the concentration of DOC. The highest DOC concentrations are associated with stemflow, overland recharge and dissolution hole waters which interact with bark lignin and exhibit strong terrestrial-derived characteristics. The groundwater samples exhibit the lowest concentrations of DOC and are comprised of refractory humic-like organic matter. The heterotrophic response seems to be controlled by the concentration of DOC in the sample. The terrestrially sourced humic-like matter in the stemflow and dissolution hole samples was highly labile, thus increasing the amount of biologically produced CO2 to drive dissolution. Based on the calculated respiration rates, microbial activity could enhance carbonate dissolution, increasing porosity generation by a maximum of 1%kyr−1 at the top of the freshwater lens

Peace and Justice through a Feminist Lens: Gender Justice and the Women’s Court for the Former Yugoslavia

Post-conflict interventions to ‘deal with’ violent pasts have moved from exception to global norm. Early efforts to achieve peace and justice were critiqued as ‘gender-blind’—for failing to address sexual and gender-based violence, and neglecting the gender-specific interests and needs of women in transitional settings. The advent of UN Security Council resolutions on ‘Women, Peace and Security’ provided a key policy framework for integrating both women and gender issues into transitional justice processes and mechanisms. Despite this, gender justice and equality in (post-)conflict settings remain largely unachieved. This article explores efforts to attain gender-just peace in post-conflict Bosnia and Herzegovina (BiH). It critically examines the significance of a recent ‘bottom-up’ truth-telling project—the Women’s Court for the former Yugoslavia—as a locally engaged approach to achieving justice and redress for women impacted by armed conflict. Drawing on participant observation, documentary analysis, and interviews with women activists, the article evaluates the successes and shortcomings of responding to gendered forms of wartime violence through truth-telling. Extending Nancy Fraser’s tripartite model of justice to peacebuilding contexts, the article advances notions of recognition, redistribution and representation as crucial components of gender-just peace. It argues that recognizing women as victims and survivors of conflict, achieving a gender-equitable distribution of material and symbolic resources, and enabling women to participate as agents of transitional justice processes are all essential for transforming the structural inequalities that enable gender violence and discrimination to materialize before, during, and after conflict

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Wear Testing of a Canine Hip Resurfacing Implant That Uses Highly Cross‐Linked Polyethylene

Hip resurfacing offers advantages for young, active patients afflicted with hip osteoarthritis and may also be a beneficial treatment for adult canines. Conventional hip resurfacing uses metal‐on‐metal bearings to preserve bone stock, but it may be feasible to use metal‐on‐polyethylene bearings to reduce metal wear debris while still preserving bone. This study characterized the short‐term wear behavior of a novel hip resurfacing implant for canines that uses a 1.5 mm thick liner of highly cross‐linked polyethylene in the acetabular component. This implant was tested in an orbital bearing machine that simulated canine gait for 1.1 million cycles. Wear of the liner was evaluated using gravimetric analysis and by measuring wear depth with an optical scanner. The liners had a steady‐state mass wear rate of 0.99 ± 0.17 mg per million cycles and an average wear depth in the central liner region of 0.028 mm. No liners, shells, or femoral heads had any catastrophic failure due to yielding or fracture. These results suggest that the thin liners will not prematurely crack after implantation in canines. This is the first hip resurfacing device developed for canines, and this study is the first to characterize the in vitro wear of highly cross‐linked polyethylene liners in a hip resurfacing implant. The canine implant developed in this study may be an attractive treatment option for canines afflicted with hip osteoarthritis, and since canines are the preferred animal model for human hip replacement, this implant can support the development of metal‐on‐polyethylene hip resurfacing technology for human patients

Quantifying Wear Depth in Hip Prostheses Using a 3D Optical Scanner

The visualization of wear depth in hip prostheses can assist the evaluation of new bearing materials and implant designs. The goal of this study was to develop an accurate, fast, and economical methodology to generate colorimetric maps of wear depth in hip implants using a structured light 3D optical scanning system. The accuracy and precision of this novel technique were determined using reference blocks with known wear depths. This technique was then used to measure the in vitro wear of a hip resurfacing device for canines that incorporates a highly cross-linked polyethylene liner. The 3D optical scanner had an average accuracy of 2.1 µm and an average precision of 1.4 µm, which corresponded to errors less than 10% when measuring wear depths of 20 µm or greater. The scanner was able to repeatedly generate 3D colorimetric maps of wear depth in highly cross-linked polyethylene liners in 20 min or less. These colorimetric maps identified localized regions with 3-fold greater wear than the average wear depth, and revealed liners with asymmetric wear patterns. For the first time, this study has validated the use of 3D optical scanning to quantify in vitro surface wear in a hip replacement device

Polycyclic Aromatic Hydrocarbon-Induced Signaling Events Relevant to Inflammation and Tumorigenesis in Lung Cells Are Dependent on Molecular Structure

<div><p>Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.</p></div

MAP kinases differentially bind and phosphorylate NOS3 via two unique NOS3 sites

Nitric oxide synthase 3 (NOS3) is a major vasoprotective enzyme that catalyzes the conversion of L-arginine to nitric oxide (NO) in response to a significant number of signaling pathways. Here, we provide evidence that NOS3 interactions with MAP kinases have physiological relevance. Binding interactions of NOS3 with c-Jun N-terminal kinase (JNK1 ), p38α, and ERK2 were characterized using optical biosensing with full length NOS3 and NOS3 specific peptides and phospho-peptides. Like p38α and ERK2, JNK1 exhibited high affinity binding to full length NOS3 (K 15 nM). Rate constants exhibited fast-on, slow-off binding (k = 4106 M s ; k = 6.2 x 10 s ). Further analysis using synthetic NOS3 peptides revealed two MAP kinase binding sites unique to NOS3. p38α evinced similar affinity with both NOS3 binding sites. For ERK2 and JNK1 the affinity at the two sites differed. However, NOS3 peptides with a phosphate at either S114 or S633 did not meaningfully interact with the kinases. Immunoblotting revealed that each kinase phosphorylated NOS3 with a unique pattern. JNK1 predominantly phosphorylated NOS3 at S114, ERK2 at S600, and p38α phosphorylated both residues. In vitro production of NO was unchanged by phosphorylation at these sites. In human microvascular endothelial cells, endogenous interactions of all the MAP kinases with NOS3 were captured using proximity ligation assay in resting cells. Our results underscore the importance of MAP kinase interactions, identifying two unique NOS3 interaction sites with potential for modulation by MAP kinase phosphorylation (S114) and other signaling inputs, like protein kinase A (S633)

Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor, pleiotrophin (PTN), in regulating HSC function in the niche. PTN(−/−) mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking the protein tyrosine phosphatase receptor-zeta (PTPRZ), which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC-autonomous but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche which regulates HSC self-renewal and retention in vivo