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This article reviews the surgical management of coronary artery disease (CAD). The authors cover the background, presentation, diagnosis, heart team evaluation, and development of treatment strategies tailored to individual patients with significant CAD. Special attention is given to conduit selection and configuration as well as alternative revascularization approaches that differ from traditional coronary artery bypass grafting.

Fermentation of dietary fibre by the gut microbiota leads to the production of metabolites called short-chain fatty acids (SCFAs), which have emerged as potent regulators of immune, metabolic, and tissue barrier functions. More recently, a high fibre diet and SCFA supplementation were shown to lower blood pressure and be cardio-protective. SCFAs activate host signalling responses via the receptors GPR41 and GPR43, which have redundancy in their signalling pathways. Whether these receptors play a role in hypertension or mediate the cardio-protective effects of fibre remains unknown. Using an experimental model that lacks both GPR41 and GPR43, we show that lack of signalling via these receptors increases risk to high blood pressure and leads to cardiorenal fibrosis and hypertrophy.Moreover, we demonstrate that GPR41/43 signalling is essential in maintaining gut epithelial barrier, which prevents the translocation of the bacterial toxins lipopolysaccharides (LPS) from entering the peripheral circulation. In the absence of GPR41/43, this is accompanied by macrophage infiltration to the kidneys, resulting in pro-inflammatory cytokine production.Using an antagonist against the LPS’ receptor, TLR4, a potent pro-inflammatory signalling pathway, we were able to rescue the cardiovascular phenotype in GPR41/43 knockout mice. We also demonstrate that GPR41/43 are, at least partially, responsible for the blood pressure- lowering and cardio-protective effects of a high fibre diet; however, improvements of gut barrier integrity and macrophages in the kidney were independent of GPR41/43 signalling.Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41/43 are more prevalent in hypertensive patients. Our findings highlight that lack of SCFA-receptor signalling via both GPR41/43 increases risk of high blood pressure, suggesting these receptors could be targeted as a new treatment.

Cardiovascular disease is one of the most significant causes of death globally, especially in regions where unhealthy diets are prevalent and dietary fibre intake is low.1,2 Fibre, particularly prebiotic types that feed gut microbes, is essential for maintaining healthy gut microbial ecosystems.3 One assumption has been that cardiovascular health relates directly to lifestyle choices in adult life. Here, we show in mice that some of these benefits operate from the prenatal stage and relate to the diet and gut microbiome of the mother. Intake of fibre during pregnancy shaped the mothers’ gut microbiome, which had a lasting founding effect on the offspring’s microbial composition and function. Maternal fibre intake during pregnancy significantly changed the cardiac cellular and molecular landscape in the offspring, protecting them against the development of cardiac hypertrophy, remodelling, and inflammation. These suggest a role for foetal exposure to maternal-derived gut microbial metabolites, which are known to cross the placenta and drive epigenetic changes. Maternal fibre intake led to foetal epigenetic reprogramming of the atrial natriuretic peptide gene (Nppa), protective against heart failure. These results underscore the importance of dietary intake and the gut microbiome of the mother during pregnancy for cardiovascular disease in the offspring.

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are two debilitating disorders that develop in preterm infants exposed to supplemental oxygen to prevent respiratory failure. Both can lead to lifelong disabilities, such as chronic obstructive pulmonary disease and vision loss. Due to the lack of a standard experimental model of coincident disease, the underlying associations between BPD and ROP are not well characterized. To address this gap, we used the robust mouse model of oxygen-induced retinopathy exposing C57BL/6 mice to 75% oxygen from postnatal day 7 to 12. The cardinal features of ROP were replicated by this strategy, and the lungs of the same mice were simultaneously examined for evidence of BPD-like lung injury, investigating both the short- and long-term effects of early-life supplemental oxygen exposure. At postnatal days 12 and 18, mild lung disease was evident by histopathologic analysis together with the expected vasculopathy in the inner retina. At later time points, the lung lesion had progressed to severe airspace enlargement and alveolar simplification, with concurrent thinning in the outer layer of the retina. In addition, critical angiogenic oxidative stress and inflammatory factors reported to be dysregulated in ROP were similarly impaired in the lungs. These data shed new light on the interconnectedness of these two neonatal disorders, holding potential for the discovery of novel targets to treat BPD and ROP.

Background: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites. Methods: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg -1 ·d -1 ). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined. Results: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation. Conclusions: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.

MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours ( P P Stat4 , Col4a1 , Cd81 , Flt3l , Cxcl16 , and Smad4 . We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.

Neutrophils are the initial responders to infection and injury and are critical for host survival. Immunocompromised patients are prone to recurrent bacterial and fungal infections which may require granulocyte transfusion. However, these transfusions have minimal efficacy as donor material is limited and highly heterogeneous. Induced pluripotent stem cells (iPSCs) are a promising option for generating a defined therapeutic that can improve patient outcomes. Therefore, we aimed to engineer iPSC-derived neutrophils to improve recruitment and antimicrobial function. Prior research in the field has shown that iPSC-derived neutrophils have limited function compared to primary human neutrophils, likely due to inhibitory signaling pathways. To generate iPSC-derived neutrophils with enhanced capacity, we utilized CRISPR/Cas9 to delete the protein tyrosine phosphatase 1B (PTP1B), a negative regulator of neutrophil function. PTP1B−/− neutrophils displayed increased cellular migration and inflammatory cytokine signaling in response to bacterial stimuli versus WT cells. Additionally, upon selection of cells with mature neutrophil markers, these PTP1B−/− neutrophils show similar fungal killing ability and improved phagocytosis compared to WT. Thus, these data indicate that deletion of PTP1B can improve the antimicrobial function of iPSC neutrophils and highlights the value of our system for genetically engineering iPSC-derived neutrophils. Supported by grants from the NIH (5R01AI134749-03 and Microbes in Health and Disease T32 NIAID: T32AI055397)

Background: High fibre intake is associated with lower blood pressure (BP) in epidemiological and clinical studies. Prebiotic fibre resists digestion in the upper gastrointestinal tract and is fermented by gut microbiota in the intestine. The impact of lack of prebiotic dietary fibre in BP remains unknown. Objectives: To determine the consequences of lack of prebiotic dietary fibre to the development of hypertension through changes in the gut microbiome, associated receptors and immune-based mechanisms using a slow pressor angiotensin II (Ang II) model. Methods: C57BL/6 mice were fed a ‘no fibre’ or ‘high fibre’ diets for 3-weeks prior to sham or Ang II minipump implantation (n=4-21/group), and were followed for 4-weeks post-surgery. Gnotobiotic mice received faecal transplant from ‘no fibre’ sham or Ang II mice (n=5-6/group). Cardiac function, BP and gut microbiome (by 16S sequencing) were determined. Results: Ang II mice that received a ‘no fibre’ diet had significantly higher BP than sham (SBP mean±SEM: 143.7±3.5 vs 91.2±1.8, P Conclusions: Lack of prebiotic dietary fibre leads to the development of a hypertensinogenic gut microbiome, hypertension and its complications. SCFA might represent new therapeutic opportunities through modulation of G-coupled protein receptors and Treg cells.

Learn how one organization made clinical integration happen successfully, by accounting for the value-based contracting protocols and risk methodologies involved in putting ideas into practice.

Objective:To identify the influence of parental autonomy support, basic need satisfaction and motivation on emerging adults’ physical activity level and exercise behaviours.Design:Cross-sectional survey.Setting:This study convenience-sampled approximately 435 college students identified as emerging adults – aged 18–25 years, who did not have a child, own a home, or have sufficient income to be fully independent.Methods:Survey responses were used in a path model to investigate how parental autonomy support, psychological mediators and motivational processes influenced emerging adults’ exercise behaviour.Results:The hypothesised model was supported with minor modifications. Most notable was the influence of parental physical activity level and autonomy support on psychological mediators, motivational processes and exercise behaviour.Conclusion:Results indicate that parents influence their children both directly and indirectly. The impact of autonomy and competence support was found to promote emerging adults’ intrinsic motivation, which consequently influenced actual physical activity and behaviour.

Ventral abdominal hernia is a relatively common clinical condition that sometimes requires herniorraphy (surgical repair). The repair of ventral abdominal hernia typically requires implantation of a material to serve as a mechanical bridge across the defect in the abdominal wall. Biomaterials, such as porcine small intestinal submucosa (SIS), also serve as a lattice for cell growth into the implant and can naturally incorporate into the host tissue. Development of such repair materials benefits from use of animal models in which experimental abdominal wall defects are easily created and are amenable to repair in a reproducible fashion. The method offered here describes surgical creation and repair of ventral abdominal hernia in a rat model. When SIS is used to repair an experimental ventral abdominal hernia in this model, it is rapidly incorporated into host tissue within 28 days of implantation. Histologically, incorporation of their implanted material into host tissue is characterized by a robust fibrovascular response. Future refinements and applications of the rat abdominal hernia model may likely involve diabetic and/or obese animals as a means to more closely mimic common co-morbidities of man.

Value-based payment is gaining traction and proving to be a major factor in health care reform. But the success of those value-based models will depend on true clinical integration of providers-not just lip service to coordination.

To test the hypothesis that male harassment of females reduces adult female time spent on the water foraging (water use), and thus cannibalism by adult females on juveniles, we manipulated heterospecific prey availability, and social context in adult water striders and measured their effects on: 1) cannibalism of juveniles, 2) activity of adults and 3) habitat use of adults and juveniles. Cannibalism rarely occurred with alternative prey present, but was common without alternative prey. Without alternative prey, females cannibalized much more than males, but contrary to predictions, male presence did not reduce cannibalism rates. Male presence decreased female water use; however, this was counteracted by the fact that the lack of alternative prey increased female water use and activity while on the water. Furthermore, in groups of 4 males with 4 females, lack of alternative prey reduced male activity while on the water. Thus the predicted negative effect of sexual conflict on cannibalism was reduced by female and male responses to low food availability. Juveniles increased time off the water when more females or males were more on the water and active. Overall, cannibalism rates depended on alternative prey, male-female social dynamics, female foraging and juvenile refuge use.

We previously showed that medium chain acyl-coenzyme A dehydrogenase (MCAD, key regulator of fatty acid oxidation) is positively modulated in the heart by the cardioprotective kinase, phosphoinositide 3-kinase (PI3K(p110α)). Disturbances in cardiac metabolism are a feature of heart failure (HF) patients and targeting metabolic defects is considered a potential therapeutic approach. The specific role of MCAD in the adult heart is unknown. To examine the role of MCAD in the heart and to assess the therapeutic potential of increasing MCAD in the failing heart, we developed a gene therapy tool using recombinant adeno-associated viral vectors (rAAV) encoding MCAD. We hypothesised that increasing MCAD expression may recapitulate the cardioprotective properties of PI3K(p110α). rAAV6:MCAD or rAAV6:control was delivered to healthy adult mice and to mice with pre-existing pathological hypertrophy and cardiac dysfunction due to transverse aortic constriction (TAC). In healthy mice, rAAV6:MCAD induced physiological hypertrophy (increase in heart size, normal systolic function and increased capillary density). In response to TAC (~15 weeks), heart weight/tibia length increased by ~60% in control mice and ~45% in rAAV6:MCAD mice compared with sham. This was associated with an increase in cardiomyocyte cross-sectional area in both TAC groups which was similar. However, hypertrophy in TAC rAAV6:MCAD mice was associated with less fibrosis, a trend for increased capillary density and a more favourable molecular profile compared with TAC rAAV6:control mice. In summary, MCAD induced physiological cardiac hypertrophy in healthy adult mice and attenuated features of pathological remodelling in a cardiac disease model.

While immunotherapy employing chimeric antigen receptor (CAR) T cells can be effective against a variety of tumor types, little is known about what happens within the tumor at an ultrastructural level during tumor regression. Here, we used transmission electron microscopy to investigate morphologic and cellular features of tumors responding to immunotherapy composed of adoptive transfer of dual-specific CAR T cells and a vaccine, supported by preconditioning irradiation and interleukin-2. Tumors responded rapidly, and large areas of cell death were apparent by 4 days after treatment. The pleomorphic and metabolically active nature of tumor cells and phagocytic activity of macrophages were apparent in electron microscopic images of tumors prior to treatment. Following treatment, morphologic features of various types of tumor cell death were observed, including apoptosis, paraptosis and necrosis. Large numbers of lipid droplets were evident in tumor cells undergoing apoptosis. Macrophages were the predominant leukocyte type infiltrating tumors before treatment. Macrophages decreased in frequency and number after treatment, whereas an increasing accumulation of neutrophils and T lymphocytes was observed following treatment. Phagocytic activity of macrophages and neutrophils was apparent, while T cells could be observed in close association with tumor cells with potential immunological synapses present. These observations highlight the cellular composition and ultrastructural appearance of tumors undergoing regression mediated by immunotherapy.

Relational aggression occurs in many different contexts, including in romantic relationships. The current study examined associations between two subtypes of relational aggression (love withdrawal and social sabotage) and marital quality over a 5-year time period. Participants consisted of 311 married couples who completed a number of questionnaires on relational aggression and relationship quality once a year over a 5-year period. Results revealed that relational aggression was highly stable over time and that women used more relational aggression than men. Men's use of social sabotage and love withdrawal were bidirectionally related to both partners' perceptions of poor marital quality over time. Conversely, only women's use of love withdrawal was related to her own perceptions of poor marital quality over time. Collectively, these results suggest that relational aggression by men may be less common, though particularly toxic in a marital relationship. Couples are encouraged to find healthier ways of coping with problems in relationships. (PsycINFO Database Record

This report presents data from four studies to examine standard bone-conduction reference equivalent threshold force levels (RETFL), especially at 4 kHz where anomalous air-bone gaps are common. Design: Data were mined from studies that obtained air- and bone-conduction thresholds from normal-hearing and sensorineural hearing loss (SNHL) participants, using commercial audiometers and standard audiometric transducers. Study sample: There were 249 normal-hearing and 188 SNHL participants. Results: (1) Normal- hearing participants had small air-bone gaps at 0.5, 1.0, and 2.0 kHz ( � 1.7 to 0.3 dB) and larger air-bone gaps at 4 kHz (10.6 dB). (2) SNHL participants had small air-bone gaps at 0.5, 1.0, and 2.0 kHz ( � 0.7 to 1.7 dB) and a larger air-bone gap at 4 kHz (14.1 dB). (3) The 4-kHz air-bone gap grew with air-conduction threshold from 10.1 dB when the air- conduction threshold was 5 - 10 dB HL to 21.1 dB when the air-conduction threshold was greater than 60 dB. (4) With the 4-kHz RETFL corrected by the average SNHL air-bone gap, the relationship between RETFL and frequency is linear with a slope of � 12 dB per octave. Conclusions: The 4-kHz air-bone gaps for listeners with SNHL could be avoided by adjusting the 4-kHz RETFL by � 14.1 dB.

Needlestick and other sharps-related injuries are largely preventable with proper education, training, and the use of safety-engineered devices. In 2009, a review of clinical practice was completed at Thunder Bay Regional Health Sciences Centre. The review revealed that despite needle-free legislation, numerous years of education on the dangers of using needles, and the availability and importance of using safety devices, nurses and physicians continued to use needles when accessing intravenous tubing to administer medication. During 2010, a luer-activated intravenous administration system was introduced to replace the current split-septum intravenous administration system. Implementation of the luer-activated system was expected to decrease needlestick injuries, positively affect nursing practice, and demonstrate a commitment to a safe working environment. Reported needlestick injuries were reviewed and analysed pre- and post-implementation and a survey on nurse perception of the new system and organizational safety was distributed. Results showed that there was a 46% decrease in needlestick injuries post-implementation, along with 80% of nursing staff reporting that the new system had a positive influence on their nursing practice and belief that the organization was committed to providing a safe work environment. The results of this study emphasize and support the replacement of needles with alternative needleless products to improve the safety of the work environment.

We propose an Automatic Threat Detection (ATD) algorithm for Explosive Detection System (EDS) using our multistage Segmentation Carving (SC) followed by Support Vector Machine (SVM) classifier. The multi-stage Segmentation and Carving (SC) step extracts all suspect 3-D objects. The feature vector is then constructed for all extracted objects and the feature vector is classified by the Support Vector Machine (SVM) previously learned using a set of ground truth threat and benign objects. The learned SVM classifier has shown to be effective in classification of different types of threat materials. The proposed ATD algorithm robustly deals with CT data that are prone to artifacts due to scatter, beam hardening as well as other systematic idiosyncrasies of the CT data. Furthermore, the proposed ATD algorithm is amenable for including newly emerging threat materials as well as for accommodating data from newly developing sensor technologies. Efficacy of the proposed ATD algorithm with the SVM classifier is demonstrated by the Receiver Operating Characteristics (ROC) curve that relates Probability of Detection (PD) as a function of Probability of False Alarm (PFA). The tests performed using CT data of passenger bags shows excellent performance characteristics.

Management of post-surgical pain following herniorrhaphy remains a clinical challenge and novel methods to deliver analgesic compounds could be of great benefit. Because there is great interest in the use of natural biomaterials for hernia repair, we investigated the biocompatibility of a natural biomaterial, porcine small intestinal submucosa (SIS), which was impregnated with bupivacaine (SIS-B) via immersion in a solution of poly(lactic-co-glycolic acid) (PLGA). Groups of Sprague Dawley rats underwent surgical creation of a ventral abdominal wall defect with subsequent repair using either SIS or SIS-B. Analysis of serial blood samples showed peak bupivacaine levels (83 ng/mL) were achieved 16 h after implantation of SIS-B. One month after surgery, the rats were euthanized and implant sites harvested for mechanical strength testing and histological analysis. At the time of necropsy, adhesion extent and tenacity was greater in SIS-B rats, with 90% of SIS-B rats have adhesion to the implant site compared to only 75% of SIS rats. Microscopically, SIS implant sites were characterized by small amounts of residual SIS surrounded by mild-to-moderate chronic inflammation. In contrast, rats treated with SIS-B, residual SIS-B was surrounded by a ring of acute inflammatory cells and an outer ring of chronic inflammatory cells, possibly due to bupivacaine or residual PLGA. Mechanical strength testing of the harvested implant sites showed no significant ( p ≤ 0.05) difference between SIS and SIS-B implants. In summary, bupivacaine is readily elaborated from SIS-B; and impregnation of SIS with bupivacaine does not substantially alter the biocompatibility of the biomaterial or its mechanical strength following implantation.

Aortic subannular left ventricular aneurysm is a rare form of cardiac pathology. We report a case, including noninvasive and intraoperative imaging, of this entity in a young woman presenting with angina. The patient underwent successful surgical repair and is now asymptomatic.

In other parts of the world, previous workers have shown that sparry dolomite in carbonate rocks may be produced by the generation and movement of hot basinal brines in response to arid paleoclimates and tectonism, and that some of these brines served as the transport medium for metals fixed in Mississippi Valley-type (MVT) and sedimentary exhalative (Sedex) deposits of Zn, Pb, Ag, Au, or barite. Numerous occurrences of hydrothermal zebra dolomite (HZD), comprised of alternating layers of dark replacement and light void-filling sparry or saddle dolomite, are present in Paleozoic platform and slope carbonate rocks on the eastern side of the Great Basin physiographic province. Locally, it is associated with mineral deposits of barite, Ag-Pb-Zn, and Au. In this paper the spatial distribution of HZD occurrences, their stratigraphic position, morphological characteristics, textures and zoning, and chemical and stable isotopic compositions were determined to improve understanding of their age, origin, and relation to dolostone, ore deposits, and the tectonic evolution of the Great Basin. In northern and central Nevada, HZD is coeval and cogenetic with Late Devonian and Early Mississippian Sedex Au, Zn, and barite deposits and may be related to Late Ordovician Sedex barite deposits. In southern Nevada and southwest California, it is cogenetic with small MVT Ag-Pb-Zn deposits in rocks as young as Early Mississippian. Over Paleozoic time, the Great Basin was at equatorial paleolatitudes with episodes of arid paleoclimates. Several occurrences of HZD are crosscut by Mesozoic or Cenozoic intrusions, and some host younger pluton-related polymetallic replacement and Carlin-type gold deposits. The distribution of HZD in space (carbonate platform, margin, and slope) and stratigraphy (Late Neoproterozoic Ediacaran–Mississippian) roughly parallels that of dolostone and both are prevalent in Devonian strata. Stratabound HZD is best developed in Ediacaran and Cambrian units, whereas discordant HZD is proximal to high-angle structures at the carbonate platform margin, such as strike-slip and growth faults and dilational jogs. Fabric-selective replacement and dissolution features (e.g., collapse breccias, voids with geopetal textures) are common, with remaining void space lined with light-colored dolomite crystals that exhibit zoning under cathodoluminescence. Zoned crystals usually contain tiny ( ∼70 °C. The oxygen isotopic compositions of HZD are consistent with formation temperatures of 50–150 °C requiring brine circulation to depths of 2–5 km, or more. The few HZD occurrences with the highest concentrations of metals (especially Fe, Mn, and Zn) and the largest isotopic shifts are closely associated with Sedex or MVT deposits known to have formed from hotter brines (e.g., Th > 150–250 °C). These relationships permit that HZD formed at about the same time as dolostone, from brines produced by the evaporation of seawater during arid paleoclimates at equatorial paleolatitudes. Both dolostone and HZD may have formed as basinal brines, which migrated seaward from evaporative pans on the platform, with dolostone forming at low temperatures along shallow migration pathways through permeable limestones, and HZD forming at high temperatures along deeper migration pathways through basal aquifers and dilatant high-angle faults. The small MVT deposits were chemical traps where hot brines encountered rocks or fluids containing reduced sulfur. The abundant Sedex deposits mark sites where hot brine discharged at the seafloor in adjacent basins. Thus the distribution of HZD may map deep migration pathways and upflow zones between eastern shallow marine facies, where evaporative brine could have been generated, and western Sedex deposits, where heated brines discharged along faults into platform margin, slope, and basin facies. The small size and scarcity of Pb-Zn deposits and the abundance of barite deposits in the Great Basin suggests the brines were generally reduced, possibly due to reactions with carbonaceous rocks along deep migration pathways. While this scenario may have occurred at several times, the age and abundance of Sedex deposits suggest that such a hydrology was best developed in the Late Ordovician, Late Devonian, and Early Mississippian, possibly in response to episodes of extension and forebulge faults associated with the Antler orogeny. The improved understanding of HZD may aid future exploration for ore deposits in the Great Basin.

Acting as both a polarity regulator and a scaffolding protein, Scribble (SCRIB), coordinates intracellular signalling pathways that regulate cell proliferation, migration and apoptosis. Deregulation of SCRIB has been linked to multiple epithelial cancers but the role of SCRIB in hematopoiesis and hematopoietic malignancies remains relatively unexplored. Using different approaches, we show that SCRIB is expressed in hematopoietic stem and progenitor cells and in their differentiated progenies, implying a role for SCRIB in blood production. We investigated the effect of SCRIB loss in hematopoiesis using two conditional knockout mouse models in conjunction with an extensive phenotypic labelling regime and multi-color flow cytometry. We reveal a role for SCRIB in T cell development although subtle differences between the two mouse models were noted. Compensatory mechanisms often mask the effects of single protein deletion during steady-state so stress hematopoiesis was induced through a transplant assay to minimise these effects. Lethally irradiated recipient mice receiving a transplant of SCRIB knockout bone marrow revealed a more striking phenotype with significantly altered populations of granulocyte, macrophage, erythroid, T and B cell progenitors, and mature macrophage fractions compared to controls. Collectively, our data shows SCRIB is required for the development of multiple hematopoietic fractions and studies are currently underway to identify the underlying mechanism/s and elucidate how deregulation of SCRIB impacts on hematopoietic malignancies. Citation Format: Novita Novita, Alysha Dew, Chad Johnson, Carl R. Walkley, Louise E. Purton, Patrick O. Humbert, Phillip K. Darcy, Sarah L. Ellis. Investigating the role of polarity protein, SCRIB, in hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-183.

Although nonneurologic organ dysfunction (NNOD) has been shown to significantly affect mortality in subarachnoid hemorrhage, the contribution of NNOD to mortality after severe traumatic brain injury (TBI) has yet to be defined. We hypothesized that NNOD has a significant impact on mortality after severe TBI. The trauma registry was queried for all patients admitted between January 2004 and December 2004 who died during their initial hospitalization after severe TBI (head Abbreviated Injury Score 3 or greater). Cause of death and contributing factors to mortality were determined by an attending trauma surgeon from the medical record. The data were analyzed using both Fisher's exact and Wilcoxon rank sum. One hundred thirty-five patients met inclusion criteria. Sixty-seven per cent were males, 83 per cent were white, and the mean age was 38.5 years. Mean length of stay was 2.9 days. Fifty-four patients (40%) had isolated TBI (chest Abbreviated Injury Score = 0, abdominal Abbreviated Injury Score = 0). Of the 81 deaths attributed to a single cause, 48 (60%) patients died from nonsurvivable TBI or brain death, whereas 33 (40%) died of a nonneurologic cause. Cardiovascular and respiratory dysfunction (excluding pneumonia) contributed to mortality in 51.1 per cent and 34.1 per cent of patients, respectively. NNOD contributes to approximately two-thirds of all deaths after severe TBI. These complications occur early and are seen even among those with isolated head injuries. These findings demonstrate the impact of the extracranial manifestations of severe TBI on overall mortality and highlight potential areas for future intervention and research.

Peroxisomes were visualized for the first time in living fission yeast cells. In small, newly divided cells, the number of peroxisomes was low but increased in parallel with the increase in cell length/volume that accompanies cell cycle progression. In cells grown in oleic acid, both the size and the number of peroxisomes increased. The peroxisomal inventory of cells lacking the dynamin-related proteins Dnm1 or Vps1 was similar to that in wild type. By contrast, cells of the double mutant dnm1Delta vps1Delta contained either no peroxisomes at all or a small number of morphologically aberrant organelles. Peroxisomes exhibited either local Brownian movement or longer-range linear displacements, which continued in the absence of either microtubules or actin filaments. On the contrary, directed peroxisome motility appeared to occur in association with mitochondria and may be an indirect function of intrinsic mitochondrial dynamics. We conclude that peroxisomes are present in fission yeast and that Dnm1 and Vps1 act redundantly in peroxisome biogenesis, which is under cell cycle control. Peroxisome movement is independent of the cytoskeleton but is coupled to mitochondrial dynamics.

The impact of peracetic acid (PAA), lyophilization, and ethylene oxide (EO) sterilization on the composition and three dimensional matrix structure of small intestinal submucosa (SIS), a biologic scaffold used to stimulate the repair of damaged tissues and organs, was examined. Fibronectin and glycosaminoglycans are retained in SIS following oxidation by peracetic acid and alkylation using ethylene oxide gas. Significant amounts of FGF-2 are also retained, but VEGF is susceptible to the effects of PAA and is dramatically reduced following processing. Further, matrix oxidation, lyophilization, and sterilization with EO can be performed without irreversibly collapsing the three dimensional structure of the native SIS. These structural features and growth promoting extracellular matrix constituents are likely to be important variables underlying cellular attachment, infiltration and eventual incorporation of SIS into healing host tissues.

Background & Aims The enzyme cyclooxygenase-2 is expressed in a majority of colorectal carcinomas (CRCs) and is important in prostaglandin production. We have developed an accurate method to measure the urinary metabolite of prostaglandin E2 (PGE-M) using recently developed mass spectrometric techniques. The purpose of this pre-validation study was to determine if urinary PGE-M levels can be used as a biomarker to discriminate between healthy patients and those with colorectal disease. Methods Urine PGE-M was assessed in a total of 228 patients with CRC, colonic adenomatous polyps, Crohn's disease, and in subjects with no endoscopically detectable disease. Thirteen rectal carcinoma patients were treated with celecoxib and urinary PGE-M was measured before and after treatment. Results Urine PGE-M levels were increased among healthy men compared with healthy women (median, 8.59 [interquartile range (IQR), 5.67–22.3] vs 4.25 [IQR, 2.35–6.03], P = .0027). Urine PGE-M levels among patients with Crohn's disease (median, 19.85 [IQR, 6.89–90.2]), CRC (median, 14.65 [IQR, 5.94–92.1]), or large adenomas greater than 1 cm in size (median, 18.85 [IQR, 11.9–25.6]) were significantly increased when compared with patients who had either small polyps less than 1 cm in size (median, 9.69 [IQR, 6.41–22.2]), or no polyps (median, 7.05 [IQR, 2.35–24.7]) (P = .0001). PGE-M levels decreased significantly after celecoxib treatment in patients with rectal cancer (median, 21.7 [IQR, 16.2–29.9] vs 9.14 [IQR, 7.14–13.2], P = .009). Conclusions The increase in urinary PGE-M in patients with colorectal cancers and large adenomas suggests that urinary PGE-M is a potentially useful biomarker for the detection of advanced colorectal neoplasia.

The Donlin Creek gold deposit, southwestern Alaska, has an indicated and inferred resource of approximately 25 million ounces (Moz) Au at a cutoff grade of 1.5 g/t. The ca. 70 Ma deposit is hosted in the Late Cretaceous Kuskokwim flysch basin, which developed in the back part of the arc region of an active continental margin, on previously accreted oceanic terranes and continental fragments. A hypabyssal, mainly rhyolitic to rhyodacitic, and commonly porphyritic, 8- × 3-km dike complex, part of a regional ca. 77 to 58 Ma magmatic arc, formed a structurally competent host for the mineralization. This deposit is subdivided into about one dozen distinct prospects, most of which consist of dense quartz ± carbonate veinlet networks that fill north-northeast–striking extensional fractures in the northeast-trending igneous rocks. The sulfide mineral assemblage is dominated by arsenopyrite, pyrite, and, typically younger, stibnite; gold is refractory within the arsenopyrite. Sericitization, carbonatization, and sulfidation were the main alteration processes. Fluid inclusion studies of the quartz that hosts the resource indicate dominantly aqueous ore fluids with also about 3 to 7 mol percent CO2 ± CH4 and a few tenths to a few mole percent NaCl + KCl. The gold-bearing fluids were mainly homogeneously trapped at approximately 275° to 300°C and at depths of 1 to 2 km. Some of the younger stibnite may have been deposited by late-stage aqueous fluids at lower temperature. Measured δ 18O values for the gold-bearing quartz range between 11 and 25 per mil; the estimated δ 18O fluid values range from 7 to12 per mil, suggesting a mainly crustally derived fluid. A broad range of measured δ D values for hydrothermal micas, between –150 and –80 per mil, is suggestive of a contribution from devolatilization of organic matter and/or minor amounts of mixing with meteoric fluids. Gold-associated hydrothermal sulfide minerals are characterized by δ 34S values mainly between –16 and –10 per mil, with the sulfur derived from diagenetic pyrite and organic matter within the flysch basin. A smaller group of δ 34S measurements, which shows values as depleted as –27 per mil, suggests a different local sulfur reservoir in the basin for the later hydrothermal episode dominated by stibnite. Initial ϵ Nd of –8.7 to –3.1 and 87Sr/86Sr measurements of 0.706 to 0.709 for the ore-hosting dikes also indicate a crustal reservoir for some of the Late Cretaceous magmatism. Overlapping lead isotope data for these intrusive rocks and for sulfide minerals suggest a crustal contribution for the lead in both. Copper- and gold-bearing stockwork veinlets in hornfels occur at Dome, a prospect located at the northern end of the Donlin Creek deposit. These stockworks are cut by the younger auriferous gold veins that define the main Donlin Creek gold mineralization. Highly saline, gas-rich, heterogeneously trapped fluids deposited the stockworks at temperatures approximately 100°C hotter than those of the main gold-forming event at Donlin Creek. The genetic relationship of the Dome prospect to the main Donlin Creek gold resource is equivocal. The epizonal Donlin Creek deposit shows affinities to the gold systems interpreted by various workers as orogenic or intrusion related; it shows important differences from typical epithermal and Carlin-like deposits. The ore-forming fluids were derived by either broad-scale metamorphic devolatilization above rising mantle melts or exsolution from a magma that was dominated by a significant flysch melt component.

Objectives— Smooth muscle cells (SMCs) produce both matrix metalloproteinase (MMP)-2 and MMP-9, enzymes with similar in vitro matrix degrading abilities. We compared the specific contributions of these enzymes to SMC-matrix interactions in vitro and in vivo. Methods and Results— Using genetic models of deficiency, we investigated MMP-2 and MMP-9 roles in SMC migration in vivo in the formation of intimal hyperplasia and in vitro. In addition, we investigated potential effects of MMP-2 and MMP-9 genetic deficiency on compaction and assembly of collagen by SMCs. Conclusions— MMP-2 and MMP-9 genetic deficiency decreased by 81% and 65%, respectively ( P P P

Arteries remodel in response to environmental changes. We investigated whether mechanical strain modulates production of matrix metalloproteinase (MMP)-2 and -9 by cultured vascular smooth muscle cells (SMC). MMP-2 and MMP-9 expression were tested using human saphenous vein SMC cultured on silicone membranes at rest or subjected to physiological levels (5%) of stationary or cyclical (1 Hz) uniaxial strain. Compared with control, stationary strain significantly increased MMP-2 mRNA levels at all time points, whereas cyclic strain decreased it after 48 h. Both secreted and cell-associated pro-MMP-2 levels were increased by stationary strain at all times ( P < 0.01), whereas cyclic strain decreased secreted levels after 48 h ( P < 0.02). MMP-9 mRNA levels and pro-MMP-9 protein were increased after 48 h of stationary stretch ( P< 0.01) compared with both no strain and cyclic strain. Our study indicates that vascular SMC show a selective response to different types of strain. We suggest that local increases in stationary mechanical strain resulting from stenting, hypertension, or atherosclerosis may lead to enhanced matrix degradation by SMC.

Changes in supramolecular assembly of matrix, specifically collagen, have important functional consequences, especially for tissues requiring high mechanical strength. Thus modulation of collagen assembly could be used as a therapeutic intervention or to control the development of tissue-engineered constructs containing natural matrix. Quantitative methods that monitor such effects currently are lacking. Using live cultured cells, we developed a convenient way either to visualize by fluorescence microscopy or to measure directly, using a high throughput fluorescence assay, the supramolecular assembly of FITC-labeled collagen monomers. The wide applicability of this assay was confirmed by testing the assay using two major collagen sources, rat tail and bovine skin, and vascular smooth muscle cells from two different origins, mouse aorta and human saphenous vein. We further determined that treatments that interfere with the function of the cytoskeleton modulate collagen assembly. Use of positive and negative regulators of lysyl-oxidase indicated that while the assay does not require active production of endogenous collagen, it can be used to monitor the incorporation of such de novo synthesized collagen into labeled fibrils. Thus we have designed a novel quantitative assay that can monitor assembly of exogenous and endogenous collagen by live cells and reveal the effects of various interventions upon this process.