A clinically relevant sheep model of orthotopic heart transplantation 24 h after donor brainstem death.

BACKGROUND: Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. METHODS: BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures. RESULTS: Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures. CONCLUSIONS: We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation.

Biomarkers in vesicoureteral reflux: an overview.

Aim: This article aimed to review the role of cytokines, chemokines, growth factors and cellular adhesion molecules as biomarkers for vesicoureteral reflux (VUR) and reflux nephropathy (RN). Methods: We reviewed articles from 1979 onward by searching PubMed and Scopus utilizing the combination of words: 'VUR' or 'RN' and each one of the biomarkers. Results: Genetic, inflammatory, fibrogenic, environmental and epigenetic factors responsible for renal scarring need to be better understood. TGF-ß, IL-10, IL-6, IL-8 and TNF seem to exert a role in VUR particularly in RN based on the current literature. Serum levels of procalcitonin have been also associated with high-grade VUR and RN. These molecules should be more intensively evaluated as potential biomarkers for renal scarring in VUR. Conclusion: Further studies are necessary to define which molecules will really be of utility in clinical decisions and as therapeutic targets for VUR and RN.

Pre-clinical study protocol: Blood transfusion in endotoxaemic shock.

The Surviving Sepsis Campaign (SCC) and the American College of Critical Care Medicine (ACCM) guidelines recommend blood transfusion in sepsis when the haemoglobin concentration drops below 7.0 g/dL and 10.0 g/dL respectively, while the World Health Organisation (WHO) guideline recommends transfusion in septic shock 'if intravenous (IV) fluids do not maintain adequate circulation', as a supportive measure of last resort. Volume expansion using crystalloid and colloid fluid boluses for haemodynamic resuscitation in severe illness/sepsis, has been associated with adverse outcomes in recent literature. However, the volume expansion effect(s) following blood transfusion for haemodynamic circulatory support, in severe illness remain unclear with most previous studies having focused on evaluating effects of either different RBC storage durations (short versus long duration) or haemoglobin thresholds (low versus high threshold) pre-transfusion. •We describe the protocol for a pre-clinical randomised controlled trial designed to examine haemodynamic effect(s) of early volume expansion using packed RBCs (PRBCs) transfusion (before any crystalloids or colloids) in a validated ovine-model of hyperdynamic endotoxaemic shock.•Additional exploration of mechanisms underlying any physiological, haemodynamic, haematological, immunologic and tissue specific-effects of blood transfusion will be undertaken including comparison of effects of short (≤5 days) versus long (≥30 days) storage duration of PRBCs prior to transfusion.

Inflammatory molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates: A Systematic Review.

OBJECTIVE: To provide a systematic review investigating the role of inflammatory molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates. DATA SOURCE: Databases including PubMed, BIREME, and Scopus were systematically searched. Observational studies, as well as transversal, and cohort studies using human subjects published from 1990 to September 2017 were eligible for inclusion. Two authors independently identified eligible studies and analyzed their characteristics, quality, and accuracy in depth. DATA SYNTHESIS: 11 eligible studies clearly investigated the association between peripheral inflammation and motor and/or cognitive development in preterm infants. However, the selected populations differed in relation to the events associated with prematurity and the risk factors to abnormal motor and/or cognitive development. These studies measured circulating levels of cytokines, chemokines, adhesion molecules, acute phase proteins, and growth factors. The most commonly analyzed proteins were IL-1ß, IL-6, TNF, CCL5/RANTES, CXCL8/IL-8, IGFBP-1, and VEGF. In seven of the eligible studies, plasma levels of IL-6 correlated with development delay. Two studies reported correlation between CXCL8/IL-8 plasma levels with cognitive and motor delay. In one study, higher levels of MCP-1/CCL2 were associated with better cognitive and motor outcome. CONCLUSION: There is preliminary evidence indicating that circulating inflammatory molecules are associated with motor and cognitive development in preterm neonates, even considering different populations.

Impact of light quality on flavonoid production and growth of Hyptis marrubioides seedlings cultivated in vitro

ABSTRACT Hyptis marrubioides Epling, Lamiaceae, a species from Brazilian Cerrado, has been used against gastrointestinal infections, skin infections, pain, and cramps. Herein, H. marrubioides seedlings were cultured in vitro under different wavelengths (white, blue, green, red, and yellow) with 50 µmol m-2 s-1 irradiance and a 16-h photoperiod. After 20 and 30 days of cultivation, shoot length, leaf number, fresh mass, and dry mass were evaluated. The flavonoid rutin content was determined by the HPLC-DAD method. The shoots were longer in plants cultivated under yellow (16.603 ± 0.790 cm, 1.8-fold), red (15.465 ± 0.461 cm, 1.7-fold), and green (14.677 ± 0.737 cm, 1.6-fold) lights than in control plants exposed to white light (9.203 ± 0.388 cm). The number of leaves increased in plants exposed to red (23.425 ± 1.138, 1.1-fold) and green (22.725 ± 1.814, 1.1-fold) lights, compared to control plants (20.133 ± 0.827). Fresh (0.665 ± 0.048 g, 1.2-fold) and dry (0.066 ± 0.005 g, 1.3-fold) mass of seedlings were the highest in seedlings grown under red light, compared to seedlings grown under white light (0.553 ± 0.048 and 0.028 ± 0.004, respectively). However, rutin production was higher under white (0.308 mg g-1 of dry weight) and blue lights (0.298 mg g-1 of dry weight). Thus, red light induces plant growth and increases leaf number and dry weight in in vitro-cultivated H. marrubioides, whereas blue and white lights promote the greatest rutin accumulation.

Effects of volume resuscitation on the microcirculation in animal models of lipopolysaccharide sepsis: a systematic review.

BACKGROUND: Recent research has identified an increased rate of mortality associated with fluid bolus therapy for severe sepsis and septic shock, but the mechanisms are still not well understood. Fluid resuscitation therapy administered for sepsis and septic shock targets restoration of the macro-circulation, but the pathogenesis of sepsis is complex and includes microcirculatory dysfunction. OBJECTIVE: The objective of the study is to systematically review data comparing the effects of different types of fluid resuscitation on the microcirculation in clinically relevant animal models of lipopolysaccharide-induced sepsis. METHODS: A structured search of PubMed/MEDLINE and EMBASE for relevant publications from 1 January 1990 to 31 December 2015 was performed, in accordance with PRISMA guidelines. RESULTS: The number of published papers on sepsis and the microcirculation has increased steadily over the last 25 years. We identified 11 experimental animal studies comparing the effects of different fluid resuscitation regimens on the microcirculation. Heterogeneity precluded any meta-analysis. CONCLUSIONS: Few animal model studies have been published comparing the microcirculatory effects of different types of fluid resuscitation for sepsis and septic shock. Biologically relevant animal model studies remain necessary to enhance understanding regarding the mechanisms by which fluid resuscitation affects the microcirculation and to facilitate the transfer of basic science discoveries to clinical applications.