Episodic foresight is impaired following acute alcohol intoxication.

BACKGROUND: Alcohol intoxication disrupts many aspects of cognition, including the generation of phenomenological characteristics of future events (a component of episodic foresight), and the execution of directed preparatory behaviours (a component of prospective memory). However, no study has tested whether alcohol intoxication is also associated with deficits engaging episodic foresight to guide future-directed behaviour. AIMS: This study was designed to provide the first test of how alcohol intoxication influences the functional application of episodic foresight. The secondary aim was to establish the degree to which any observed episodic foresight difficulties associated with alcohol use might reflect broader problems in retrospective memory and executive control. Sex differences were also examined. METHODS: Healthy adult social drinkers randomly received either a moderate dose of 0.6 g/kg alcohol (n = 61) or a matched placebo drink (n = 63) and then completed a validated measure that met strict criteria for assessing the functional application of episodic foresight as well as a broader cognitive test battery. RESULTS: Relative to the placebo condition, episodic foresight was impaired by acute alcohol consumption, with this impairment related to poorer retrospective memory, but not executive control. The negative effects of alcohol intoxication on episodic foresight did not differ as a function of sex. CONCLUSIONS: Even a moderate level of intoxication impairs the ability to use episodic foresight in a functionally adaptive way. These findings have implications for understanding many of the maladaptive behaviours that are often associated with acute alcohol use.

Off-the-shelf, heparinized small diameter vascular graft limits acute thrombogenicity in a porcine model.

Thrombogenicity poses a challenge to the clinical translation of engineered grafts. Previously, small-diameter vascular grafts (sdVG) composed of fibrin hydrogel microfiber tubes (FMT) with an external poly(ε-caprolactone) (PCL) sheath supported long-term patency in mice. Towards the development of an sdVG with off-the-shelf availability, the FMT's shelf stability, scale-up, and successful conjugation of an antithrombotic drug to the fibrin scaffold are reported here. FMTs maintain mechanical stability and high-water retention after storage for one year in a freezer, in a refrigerator, or at room temperature. Low molecular weight heparin-conjugated fibrin scaffolds enabled local and sustained delivery during two weeks of enzymatic degradation. Upscaled fabrication of sdVGs provides natural biodegradable grafts with size and mechanics suitable for human application. Implantation in a carotid artery interposition porcine model exhibited no rupture with thrombi prevented in all heparinized sdVGs (n = 4) over 4-5 weeks. Remodeling of the sdVGs is demonstrated with endothelial cells on the luminal surface and initial formation of the medial layer by 4-5 weeks. However, neointimal hyperplasia at 4-5 weeks led to the stenosis and occlusion of most of the sdVGs, which must be resolved for future long-term in vivo assessments. The off-the-shelf, biodegradable heparinized fibrin sdVG layer limits acute thrombogenicity while mediating extensive neotissue formation as the PCL sheath maintains structural integrity. STATEMENT OF SIGNIFICANCE: To achieve clinical and commercial utility of small-diameter vascular grafts as arterial conduits, these devices must have off-the-shelf availability for emergency arterial bypass applications and be scaled to a size suitable for human applications. A serious impediment to clinical translation is thrombogenicity. Treatments have focused on long-term systemic drug therapy, which increases the patient's risk of bleeding complications, or coating grafts and stents with anti-coagulants, which minimally improves patient outcomes even when combined with dual anti-platelet therapy. We systematically modified the biomaterial properties to develop anticoagulant embedded, biodegradable grafts that maintain off-the-shelf availability, provide mechanical stability, and prevent clot formation through local drug delivery.

Deficits in episodic future thinking following acute alcohol consumption.

RATIONALE: Acute alcohol consumption adversely affects many cognitive abilities, including episodic memory and executive functioning. However, no study to date has tested whether these acute effects of alcohol also extend to episodic future thinking (EFT). This is a surprising omission given that EFT refers to the ability to imagine oneself experiencing the future, a highly adaptive ability that has been implicated in many important functional behaviours. EFT is also thought to impose demands on episodic memory and executive control. OBJECTIVES: The current study was designed to provide the first test of whether a moderate dose of alcohol influences EFT and whether any observed EFT difficulties are secondary to broader problems in episodic memory and executive functioning. Sex differences in EFT following acute alcohol consumption were also examined. METHODS: One hundred and twenty-four healthy adult social drinkers were recruited and randomly assigned to either the alcohol (n = 61) or placebo (n = 63) condition. Participants were administered a dose of 0.6 g/kg alcohol or a matched placebo drink. RESULTS: Relative to the placebo condition, EFT was impaired by acute alcohol consumption. This impairment was underpinned by broader difficulties with episodic memory, but not executive functioning. There were no sex differences in EFT performance following acute alcohol use. CONCLUSION: These data provide novel insights into the effects of acute alcohol consumption on EFT and the broader cognitive mechanisms that contribute to these difficulties. The results are discussed in relation to their implications for understanding many of the maladaptive behaviours commonly associated with acute alcohol use.

Prospective memory deficits following acute alcohol consumption.

BACKGROUND: Prospective memory is a critical neurocognitive capacity that refers to the ability to execute delayed intentions. To date, few studies have investigated the effects of acute alcohol consumption on prospective memory, and important questions remain about the mechanisms that might underpin acute alcohol-induced prospective memory impairment. AIMS: The current study sought to clarify the nature and magnitude of prospective memory difficulties following acute alcohol consumption and to test the degree to which any problems with prospective remembering might be a secondary consequence of broader cognitive impairment. This study also investigated whether there were potential sex differences. METHODS: In all, 124 healthy adult social drinkers were assigned to either the alcohol (n = 61) or placebo (n = 63) condition. Participants were administered a dose of 0.6 g/kg alcohol or a matched placebo drink and then asked to complete a measure of prospective memory. A broader neurocognitive test battery was also administered. RESULTS: Relative to the placebo condition, acute alcohol intoxication led to significant impairment on all prospective memory tasks, with effects mostly large in magnitude. These difficulties could not be explained by broader problems in retrospective memory, executive function or episodic future thinking. In addition, females recorded a higher blood alcohol concentration than males; however, no sex differences in prospective memory performance were identified following acute alcohol use. CONCLUSION: The results show that acutely, even a moderate dose of alcohol substantially impairs prospective memory function. These findings have potentially important implications for understanding many of the maladaptive behaviours associated with acute alcohol consumption.

HIF2A gain-of-function mutation modulates the stiffness of smooth muscle cells and compromises vascular mechanics.

Heterozygous gain-of-function (GOF) mutations of hypoxia-inducible factor 2α (HIF2A), a key hypoxia-sensing regulator, are associated with erythrocytosis, thrombosis, and vascular complications that account for morbidity and mortality of patients. We demonstrated that the vascular pathology of HIF2A GOF mutations is independent of erythrocytosis. We generated HIF2A GOF-induced pluripotent stem cells (iPSCs) and differentiated them into endothelial cells (ECs) and smooth muscle cells (SMCs). Unexpectedly, HIF2A-SMCs, but not HIF2A-ECs, were phenotypically aberrant, more contractile, stiffer, and overexpressed endothelin 1 (EDN1), myosin heavy chain, elastin, and fibrillin. EDN1 inhibition and knockdown of EDN1-receptors both reduced HIF2-SMC stiffness. Hif2A GOF heterozygous mice displayed pulmonary hypertension, had SMCs with more disorganized stress fibers and higher stiffness in their pulmonary arterial smooth muscle cells, and had more deformable pulmonary arteries compared with wild-type mice. Our findings suggest that targeting these vascular aberrations could benefit patients with HIF2A GOF and conditions of augmented hypoxia signaling.

Regenerative and durable small-diameter graft as an arterial conduit.

Despite significant research efforts, clinical practice for arterial bypass surgery has been stagnant, and engineered grafts continue to face postimplantation challenges. Here, we describe the development and application of a durable small-diameter vascular graft with tailored regenerative capacity. We fabricated small-diameter vascular grafts by electrospinning fibrin tubes and poly(ε-caprolactone) fibrous sheaths, which improved suture retention strength and enabled long-term survival. Using surface topography in a hollow fibrin microfiber tube, we enable immediate, controlled perfusion and formation of a confluent endothelium within 3-4 days in vitro with human endothelial colony-forming cells, but a stable endothelium is noticeable at 4 weeks in vivo. Implantation of acellular or endothelialized fibrin grafts with an external ultrathin poly(ε-caprolactone) sheath as an interposition graft in the abdominal aorta of a severe combined immunodeficient Beige mouse model supports normal blood flow and vessel patency for 24 weeks. Mechanical properties of the implanted grafts closely approximate the native abdominal aorta properties after just 1 week in vivo. Fibrin mediated cellular remodeling, stable tunica intima and media formation, and abundant matrix deposition with organized collagen layers and wavy elastin lamellae. Endothelialized grafts evidenced controlled healthy remodeling with delayed and reduced macrophage infiltration alongside neo vasa vasorum-like structure formation, reduced calcification, and accelerated tunica media formation. Our studies establish a small-diameter graft that is fabricated in less than 1 week, mediates neotissue formation and incorporation into the native tissue, and matches the native vessel size and mechanical properties, overcoming main challenges in arterial bypass surgery.

Episodic foresight deficits in regular, but not recreational, cannabis users.

BACKGROUND: Cannabis use is associated with a range of neurocognitive deficits, including impaired episodic memory. However, no study to date has assessed whether these difficulties extend to episodic foresight, a core component of which is the ability to mentally travel into one's personal future. This is a particularly surprising omission given that episodic memory is considered to be critical to engage episodic foresight. AIMS: In the present study, we provide the first test of how episodic foresight is affected in the context of differing levels of cannabis use, and the degree to which performance on a measure of this construct is related to episodic memory. RESULTS: Fifty-seven regular cannabis users (23 recreational, 34 regular) and 57 controls were assessed using an adapted version of the Autobiographical Interview. The results showed that regular-users exhibited greater impairment of episodic foresight and episodic memory than both recreational-users and cannabis-naïve controls. CONCLUSIONS: These data therefore show for the first time that cannabis-related disruption of cognitive functioning extends to the capacity for episodic foresight, and they are discussed in relation to their potential implications for functional outcomes in this group.

Human Pluripotent Stem Cells to Engineer Blood Vessels.

Development of pluripotent stem cells (PSCs) is a remarkable scientific advancement that allows scientists to harness the power of regenerative medicine for potential treatment of disease using unaffected cells. PSCs provide a unique opportunity to study and combat cardiovascular diseases, which continue to claim the lives of thousands each day. Here, we discuss the differentiation of PSCs into vascular cells, investigation of the functional capabilities of the derived cells, and their utilization to engineer microvascular beds or vascular grafts for clinical application. Graphical Abstract Human iPSCs generated from patients are differentiated toward ECs and perivascular cells for use in disease modeling, microvascular bed development, or vascular graft fabrication.

Three-dimensional culture of small-diameter vascular grafts.

In this review we analyze a representative sample of efforts to engineer three dimensional small-diameter (<6 mm) vascular grafts, concentrating on biomaterial substrates, cellular choices, and biomechanical stimulation. Natural or synthetic scaffolds for vascular engineering need to mimic the natural extracellular matrix microenvironment, maintain physiological mechanical properties, be biocompatible and cell adhesive, and control cellular structure and function. Additionally, multicellular culture with stem cells that are highly proliferative and differentiable should be used to better recapitulate native vasculature. Fluid flow and co-culture of perivascular and endothelial cells produce synergistic effects. Also, fluid flow prevents cell disengagement and facilitates appropriate cellular orientation, making bioreactors an auspicious addition to graft culturing techniques. Overall, stem cells, co-culture, and pulsatile flow are important for the rapid and successful development of a viable small-diameter tissue engineered vascular graft for in vivo use.

Weekly versus daily changes of in-line suction catheters: impact on rates of ventilator-associated pneumonia and associated costs.

BACKGROUND: An earlier randomized, controlled trial showed that weekly or as-needed (as opposed to daily) changes of in-line suction catheters were associated with substantial cost savings, without a higher rate of ventilator-associated pneumonia (VAP). To examine the impact of decreasing the frequency of in-line suction catheter changes in our medical intensive care unit, we conducted an observational study, comparing the catheter costs and frequency of VAP during (1) a control period, during which in-line suction catheters were changed daily, and (2) a treatment period, during which the catheters were changed every 7 days or sooner if needed, for mechanical failure or soilage. METHODS: All adult patients admitted to our 18-bed medical intensive care unit were evaluated for the 3-month interval 1 year prior to the practice change (May through July 1998) and for the 3 months after implementing the new policy (May through July 1999). To avoid bias related to usual seasonal variation in VAP frequency, we also determined (via medical records) the VAP rate during May through July 1997. The occurrence of VAP was ascertained by an infection control practitioner, using criteria established by the Centers for Disease Control and applied in a standard fashion. The VAP rate was calculated as the mean number of VAPs per 100 ventilator-days for each 3-month interval. Use of ventilators, humidifiers, and non-heated-wire, disposable circuits was uniform during the study, as were policies regarding humidity, temperature settings, and frequency of routine ventilator circuit changes. RESULTS: During the control period 146 patients accounted for 1,075 ventilator-days and there were 2 VAPs (0.19 VAPs per 100 ventilator-days). During the treatment period 143 patients accounted for 1,167 ventilator-days and there were no VAPs. The mean +/- SD duration of in-line suction catheter use during the treatment period was 3.8 +/- 0.8 days, and 51% of the patients had the same catheter in place for > 3 days (range 4-9 days). The actual cost of catheters used during the treatment period was lower than during the control period ($1,330 vs $6,026), predicting annual catheter cost savings of $18,782. CONCLUSIONS: We conclude that (1) a policy of weekly (vs daily) change of in-line suction catheter is associated with substantial cost savings, with no significant increase in the frequency of VAP, and (2) to the extent that these findings confirm the results of prior studies they support a policy of changing in-line suction catheters weekly rather than daily.