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Trummer-Menzi E.,University of Lausanne | Gremlich S.,University of Lausanne | Schittny J.C.,University of Bern | Denervaud V.,University of Lausanne | And 4 more authors.
Pediatric Pulmonology | Year: 2012

Mechanical ventilation (MV) is life-saving but potentially harmful for lungs of premature infants. So far, animal models dealt with the acute impact of MV on immature lungs, but less with its delayed effects. We used a newborn rodent model including non-surgical and therefore reversible intubation with moderate ventilation and hypothesized that there might be distinct gene expression patterns after a ventilation-free recovery period compared to acute effects directly after MV. Newborn rat pups were subjected to 8 hr of MV with 60% oxygen (O2), 24 hr after injection of lipopolysaccharide (LPS), intended to create a low inflammatory background as often recognized in preterm infants. Animals were separated in controls (CTRL), LPS injection (LPS), or full intervention with LPS and MV with 60% O2 (LPS + MV + O2). Lungs were recovered either directly following (T:0 hr) or 48 hr after MV (T:48 hr). Histologically, signs of ventilator-induced lung injury (VILI) were observed in LPS + MV + O2 lungs at T:0 hr, while changes appeared similar to those known from patients with chronic lung disease (CLD) with fewer albeit larger gas exchange units, at T:48 hr. At T:0 hr, LPS + MV + O 2 increased gene expression of pro-inflammatory MIP-2. In parallel anti-inflammatory IL-1Ra gene expression was increased in LPS and LPS + MV + O2 groups. At T:48 hr, pro- and anti-inflammatory genes had returned to their basal expression. MMP-2 gene expression was decreased in LPS and LPS + MV + O2 groups at T:0 hr, but no longer at T:48 hr. MMP-9 gene expression levels were unchanged directly after MV. However, at T:48 hr, gene and protein expression increased in LPS + MV + O2 group. In conclusion, this study demonstrates the feasibility of delayed outcome measurements after a ventilation-free period in newborn rats and may help to further understand the time-course of molecular changes following MV. The differences obtained from the two time points could be interpreted as an initial transitory increase of inflammation and a delayed impact of the intervention on structure-related genes. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

O'Connor D.L.,Physiology and Experimental Medicine Program | O'Connor D.L.,University of Toronto | Weishuhn K.,University of Toronto | Rovet J.,University of Toronto | And 9 more authors.
Journal of Parenteral and Enteral Nutrition | Year: 2012

Background: Human milk (HM) is the optimal way to nourish preterm low birth weight (LBW) infants after hospital discharge. However, there are few data on which to assess whether HM alone is sufficient to address hospital-acquired nutrition deficits, and no adequately powered studies have examined this question using neurodevelopment as an outcome. The purpose of this work was to determine whether adding extra energy and nutrients to the feedings of predominantly HM-fed LBW infants early after discharge improves their visual development. Visual development was used in this study as a surrogate marker for neurodevelopment. Methods: At discharge, 39 predominantly HM-fed LBW infants (750-1800 g, 1288 ± 288 g) were randomized to receive human milk alone (control) or around half of the HM received daily mixed with a multinutrient fortifier (intervention) for 12 weeks. Grating acuity (ie, visual acuity) and contrast sensitivity were assessed using sweep visual-evoked potential tests at 4 and 6 months corrected age. Results: At 4 and 6 months corrected age, intervention infants demonstrated higher grating acuity compared to those in the control group (intervention: 7.8 ± 1.3 and 9.7 ± 1.2 [cycles/degree] vs control 6.9 ± 1.2 and 8.2 ± 1.3, P =.02). Differences in contrast sensitivity did not reach statistical significance (P =.11). Conclusion: Adding a multinutrient fortifier to a portion of the expressed breast milk provided to predominantly HM-fed LBW infants early after discharge improves their early visual development. Whether these subtle differences in visual development apply to other aspects of development or longer term neurodevelopment are worthy of future investigation. © 2012 American Society for Parenteral and Enteral Nutrition.

McNamara P.J.,University of Toronto | Engelberts D.,Physiology and Experimental Medicine Program | Finelli M.,Hospital for Sick Children | Adeli K.,Pediatric Laboratory Medicine | Kavanagh B.P.,University of Toronto
Pediatric Research | Year: 2014

Background:Epinephrine is a component of all resuscitation algorithms. Vasopressin is a pulmonary vasodilator and systemic vasopressor. We investigated the effect of epinephrine vs. vasopressin on survival and hemodynamics after neonatal porcine cardiac arrest (CA).Methods:A 4-min asphyxial CA was induced, after which cardiopulmonary resuscitation (CPR) was commenced. Animals were randomized to low- (LDE: 0.01 mg/kg) or high-dose epinephrine (HDE: 0.03 mg/kg), low- (LDV: 0.2 U/kg) or high-dose vasopressin (HDV: 0.4 U/kg), or control (saline). Clinical and echocardiography indexes were monitored.Results:Sixty- nine animals were randomized. Survival was greater in HDV (n = 8 (89%); P < 0.05 ANOVA) vs. control (n = 7 (43%)) and LDE (n = 5 (36%)) but not vs. HDE (n = 7 (64%)) or LDV (n = 6 (75%)). Animals resuscitated with LDE required more shocks (2.5 (interquartile range: 2-6); P < 0.05) and higher doses of energy (15 J (interquartile range: 10-20); P < 0.05). Left ventricular output was comparable between groups, but a greater increase in superior vena caval flow was seen after HDV (P < 0.001 vs. control, LDE, and HDE). Plasma troponin was greatest in the HDE group (P < 0.05 vs. control and HDV).Conclusion: Vasopressin results in improved survival, lower postresuscitation troponin, and less hemodynamic compromise after CA in newborn piglets. Vasopressin may be a candidate for testing in human neonates. Copyright © 2014 International Pediatric Research Foundation, Inc.

Hofshi A.,Technion - Israel Institute of Technology | Itzhaki I.,Technion - Israel Institute of Technology | Gepstein A.,Technion - Israel Institute of Technology | Arbel G.,Technion - Israel Institute of Technology | And 2 more authors.
Heart Rhythm | Year: 2011

Background Abnormal conduction underlies both bradyarrhythmias and re-entrant tachyarrhythmias. However, no practical way exists for restoring or improving conduction in areas of conduction slowing or block. Objective This study sought to test the feasibility of a novel strategy for conduction repair using genetically engineered cells designed to form biological "conducting cables." Methods An in vitro model of conduction block was established using spatially separated, spontaneously contracting, nonsynchronized human embryonic stem cellderived cardiomyocytes clusters. Immunostaining, dye transfer, intracellular recordings, and multielectrode array (MEA) studies were performed to evaluate the ability of genetically engineered HEK293 cells, expressing the SCN5A-encoded Na + channel, to couple with cultured cardiomyocytes and to synchronize their electrical activity. Results Connexin-43 immunostaining and calcein dye-transfer experiments confirmed the formation of functional gap junctions between the engineered cells and neighboring cardiomyocytes. MEA and intracellular recordings were performed to assess the ability of the engineered cells to restore conduction in the co-cultures. Synchronization was defined by establishment of fixed local activation time differences between the cardiomyocytes clusters and convergence of their activation cycle lengths. Nontransfected control cells were able to induce synchronization between cardiomyocytes clusters separated by distances up to 300 μm (n = 21). In contrast, the Na + channel-expressing cells synchronized contractions between clusters separated by up to 1,050 μm, the longest distance studied (n = 23). Finally, engineered cells expressing the voltage-sensitive K v1.3 potassium channel prevented synchronization at any distance. Conclusion Genetically engineered cells, transfected to express Na + channels, can form biological conducting cables bridging and coupling spatially separated cardiomyocytes. This novel cell therapy approach might be useful for the development of therapeutic strategies for both bradyarrhythmias and tachyarrhythmias. © 2011 Heart Rhythm Society.

Welsh C.,Physiology and Experimental Medicine Program | Pan J.,Physiology and Experimental Medicine Program | Belik J.,Physiology and Experimental Medicine Program | Belik J.,University of Toronto
Pediatric Research | Year: 2015

Background: Feeding intolerance is commonly documented in premature infants. Caffeine is routinely utilized for apnea of prematurity treatment and known to reduce the lower esophageal sphincter (LES) muscle tone, but the caffeine effect on the newborn gastrointestinal function is unknown. We hypothesized that caffeine impairs esophageal and gastrointestinal motor function. As such, we investigated the drug effect on the tissue's mechanical properties and the newborn rat's in vivo gastric emptying rate.Methods:The effects of caffeine on LES, gastric fundal and antrum, as well as ileal and colonic muscle force potential and relaxation response, were measured in newborn and adult rats. The caffeine-induced (10 mg/kg i.p.) newborn gastric emptying rate changes were evaluated following 3 h of fasting.Results:Caffeine relaxed the precontracted LES and fundal muscle (P < 0.01), reduced the gastric and intestinal muscle contraction (P < 0.01), and delayed the pups' gastric emptying time (P < 0.01). The caffeine-induced muscle relaxant effect was independent of age and mediated via ryanodine receptors.Conclusion:Caffeine administration to newborn rats at a dose comparable to the one therapeutically used for preterm neonates impairs LES and gastrointestinal motor function. Further clinical investigation on the possible contribution of caffeine to neonatal feeding intolerance is warranted. © 2015 International Pediatric Research Foundation, Inc.

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