Metabolic characteristics of human hearts preserved for 12 hours by static storage, antegrade perfusion, or retrograde coronary sinus perfusion

ObjectiveMachine perfusion of donor hearts is a promising strategy to increase the donor pool. Antegrade perfusion is effective but can lead to aortic valve incompetence and nonnutrient flow. Experience with retrograde coronary sinus perfusion of donor hearts has been limited. We tested the hypothesis that retrograde perfusion could support myocardial metabolism over an extended donor ischemic interval.MethodsHuman hearts from donors that were rejected or not offered for transplantation were preserved for 12 hours in University of Wisconsin Machine Perfusion Solution by: (1) static hypothermic storage; (2) hypothermic antegrade machine perfusion; or (3) hypothermic retrograde machine perfusion. Myocardial oxygen consumption (MVO2), and lactate accumulation were measured. Ventricular tissue was collected for proton and phosphorus 31 magnetic resonance spectroscopy (MRS) to evaluate the metabolic state of the myocardium. Myocardial water content was determined at the end of the experiment.ResultsStable perfusion parameters were maintained throughout the perfusion period with both perfusion techniques. Lactate/alanine ratios were lower in perfused hearts compared with static hearts (P < .001). Lactate accumulation (antegrade 2.0 ± 0.7 mM, retrograde 1.7 ± 0.1 mM) and MVO2 (antegrade 0.25 ± 0.2 mL, retrograde 0.26 ± 0.3 mL O2/min/100 g) were similar in machine-perfused groups. High-energy phosphates were better preserved in both perfused groups (P < .05). Left ventricular myocardial water content was increased in retrograde perfused hearts (80.2 ± 0.8%) compared with both antegrade perfused hearts (76.6 ± 0.8%, P = .02) and static storage hearts (76.7 ± 1%, P = .02).ConclusionsMachine perfusion by either the antegrade or the retrograde technique can support myocardial metabolism over long intervals. Machine perfusion seems promising for long-term preservation of human donor hearts

A combined geomorphological and geophysical approach to characterising relict landslide hazard on the Jurassic Escarpments of Great Britain

The Jurassic Escarpment in the North York Moors in Northern Britain has a high density of deep-seated relict landslides but their regional hazard is poorly understood due to a lack of detailed case studies. Investigation of a typical relict landslide at Great Fryup Dale suggests that the crop of the Whitby Mudstone Formation is highly susceptible to landslide hazards. The mudstone lithologies along the Escarpment form large multiple rotational failures which break down at an accelerated rate during wetter climates and degrade into extensive frontal mudflows. Geomorphological mapping, high resolution LiDAR imagery, boreholes, and geophysical ERT surveys are deployed in a combined approach to delimit internal architecture of the landslide. Cross-sections developed from these data indicate that the main movement displaced a bedrock volume of c. 1 × 107 m3 with a maximum depth of rupture of c. 50 m. The mode of failure is strongly controlled by lithology, bedding, joint pattern, and rate of lateral unloading. Dating of buried peats using the AMS method suggests that the 10 m thick frontal mudflow complex was last active in the Late Holocene, after c. 2270 ± 30 calendar years BP. Geomorphic mapping and dating work indicates that the landslide is dormant, but slope stability modelling suggests that the slope is less stable than previously assumed; implying that this and other similar landslides in Britain may become more susceptible to reactivation or extension during future wetter climatic phases. This study shows the value of a multi-technique approach for landslide hazard assessment and to enhance national landslide inventories

A High-Resolution Airborne Color-Infrared Camera Water Mask for the NASA ABoVE Campaign

The airborne AirSWOT instrument suite, consisting of an interferometric Ka-band synthetic aperture radar and color-infrared (CIR) camera, was deployed to northern North America in July and August 2017 as part of the NASA Arctic-Boreal Vulnerability Experiment (ABoVE). We present validated, open (i.e., vegetation-free) surface water masks produced from high-resolution (1 m), co-registered AirSWOT CIR imagery using a semi-automated, object-based water classification. The imagery and resulting high-resolution water masks are available as open-access datasets and support interpretation of AirSWOT radar and other coincident ABoVE image products, including LVIS, UAVSAR, AIRMOSS, AVIRIS-NG, and CFIS. These synergies offer promising potential for multi-sensor analysis of Arctic-Boreal surface water bodies. In total, 3167 km2 of open surface water were mapped from 23,380 km2 of flight lines spanning 23 degrees of latitude and broad environmental gradients. Detected water body sizes range from 0.00004 km2 (40 m2) to 15 km2. Power-law extrapolations are commonly used to estimate the abundance of small lakes from coarser resolution imagery, and our mapped water bodies followed power-law distributions, but only for water bodies greater than 0.34 (±0.13) km2 in area. For water bodies exceeding this size threshold, the coefficients of power-law fits vary for different Arctic-Boreal physiographic terrains (wetland, prairie pothole, lowland river valley, thermokarst, and Canadian Shield). Thus, direct mapping using high-resolution imagery remains the most accurate way to estimate the abundance of small surface water bodies. We conclude that empirical scaling relationships, useful for estimating total trace gas exchange and aquatic habitats on Arctic-Boreal landscapes, are uniquely enabled by high-resolution AirSWOT-like mappings and automated detection methods such as those developed here

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals

Purpose To probe the cardiac metabolism of carbohydrates and short chain fatty acids simultaneously in vivo following the injection of a hyperpolarized 13C-labeled substrate mixture prepared using photo-induced nonpersistent radicals. Methods Droplets of mixed [1-13C]pyruvic and [1-13C]butyric acids were frozen into glassy beads in liquid nitrogen. Ethanol addition was investigated as a means to increase the polarization level. The beads were irradiated with ultraviolet light and the radical concentration was measured by ESR spectroscopy. Following dynamic nuclear polarization in a 7T polarizer, the beads were dissolved, and the radical-free hyperpolarized solution was rapidly transferred into an injection pump located inside a 9.4T scanner. The hyperpolarized solution was injected in healthy rats to measure cardiac metabolism in vivo. Results Ultraviolet irradiation created nonpersistent radicals in a mixture containing 13C-labeled pyruvic and butyric acids, and enabled the hyperpolarization of both substrates by dynamic nuclear polarization. Ethanol addition increased the radical concentration from 16 to 26 mM. Liquid-state 13C polarization was 3% inside the pump at the time of injection, and increased to 5% by addition of ethanol to the substrate mixture prior to ultraviolet irradiation. In the rat heart, the in vivo 13C signals from lactate, alanine, bicarbonate, and acetylcarnitine were detected following the metabolism of the injected substrate mixture. Conclusion Copolarization of two different 13C-labeled substrates and the detection of their myocardial metabolism in vivo was achieved without using persistent radicals. The absence of radicals in the solution containing the hyperpolarized 13C-substrates may simplify the translation to clinical use, as no radical filtration is required prior to injection

Gene Expression Signature of Normal Cell-of-Origin Predicts Ovarian Tumor Outcomes

The potential role of the cell-of-origin in determining the tumor phenotype has been raised, but not adequately examined. We hypothesized that distinct cells-of-origin may play a role in determining ovarian tumor phenotype and outcome. Here we describe a new cell culture medium for in vitro culture of paired normal human ovarian (OV) and fallopian tube (FT) epithelial cells from donors without cancer. While these cells have been cultured individually for short periods of time, to our knowledge this is the first long-term culture of both cell types from the same donors. Through analysis of the gene expression profiles of the cultured OV/FT cells we identified a normal cell-of-origin gene signature that classified primary ovarian cancers into OV-like and FT-like subgroups; this classification correlated with significant differences in clinical outcomes. The identification of a prognostically significant gene expression signature derived solely from normal untransformed cells is consistent with the hypothesis that the normal cell-of-origin may be a source of ovarian tumor heterogeneity and the associated differences in tumor outcome

Age-related differences in affective behaviors in mice: possible role of prefrontal cortical-hippocampal functional connectivity and metabolomic profiles

IntroductionThe differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation.MethodsWe assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics.ResultsOur results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and during re-testing in a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups.DiscussionThe results support differential expression of ‘emotionality’ across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry

Better Than You Think—Appropriate Use of Implantable Cardioverter-Defibrillators at a Single Academic Center: A Retrospective Review

Background: Implantable cardioverter-defibrillators (ICDs) can be life-saving devices, although they are expensive and may cause complications. In 2013, several professional societies published joint appropriate use criteria (AUC) assessing indications for ICD implantation. Data evaluating the clinical application of AUC are limited. Previous registry-based studies estimated that 22.5% of primary prevention ICD implantations were “non-evidence-based” implantations. On the basis of AUC, we aimed to determine the prevalence of “rarely appropriate” ICD implantation at our institution for comparison with previous estimates. Methods: We reviewed 286 patients who underwent ICD implantation between 2013 and 2016. Appropriateness of each ICD implantation was assessed by independent review and rated on the basis of AUC. Results: Of 286 ICD implantations, two independent reviewers found that 89.5% and 89.2%, respectively, were appropriate, 5.6% and 7.3% may be appropriate, and 1.8% and 2.1% were rarely appropriate. No AUC indication was found for 3.5% and 3.4% of ICD implantations, respectively. Secondary prevention ICD implantations were more likely rarely appropriate (2.6% vs. 1.2% and 3.6% vs. 1.1%) or unrated (6.0% vs. 1.2% and 2.7% vs. 0.6%). The reviewers found 3.5% and 3.4% of ICD implantations, respectively, were non-evidence-based implantations. The difference in rates between reviewers was not statistically significant. Conclusion: Compared with prior reports, our prevalence of rarely appropriate ICD implantation was very low. The high appropriate use rate could be explained by the fact that AUC are based on current clinical practice. The AUC could benefit from additional secondary prevention indications. Most importantly, clinical judgement and individualized care should determine which patients receive ICDs irrespective of guidelines or criteria. </p

In Vivo Carbon-13 Dynamic MRS and MRSI of Normal and Fasted Rat Liver with Hyperpolarized 13C-Pyruvate

BACKGROUND: The use of in vivo (13)C nuclear magnetic resonance spectroscopy in probing metabolic pathways to study normal metabolism and characterize disease physiology has been limited by its low sensitivity. However, recent technological advances have enabled greater than 50,000-fold enhancement of liquid-state polarization of metabolically active (13)C substrates, allowing for rapid assessment of (13)C metabolism in vivo. The present study applied hyperpolarized (13)C magnetic resonance spectroscopy to the investigation of liver metabolism, demonstrating for the first time the feasibility of applying this technology to detect differences in liver metabolic states. PROCEDURES: [1-(13)C]pyruvate was hyperpolarized with a dynamic nuclear polarization instrument and injected into normal and fasted rats. The uptake of pyruvate and its conversion to the metabolic products lactate and alanine were observed with slice-localized dynamic magnetic resonance spectroscopy and 3D magnetic resonance spectroscopic imaging (3D-MRSI). RESULTS: Significant differences in lactate to alanine ratio (P < 0.01) between normal and fasted rat liver slice dynamic spectra were observed. 3D-MRSI localized to the fasted livers demonstrated significantly decreased (13)C-alanine levels (P < 0.01) compared to normal. CONCLUSIONS: This study presents the initial demonstration of characterizing metabolic state differences in the liver with hyperpolarized (13)C spectroscopy and shows the ability to detect physiological perturbations in alanine aminotransferase activity, which is an encouraging result for future liver disease investigations with hyperpolarized magnetic resonance technology