Physcomitrium patens (Hedw.) Mitt. growing in the dark defaults to an auxin- and cytokinin-independent developmental programme.

Auxin and cytokinin partially restore Physcomitrium (formerly Physcomitrella ) patens gametophores that have developed in the dark to a form more typical of those grown in light. Auxin synthesis and/or transport in gametophores decrease with time spent in the dark. Auxin synthesis resumes in the apices of dark-grown gametophores upon their return to the light. Red light and to a lesser extent blue light are sufficient for this. The mas and GH3 promoters are both auxin-inducible but respond differentially to spatial cues.

A Primed Neutrophil Subset Predicts the Risk of Bloodstream Infections in Allogeneic Hematopoietic Stem-Cell Transplant Patients: A Prospective Study.

BACKGROUND: Bloodstream infections (BSIs) are the most common infectious complication in patients who receive allogeneic hematopoietic stem-cell transplants (allo-HSCTs). Polymorphonuclear neutrophils (PMNs) are quantified to monitor the susceptibility to BSIs; however, their degree of activation is not. We previously identified a population of primed PMNs (pPMNs) with distinct markers of activation representing approximately 10% of PMNs in circulation. In this study, we investigate whether susceptibility to BSIs is related to the proportion of pPMNs rather than strictly PMN counts. METHODS: In this prospective observational study, we used flow cytometry to assess pPMNs in blood and oral rinse samples collected from patients receiving an allo-HSCT over the course of their treatment. We used the proportion of pPMNs in the blood on day 5 post-transplant to categorize patients into a high- or a low-pPMN group (>10% or <10% pPMNs). These groups were then used as a predictor of BSIs. RESULTS: A total of 76 patients were enrolled in the study with 36 in the high-pPMN group and 40 in the low-pPMN group. Patients in the low-pPMN group had lower expression of PMN activation and recruitment markers and displayed a delay in PMN repopulation of the oral cavity after the transplant. These patients were more susceptible to BSIs compared with patients in the high-pPMN group with an odds ratio of 6.5 (95% confidence interval, 2.110-25.07; P = .002). CONCLUSIONS: In patients who receive an allo-HSCT, having <10% pPMNs early in the post-transplant phase can be an independent predictor of BSI in allo-HSCT patients.

Frailty Measures of Patient-reported Activity and Fatigue May Predict 1-year Outcomes in Ambulatory Advanced Heart Failure: A Report From the REVIVAL Registry.

BACKGROUND: The Fried Frailty Phenotype predicts adverse outcomes in geriatric populations, but has not been well-studied in advanced heart failure (HF). The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life (REVIVAL) study prospectively collected frailty measures in patients with advanced HF to determine relevant assessments and their impact on clinical outcomes. METHODS AND RESULTS: HF-Fried Frailty was defined by 5 baseline components (1 point each): (1) weakness: hand grip strength less than 25% of body weight; (2) slowness based on time to walk 15 feet; (3) weight loss of more than 10 lbs in the past year; (4) inactivity; and (5) exhaustion, both assessed by the Kansas City Cardiomyopathy Questionnaire. A score of 0 or 1 was deemed nonfrail, 2 prefrail, and 3 or greater was considered frail. The primary composite outcome was durable mechanical circulatory support implantation, cardiac transplant or death at 1 year. Event-free survival for each group was determined by the Kaplan-Meier method and the hazard of prefrailty and frailty were compared with nonfrailty with proportional hazards modeling. Among 345 patients with all 5 frailty domains assessed, frailty was present in 17%, prefrailty in 40%, and 43% were nonfrail, with 67% (n = 232) meeting the criteria based on inactivity and 54% (n = 186) for exhaustion. Frail patients had an increased risk of the primary composite outcome (unadjusted hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.52-5.24; adjusted HR 3.41, 95% CI 1.79-6.52), as did prefrail patients (unadjusted HR 1.97, 95% CI 1.14-3.41; adjusted HR 2.11, 95% CI 1.21-3.66) compared with nonfrail patients, however, the predictive value of HF-Fried Frailty criteria was modest (Harrel's C-statistic of 0.603, P = .004). CONCLUSIONS: The HF-Fried Frailty criteria had only modest predictive power in identifying ambulatory patients with advanced HF at high risk for durable mechanical circulatory support, transplant, or death within 1 year, driven primarily by assessments of inactivity and exhaustion. Focus on these patient-reported measures may better inform clinical trajectories in this population.

Caregiver Health-Related Quality of Life, Burden, and Patient Outcomes in Ambulatory Advanced Heart Failure: A Report From REVIVAL.

Background Heart failure (HF) imposes significant burden on patients and caregivers. Longitudinal data on caregiver health-related quality of life (HRQOL) and burden in ambulatory advanced HF are limited. Methods and Results Ambulatory patients with advanced HF (n=400) and their participating caregivers (n=95) enrolled in REVIVAL (Registry Evaluation of Vital Information for VADs [Ventricular Assist Devices] in Ambulatory Life) were followed up for 24 months, or until patient death, left ventricular assist device implantation, heart transplantation, or loss to follow-up. Caregiver HRQOL (EuroQol Visual Analog Scale) and burden (Oberst Caregiving Burden Scale) did not change significantly from baseline to follow-up. At time of caregiver enrollment, better patient HRQOL by Kansas City Cardiomyopathy Questionnaire was associated with better caregiver HRQOL (P=0.007) and less burden by both time spent (P<0.0001) and difficulty (P=0.0007) of caregiving tasks. On longitudinal analyses adjusted for baseline values, better patient HRQOL (P=0.034) and being a married caregiver (P=0.016) were independently associated with better caregiver HRQOL. Patients with participating caregivers (versus without) were more likely to prefer left ventricular assist device therapy over time (odds ratio, 1.43; 95% CI, 1.03-1.99; P=0.034). Among patients with participating caregivers, those with nonmarried (versus married) caregivers were at higher composite risk of HF hospitalization, death, heart transplantation or left ventricular assist device implantation (hazard ratio, 2.99; 95% CI, 1.29-6.96; P=0.011). Conclusions Patient and caregiver characteristics may impact their HRQOL and other health outcomes over time. Understanding the patient-caregiver relationship may better inform medical decision making and outcomes in ambulatory advanced HF.

Global Trends of Benthic Bacterial Diversity and Community Composition Along Organic Enrichment Gradients of Salmon Farms.

The analysis of benthic bacterial community structure has emerged as a powerful alternative to traditional microscopy-based taxonomic approaches to monitor aquaculture disturbance in coastal environments. However, local bacterial diversity and community composition vary with season, biogeographic region, hydrology, sediment texture, and aquafarm-specific parameters. Therefore, without an understanding of the inherent variation contained within community complexes, bacterial diversity surveys conducted at individual farms, countries, or specific seasons may not be able to infer global universal pictures of bacterial community diversity and composition at different degrees of aquaculture disturbance. We have analyzed environmental DNA (eDNA) metabarcodes (V3-V4 region of the hypervariable SSU rRNA gene) of 138 samples of different farms located in different major salmon-producing countries. For these samples, we identified universal bacterial core taxa that indicate high, moderate, and low aquaculture impact, regardless of sampling season, sampled country, seafloor substrate type, or local farming and environmental conditions. We also discuss bacterial taxon groups that are specific for individual local conditions. We then link the metabolic properties of the identified bacterial taxon groups to benthic processes, which provides a better understanding of universal benthic ecosystem function(ing) of coastal aquaculture sites. Our results may further guide the continuing development of a practical and generic bacterial eDNA-based environmental monitoring approach.

Circulating microparticle concentrations across acute and chronic cardiovascular disease conditions.

Concentrations of different circulating microparticles (MPs) may have clinical and physiological relevance to cardiovascular disease pathologies. PURPOSE: To quantify plasma concentrations of CD31+/CD42b-, CD62E+, and CD34+ MPs across healthy individuals and those with coronary artery disease (CAD) or acute cardiovascular events (non-ST elevation myocardial infarction (NSTEMI)). Fasted blood was obtained from CAD patients (n = 10), NSTEMI patients (n = 13), and healthy older men (n = 15) 60-75 years old. METHODS: CD31+/CD42b-, CD62E+, and CD34+ MPs were isolated from plasma and quantified using flow cytometry. Relationships between MP subtypes, fasting blood lipids, blood glucose, blood pressure, body mass index, and total number of medications were assessed. RESULTS: Concentrations of CD31+/CD42b- MPs were significantly lower in CAD and NSTEMI subjects compared with healthy individuals (p = .02 and .003, respectively). No differences between groups were found for CD62E+ or CD34+ MPs (p > .05 for both). Surprisingly, among all variables assessed, only CD62E+ MP concentrations were positively correlated with triglyceride levels (p = .012) and inversely correlated with SBP (p = .03). CONCLUSIONS: Our findings provide support for the use of different MP subtypes, specifically CD31+/CD42b- MPs, as a potential biomarker of cardiovascular disease. Importantly, results from this study should be looked at in adjunct to previous MP work in CVD conditions as a way of highlighting the complex interactions of variables such as comorbid conditions and medications on MP concentrations.

Comorbid Conditions and Health-Related Quality of Life in Ambulatory Heart Failure Patients: REVIVAL (Registry Evaluation of Vital Information for VADs in Ambulatory Life REVIVAL).

BACKGROUND: Patients with heart failure (HF) often have multiple chronic conditions that may impact health-related quality of life (HRQOL) despite HF therapy. We sought to determine the association between noncardiac comorbidities and HRQOL in ambulatory patients with advanced HF. METHODS: Baseline data from 373 subjects in REVIVAL (Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life) were analyzed using multivariable general linear models to evaluate the relationship between comorbidities and HRQOL (EuroQol Visual Analogue Scale, EQ-5D-3L Index Score, and Kansas City Cardiomyopathy Questionnaire). The primary independent variables were a comorbidity index (sum of 14 noncardiac conditions), a residual comorbidity index (without depression), and depression alone. The median (25th to 75th percentile) number of comorbidities was 3 (2-4). RESULTS: Increasing comorbidity burden was associated with a reduction in generic (EQ-5D Index, P=0.005) and HF-specific (Kansas City Cardiomyopathy Questionnaire, P=0.001) HRQOL. The residual comorbidity index was not associated with HRQOL when depression included in the model independently, while depression was associated with HRQOL across all measures. Participants with depression (versus without) scored on average 13 points (95% CI, 8-17) lower on the EuroQol Visual Analogue Scale, 0.15 points (95% CI, 0.12-0.18) lower on the EQ-5D Index, and 24.9 points (95% CI, 21.2-28.5) lower on the Kansas City Cardiomyopathy Questionnaire overall summary score. CONCLUSIONS: While noncardiac comorbidities were prevalent in ambulatory advanced HF patients, only depression was associated with decreased generic and HF-specific HRQOL. Other than depression, the presence of noncardiac comorbidities should not impact expected gains in HRQOL following ventricular assist device implantation, provided the conditions are not a contraindication to implant. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01369407.

Consumption of organic wastes from coastal salmon aquaculture by wild decapods.

Rock crab Cancer irroratus and American lobster Homarus americanus are important commercial species in coastal areas where intensive salmon aquaculture occurs in eastern Canada. Such aquaculture releases organic wastes, especially feed waste (i.e. food pellets made in part from terrestrial feed ingredients). Terrestrial compounds from feed wastes were used to trace their consumption by the two decapods in the Bay of Fundy, Canada. Both species were collected in farms and reference sites and their fatty acid profiles evaluated. Individuals in close proximity to salmon farms were found to consume waste feed (high proportions of 18:1n-9 and 18:2n-6 and low proportions of 20:5n-3 and 22:6n-3). This consumption is associated with a reduction in diet diversity and a trend of increased lipid content in rock crab, suggesting that this species is more receptive to the waste feed than the American lobster, which did not show evidence of diet diversity loss and of increased lipid content. Fatty acid profiles from rock crab ovaries were also affected by the diet shift toward waste feed (low proportion of long-chain essential fatty acids), suggesting a potential influence on crab reproductive success. However, this remains to be assessed. Resulting effects of diet shifts on the ecosystem (e.g. reduction in the consumption of primary consumers and change of fatty acids transferred to predatory fish or gulls through decapods) should be evaluated to assess the spatial and temporal scales of the salmon aquaculture footprint. If the assessment reveals a strong footprint, measures to reduce wastes could be considered (e.g. pellets with greater buoyancy or with different recipe).

Quality of life and treatment preference for ventricular assist device therapy in ambulatory advanced heart failure: A report from the REVIVAL study.

BACKGROUND: The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life study is a prospective multicenter cohort of 400 ambulatory patients with advanced chronic systolic heart failure (HF). The aim of the study is to better understand disease trajectory and optimal timing of advanced HF therapies. We examined patient health-related quality of life (HRQOL) data collected at enrollment and their association with patient treatment preferences for VAD placement. METHODS: Baseline assessment of HRQOL included the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQol EQ-5D-3L Visual Analogue Scale (VAS), along with patient self-assessment of remaining life (PSARL). Descriptive statistics were used to present baseline HRQOL data and Spearman correlation tests to assess the association between KCCQ, VAS, and VAD treatment preference with patient clinical characteristics of interest. RESULTS: The median age was 60 years, 75% were male, and the median left ventricular ejection fraction was 20%. The median (25th percentile, 75th percentile), baseline KCCQ summary score was 64 (48, 78), VAS score 65 (50, 75), and PSARL 7 years (5, 10). There were statistically significant associations of baseline KCCQ and VAS with New York Heart Association class and Interagency Registry of Mechanically Assisted Circulatory Support profile (p < 0.005 for all comparisons). Baseline KCCQ and VAS revealed a modest association with PSARL (correlation = 0.45 and 0.35, respectively; p < 0.001), and many patients were overly optimistic about their expected survival. VAD treatment preference was associated with KCCQ scores (p < 0.031), but the absolute differences were small. VAD treatment preference was independent of other key clinical characteristics such as subject age, VAS, and PSARL. CONCLUSIONS: We found a lack of strong association between HRQOL and patient preference for VAD therapy. Better understanding of patients' perceptions of their illness and how this relates to HRQOL outcomes, clinician risk assessment, and patient decision-making is needed. This may in turn allow better guidance toward available HF therapies in this vulnerable population.

Association of a Giant Lymphoma Mass With Occupational Benzene Exposure.

Benzene is a chemical widely used in industrial settings and known to have hematopoietic toxicity. Previous literature has been inconsistent regarding a direct association of benzene exposure with lymphoma. A young patient with a strong history of benzene exposure presented with a 17-cm chest wall lymphoma and purulent drainage from the mass. He underwent resection of the mass. Pathologic analysis revealed a high-grade diffuse large B-cell lymphoma. The wound ultimately healed well and the patient received adjuvant chemotherapy. Though the overall literature has been inconsistent regarding the association of benzene with lymphoma, our report highlights the possibility that a very extensive exposure history may be a risk factor for the development of lymphoma.

A different type of perforation: appendicitis after colonoscopy.

Physicians who perform colonoscopy should consider appendicitis in the differential diagnosis of post procedure abdominal pain. Diagnostic laparoscopy is a safe adjunct for evaluation in patients with suspected perforation after colonoscopy. It is important that all physicians be aware of this complication to ensure prompt diagnosis and intervention.

Intestinal obstruction caused by desmoid tumours: a review of the literature.

Intraabdominal desmoid tumours are rare and can cause intestinal obstruction. Based on the review of the literature, surgical resection with negative margins and adjuvant chemotherapy is the optimal strategy for treatment of this pathology.

Demographics and socioeconomic status as predictors of weight loss after laparoscopic sleeve gastrectomy: A prospective cohort study.

BACKGROUND: Prior studies have established that race and socioeconomic factors may influence weight loss after bariatric surgery. Few studies have focused on laparoscopic sleeve gastrectomy (LSG). The objective of this study is to determine if demographic factors may predict postoperative weight loss following LSG. METHODS: Prospectively collected data on 713 consecutive primary LSG operations performed with the same technique between February 2010 and May 2016 by a single surgeon (PG) were analyzed. Multiple regression analysis was done to determine if gender, race, or socioeconomic factors such as insurance and employment status correlated with postoperative weight loss. The presence of chronic comorbidities affecting quality of life such as Type II Diabetes and Obstructive Sleep Apnea (OSA) were also recorded and analyzed. RESULTS: All studied groups had similar preoperative body mass index (BMI) (mean 46 kg/m2). Race was not significantly associated with weight loss at any postoperative interval. Male gender was associated with increased weight loss through the first three months (48.2 ±â€¯12.5 lbs vs. 40.5 ±â€¯11 lbs; p = 0.0001). Patients with diabetes had significantly less weight loss at the 6 through 18 month intervals (50.4 ±â€¯17.9 lbs vs. 59.6 ±â€¯15.6 lbs at six months; p = 0.00032; 53.3 ±â€¯25.4lbs vs. 80.5 ±â€¯31.3lbs at 18 months; p = 0.008). Patients with obstructive sleep apnea had significantly less weight loss at the two-year interval (57.5 ±â€¯29.2 lbs) vs. those without obstructive sleep apnea (69.6 ±â€¯23.5 lbs; p = 0.047). Those with Medicare compared to Medicaid or commercial insurance had decreased weight loss through the first year (52.8 ±â€¯20.8 lbs vs. 71.4 ±â€¯26.4 lbs vs. 68.6 ±â€¯24.7 lbs; p = 0.0496). Notably, a higher percentage of patients in the Medicare insurance group were also diabetic and had OSA (65% vs. 34% vs. 36%; p = 0.002; 80% vs. 55% vs. 57%; p = 0.01). Finally, those patients who were students had the greatest weight loss at two years postoperatively with the least weight loss seen in retired patients followed by those on disability (108.0 ±â€¯21.5 lbs vs. 26.0 lbs vs. 46.0 ±â€¯19.7 lbs; p = 0.04). CONCLUSIONS: Several demographic factors including comorbidities, insurance status, and employment may significantly affect weight loss patterns following LSG. Further studies are needed to evaluate whether demographic differences impact long term weight loss. Differences in outcomes based on patient demographics may be beneficial in the planning of the allocation of healthcare resources.

A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans.

Idiopathic dilated cardiomyopathy (IDC) is the most common form of non-ischemic chronic heart failure. Despite the higher prevalence of IDC in African Americans, the genetics of IDC have been relatively understudied in this ethnic group. We performed a genome-wide association study to identify susceptibility genes for IDC in African Americans recruited from five sites in the U.S. (662 unrelated cases and 1167 controls). The heritability of IDC was calculated to be 33% (95% confidence interval: 19-47%; p = 6.4 × 10-7). We detected association of a variant in a novel intronic locus in the CACNB4 gene meeting genome-wide levels of significance (p = 4.1 × 10-8). The CACNB4 gene encodes a calcium channel subunit expressed in the heart that is important for cardiac muscle contraction. This variant has not previously been associated with IDC in any racial group. Pathway analysis, based on the 1000 genes most strongly associated with IDC, showed an enrichment for genes related to calcium signaling, growth factor signaling, neuronal/neuromuscular signaling, and various types of cellular level signaling, including gap junction and cAMP signaling. Our results suggest a novel locus for IDC in African Americans and provide additional insights into the genetic architecture and etiology.

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

Robotic repair of a right-sided Bochdalek hernia: a case report and literature review.

BACKGROUND: Bochdalek hernias (BHs) are usually diagnosed in the neonatal period, occurring in 1/2200-1/12,500 live births. There are few reported cases of BHs in adults. Robotic repair has not been described in current literature as opposed to the laparoscopic approach. Here we present a case of an adult with clinical signs of bowel obstruction secondary to a BH which was repaired using a robotic approach. CASE REPORT: A 74-year-old gentleman with past medical history of benign prostatic hyperplasia presented to the emergency department with a 1-week history of nausea, vomiting, diarrhea, and decline in appetite. Computed tomography (CT) imaging of the chest and abdomen revealed elevation of the right hemidiaphragm and evidence of small bowel obstruction. The patient was managed conservatively with nasogastric tube placement and bowel rest. He underwent colonoscopy which could not be completed secondary to a transverse colon stricture which was confirmed by barium enema. Upon repeat CT imaging, the patient was found to have herniated colon through a right-sided diaphragmatic hernia which caused colonic narrowing. The patient's intestinal obstruction improved clinically with continued conservative management and he underwent robotic repair of a right posterior diaphragmatic hernia. The hernia defect was closed with interrupted figure of eight Ethibond sutures. A right-sided chest tube was placed. Intraoperatively, the herniated proximal transverse colon was noted to be ischemic and a right hemicolectomy was performed. He recovered well and was discharged home on postoperative day 5. CONCLUSION: Congenital diaphragmatic hernias usually present in the neonatal period and are rare in adults. Operative repair is recommended and laparoscopic repair has been described. Based on the existing literature regarding laparoscopic repair and the current case report, robotic repair also appears to be a viable and safe option.

A New Clinically Applicable Measure of Functional Status in Patients With Heart Failure: The 60-Foot Walk Test.

OBJECTIVES: This study reports the development and predictive value of the 60-foot walk test (60ftWT), a brief functional status measure for patients with heart failure (HF). The goal was to develop a test suitable for clinical settings and appropriate for patients with walking impairments. BACKGROUND: The 6-min walk test (6MWT) has considerable predictive value, but requires a long walking course and has limited utility in patients with mobility-related comorbidities. A shorter, more clinically practical test is therefore needed. METHODS: A total of 144 patients (age 57.4 ± 11.4 years; 111 males) with symptomatic HF received baseline assessments using the 60ftWT, 6MWT, and self-reported symptom and health status. Patients were tested 3 months later to determine stability of assessments. HF hospitalizations or death from any cause were recorded for 3.5 years following baseline. RESULTS: Median 60ftWT completion time was 26 s (interquartile range: 22 to 31 s). Longer 60ftWT time was associated with shorter 6MWT distance (r = -0.75; p < 0.001), and with higher symptom severity at baseline (r = -0.40; p < 0.001). Longer 60ftWT times also predicted increases in 6MWT and symptoms from baseline to 3 months (p < 0.01). Both WTs predicted long-term clinical outcomes, with patients taking longer than 31 s to complete the 60ftWT at greatest risk for HF hospitalization or death (hazard ratio: 2.13; 95% confidence interval: 1.18 to 3.84; p = 0.01). CONCLUSIONS: The 60ftWT is an easily administered functional status measure that predicts adverse events, symptoms, and health status. It has the potential for considerable clinical utility to help identify patients at risk for future events and to calibrate treatments designed to improve functional status and quality of life.

Investigating the extremes of the continuum of paracrine functions in CD34-/CD31+ CACs across diverse populations.

Paracrine function of circulating angiogenic cells (CACs) is thought to contribute to vascular maintenance. We previously identified S100A8 and S100A9 secreted from physically inactive individuals' CD34-/CD31+ CACs as negative regulators of capillary-like network formation. The purpose of this study was to investigate further the extremes of the continuum of CAC paracrine actions using two distinctly different groups representing "healthy" and "impaired" CAC function. We aimed to determine how capillary-like network formation in human umbilical vein endothelial cells (HUVECs) is affected by S100A8 and S100A9 in concentrations secreted by CACs from different ends of the health spectrum. CD34-/CD31+ CACs were isolated and cultured from 10 impaired function individuals defined as older (50-89 yr), non-ST-elevation myocardial infarction patients and 10 healthy individuals defined as younger (18-35 yr), healthy individuals, and conditioned media (CM) was generated. CM from the impaired function group's CACs significantly diminished network formation compared with CM from the healthy group (P < 0.05). We identified elevations in S100A8, S100A9, and S100A8/A9 in the CM from the impaired function group (P < 0.05). Pretreatment of HUVECs with inhibitors to a known S100A8 and S100A9 receptor, Toll-like receptor 4 (TLR4), but not receptor for advanced glycation end products, improved HUVEC network formation (P < 0.05) compared with CM alone in the impaired function conditions. Exposure of HUVECs to the TLR4 signaling inhibitor also blocked recombinant S100A8- and S100A9-mediated reductions in network formation. Collectively, the results suggest that the mechanisms behind impaired CAC CD34-/CD31+ CM-mediated reductions in capillary-like network formation involve secretion of S100A8 and S100A9 and binding of these proteins to TLR4 receptors on HUVECs. NEW & NOTEWORTHY: S100A8 and S100A9 proteins in concentrations secreted by CD34-/CD31+ circulating angiogenic cells (CACs) with impaired function reduce endothelial cell capillary-like network formation. These effects appear to be mediated by Toll-like receptor 4 and are absent with S100A8 and S100A9 in concentrations secreted by healthy CD34-/CD31+ CACs.