Euglycemic Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter-2 Inhibitors After Cardiac Surgery: A Review of Current Literature.

There is growing evidence to support the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for type 2 diabetes mellitus (T2DM) and the management of heart failure. As such, more patients undergoing cardiac surgery are on SGLT2-inhibitor therapy. Despite the numerous benefits of SGLT2 inhibitors on cardiac health, they can be associated with an increased risk of diabetic ketoacidosis, often with normal glucose levels (euglycemic diabetic ketoacidosis or EDKA), which potentially can be detrimental in this vulnerable patient population. In this narrative review, the authors discuss 17 papers that described EDKA in perioperative cardiac surgical patients. The authors discuss suggested preventative measures and management options, with a particular emphasis on raising the clinical awareness of the care teams toward this complication. SGLT2 inhibitor-induced EDKA is a medical emergency that can be difficult to identify in the postcardiac surgical patient due to the overlap of signs and symptoms with other frequent scenarios in these patients. A reduction in SGLT2 inhibitor-associated EDKA can be mitigated by the appropriate perioperative discontinuation of the medication, clinical awareness, and early investigation to diagnose the condition, with emphasis on serum ß-hydroxybutyrate. Future quality improvement initiatives are needed to assist in reducing EDKA in patients taking SGLT2 inhibitors in the perioperative surgical setting.

Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1α Enhances Myocardial Repair.

First generation cardiac stem cell products provide indirect cardiac repair but variably produce key cardioprotective cytokines, such as stromal-cell derived factor 1α, which opens the prospect of maximizing up-front paracrine-mediated repair. The mesenchymal subpopulation within explant derived human cardiac stem cells underwent lentiviral mediated gene transfer of stromal-cell derived factor 1α. Unlike previous unsuccessful attempts to increase efficacy by boosting the paracrine signature of cardiac stem cells, cytokine profiling revealed that stromal-cell derived factor 1α over-expression prevented lv-mediated "loss of cytokines" through autocrine stimulation of CXCR4+ cardiac stem cells. Stromal-cell derived factor 1α enhanced angiogenesis and stem cell recruitment while priming cardiac stem cells to readily adopt a cardiac identity. As compared to injection with unmodified cardiac stem cells, transplant of stromal-cell derived factor 1α enhanced cells into immunodeficient mice improved myocardial function and angiogenesis while reducing scarring. Increases in myocardial stromal-cell derived factor 1α content paralleled reductions in myocyte apoptosis but did not influence long-term engraftment or the fate of transplanted cells. Transplantation of stromal-cell derived factor 1α transduced cardiac stem cells increased the generation of new myocytes, recruitment of bone marrow cells, new myocyte/vessel formation and the salvage of reversibly damaged myocardium to enhance cardiac repair after experimental infarction. Stem Cells 2016;34:1826-1835.

Human blood and cardiac stem cells synergize to enhance cardiac repair when cotransplanted into ischemic myocardium.

BACKGROUND: Blood-derived circulatory angiogenic cells (CACs) and resident cardiac stem cells (CSCs) have both been shown to improve cardiac function after myocardial infarction. The superiority of either cell type has long been an area of speculation with no definitive head-to-head trial. In this study, we compared the effect of human CACs and CSCs, alone or in combination, on myocardial function in an immunodeficient mouse model of myocardial infarction. METHODS AND RESULTS: CACs and CSCs were cultured from left atrial appendages and blood samples obtained from patients undergoing clinically indicated heart surgery. CACs expressed a broader cytokine profile than CSCs, with 3 cytokines in common. Coculture of CACs and CSCs further enhanced the production of stromal cell-derived factor-1α and vascular endothelial growth factor (P ≤ 0.05). Conditioned media promoted equivalent vascular networks and CAC recruitment with superior effects using cocultured conditioned media. Intramyocardial injection of CACs or CSCs alone improved myocardial function and reduced scar burdens when injected 1 week after myocardial infarction (P ≤ 0.05 versus negative controls). Cotransplantation of CACs and CSCs together improved myocardial function and reduced scar burdens to a greater extent than either stem cell therapy alone (P ≤ 0.05 versus CAC or CSC injection alone). CONCLUSIONS: CACs and CSCs provide unique paracrine repertoires with equivalent effects on angiogenesis, stem cell migration, and myocardial repair. Combination therapy with both cell types synergistically improves postinfarct myocardial function greater than either therapy alone. This synergy is likely mediated by the complimentary paracrine signatures that promote revascularization and the growth of new myocardium.

Hemadsorption for removal of ticagrelor and direct oral anticoagulants in cardiac surgery.

INTRODUCTION: Cardiac patients on antiplatelets or oral anticoagulation undergoing emergent cardiac surgery without appropriate washout periods are at increased risk for developing perioperative bleeding. CytoSorb is a commercially available hemadsorption adsorber that can simultaneously remove a wide range of substances including ticagrelor, and direct oral anticoagulants (DOACs). AREAS COVERED: Although CytoSorb has been used to remove various protein-bound substances, this review will specifically evaluate and review current evidence for applying CytoSorb in removing ticagrelor and DOACs using four in vitro studies, three case reports, one retrospective study and two cost analysis studies. Based on limited evidence, CytoSorb may be effective in reducing perioperative bleeding by reducing chest tube output, blood product transfusions, and re-thoracotomy rates. CytoSorb can also reduce length of intensive care unit (ICU) and hospital stay. Although, CytoSorb has an initial upfront cost, it was proven to be cost-effective due to potential health resource savings on both short- and long-term projections. EXPERT COMMENTARY: CytoSorb provides a novel strategy to remove ticagrelor and DOACs in patients requiring emergency cardiac surgery. Although promising results, more solid evidence is required to establish its clinical effectiveness in reducing perioperative bleeding, bleeding-related complications, mortality, and finally, its overall safety.

Cannabis and its derivatives for the use of motor symptoms in Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Recent changes to the legal status of cannabis across various countries have renewed interest in exploring its use in Parkinson's disease (PD). The use of cannabinoids for alleviation of motor symptoms has been extensively explored in pre-clinical studies. OBJECTIVE: We aim to systematically review and meta-analyze literature on the use of medical cannabis or its derivatives (MC) in PD patients to determine its effect on motor function and its safety profile. METHODS: We reviewed and analyzed original, full-text randomized controlled trials (RCTs) and observational studies. Primary outcomes were change in motor function and dyskinesia. Secondary outcomes included adverse events and side effects. All studies were analyzed for risk of bias. RESULTS: Fifteen studies, including six RCTs, were analyzed. Of these, 12/15 (80%) mention concomitant treatment with antiparkinsonian medications, most commonly levodopa. Primary outcomes were most often measured using the Unified Parkinson Disease Rating Scale (UPDRS) among RCTs and patient self-report of symptom improvement was widely used among observational studies. Most of the observational data lacking appropriate controls had effect estimates favoring the intervention. However, the controlled studies demonstrated no significant motor symptom improvement overall. The meta-analysis of three RCTs, including a total of 83 patients, did not demonstrate a statistically significant improvement in UPDRS III score variation (MD -0.21, 95% CI -4.15 to 3.72; p = 0.92) with MC use. Only one study reported statistically significant improvement in dyskinesia (p < 0.05). The intervention was generally well tolerated. All RCTs had a high risk of bias. CONCLUSION: Although observational studies establish subjective symptom alleviation and interest in MC among PD patients, there is insufficient evidence to support its integration into clinical practice for motor symptom treatment. This is primarily due to lack of good quality data.

In tropical lowland rain forests monocots have tougher leaves than dicots, and include a new kind of tough leaf.

BACKGROUND AND AIMS: There has been little previous work on the toughness of the laminae of monocots in tropical lowland rain forest (TLRF) despite the potential importance of greater toughness in inhibiting herbivory by invertebrates. Of 15 monocot families with >100 species in TLRF, eight have notably high densities of fibres in the lamina so that high values for toughness are expected. METHODS: In north-eastern Australia punch strength was determined with a penetrometer for both immature leaves (approx. 30 % final area on average) and fully expanded, fully toughened leaves. In Singapore and Panama, fracture toughness was determined with an automated scissors apparatus using fully toughened leaves only. KEY RESULTS: In Australia punch strength was, on average, 7x greater in shade-tolerant monocots than in neighbouring dicots at the immature stage, and 3x greater at the mature stage. In Singapore, shade-tolerant monocots had, on average, 1.3x higher values for fracture toughness than neighbouring dicots. In Panama, both shade-tolerant and gap-demanding monocots were tested; they did not differ in fracture toughness. The monocots had markedly higher values than the dicots whether shade-tolerant or gap-demanding species were considered. CONCLUSIONS: It is predicted that monocots will be found to experience lower rates of herbivory by invertebrates than dicots. The tough monocot leaves include both stiff leaves containing relatively little water at saturation (e.g. palms), and leaves which lack stiffness, are rich in water at saturation and roll readily during dry weather or even in bright sun around midday (e.g. gingers, heliconias and marants). Monocot leaves also show that it is possible for leaves to be notably tough throughout the expansion phase of development, something never recorded for dicots. The need to broaden the botanist's mental picture of a 'tough leaf' is emphasized.

Monocot leaves are eaten less than dicot leaves in tropical lowland rain forests: correlations with toughness and leaf presentation.

BACKGROUND AND AIMS: In tropical lowland rain forest (TLRF) the leaves of most monocots differ from those of most dicots in two ways that may reduce attack by herbivores. Firstly, they are tougher. Secondly, the immature leaves are tightly folded or rolled until 50-100 % of their final length. It was hypothesized that (a) losses of leaf area to herbivorous invertebrates are generally greatest during leaf expansion and smaller for monocots than for dicots, and (b) where losses after expansion are appreciable any difference between monocots and dicots then is smaller than that found during expansion. METHODS: At six sites on four continents, estimates were made of lamina area loss from the four most recently mature leaves of focal monocots and of the nearest dicot shoot. Measurements of leaf mass per unit area, and the concentrations of water and nitrogen were made for many of the species. In Panama, the losses from monocots (palms) and dicots were also measured after placing fully expanded palm leaflets and whole dicot leaves on trails of leaf-cutter ants. KEY RESULTS: At five of six sites monocots experienced significantly smaller leaf area loss than dicots. The results were not explicable in terms of leaf mass per unit area, or concentrations of water or nitrogen. At only one site was the increase in loss from first to fourth mature leaf significant (also large and the same in monocots and dicots), but the losses sustained during expansion were much smaller in the monocots. In the leaf-cutter ant experiment, losses were much smaller for palms than for dicots. CONCLUSIONS: The relationship between toughness and herbivory is complex; despite the negative findings of some recent authors for dicots we hypothesize that either greater toughness or late folding can protect monocot leaves against herbivorous insects in tropical lowland rain forest, and that the relative importance varies widely with species. The difficulties of establishing unequivocally the roles of leaf toughness and leaf folding or rolling in a given case are discussed.

Isolation of human explant derived cardiac stem cells from cryopreserved heart tissue.

The value of preserving high quality bio specimens for fundamental research is significant as linking cellular and molecular changes to clinical and epidemiological data has fueled many recent advances in medicine. Unfortunately, storage of traditional biospecimens is limited to fixed samples or isolated genetic material. Here, we report the effect of cryopreservation of routine myocardial biopsies on explant derived cardiac stem cell (EDC) culture outcomes. We demonstrate that immediate cryopreservation or delayed cryopreservation after suspension within cardioplegia for 12 hours did not alter EDC yields, proliferative capacity, antigenic phenotype or paracrine signature. Cryopreservation had negligible effects on the ability of EDCs to adopt a cardiac lineage, stimulate new vessel growth, attract circulating angiogenic cells and repair injured myocardium. Finally, cryopreservation did not influence the ability of EDCs to undergo genetic reprogramming into inducible pluripotent stem cells. This study establishes a means of storing cardiac samples as a retrievable live cell source for cardiac repair or disease modeling.

Paracrine Engineering of Human Cardiac Stem Cells With Insulin-Like Growth Factor 1 Enhances Myocardial Repair.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) activates prosurvival pathways and improves postischemic cardiac function, but this key cytokine is not robustly expressed by cultured human cardiac stem cells. We explored the influence of an enhanced IGF-1 paracrine signature on explant-derived cardiac stem cell-mediated cardiac repair. METHODS AND RESULTS: Receptor profiling demonstrated that IGF-1 receptor expression was increased in the infarct border zones of experimentally infarcted mice by 1 week after myocardial infarction. Human explant-derived cells underwent somatic gene transfer to overexpress human IGF-1 or the green fluorescent protein reporter alone. After culture in hypoxic reduced-serum media, overexpression of IGF-1 enhanced proliferation and expression of prosurvival transcripts and prosurvival proteins and decreased expression of apoptotic markers in both explant-derived cells and cocultured neonatal rat ventricular cardiomyocytes. Transplant of explant-derived cells genetically engineered to overexpress IGF-1 into immunodeficient mice 1 week after infarction boosted IGF-1 content within infarcted tissue and long-term engraftment of transplanted cells while reducing apoptosis and long-term myocardial scarring. CONCLUSIONS: Paracrine engineering of explant-derived cells to overexpress IGF-1 provided a targeted means of improving cardiac stem cell-mediated repair by enhancing the long-term survival of transplanted cells and surrounding myocardium.

Expression of sall4 in taste buds of zebrafish.

We characterized the expression of sall4, a gene encoding a zinc finger transcription factor involved in the maintenance of embryonic stem cells, in taste buds of zebrafish (Danio rerio). Using an enhancer trap line (ET5), we detected enhanced green fluorescent protein (EGFP) in developing and adult transgenic zebrafish in regions containing taste buds: the lips, branchial arches, and the nasal and maxillary barbels. Localization of EGFP to taste cells of the branchial arches and lips was confirmed by co-immunolabeling with antibodies against calretinin and serotonin, and a zebrafish-derived neuronal marker (zn-12). Transgenic insertion of the ET construct into the zebrafish genome was evaluated and mapped to chromosome 23 in proximity (i.e. 23 kb) to the sall4 gene. In situ hybridization and expression analysis between 24 and 96 h post-fertilization (hpf) demonstrated that transgenic egfp expression in ET5 zebrafish was correlated with the spatial and temporal pattern of expression of sall4 in the wild-type. Expression was first observed in the central nervous system and branchial arches at 24 hpf. At 48 hpf, sall4 and egfp expression was observed in taste bud primordia surrounding the mouth and branchial arches. At 72 and 96 hpf, expression was detected in the upper and lower lips and branchial arches. Double fluorescence in situ hybridization at 3 and 10 dpf confirmed colocalization of sall4 and egfp in the lips and branchial arches. These studies reveal sall4 expression in chemosensory cells and implicate this transcription factor in the development and renewal of taste epithelia in zebrafish.