Influence of cardiac nerve status on cardiovascular regulation and cardioprotection

Neural elements of the intrinsic cardiac nervous system transduce sensory inputs from the heart, blood vessels and other organs to ensure adequate cardiac function on a beat-to-beat basis. This inter-organ crosstalk is critical for normal function of the heart and other organs; derangements within the nervous system hierarchy contribute to pathogenesis of organ dysfunction. The role of intact cardiac nerves in development of, as well as protection against, ischemic injury is of current interest since it may involve recruitment of intrinsic cardiac ganglia. For instance, ischemic conditioning, a novel protection strategy against organ injury, and in particular remote conditioning, is likely mediated by activation of neural pathways or by endogenous cytoprotective bloodborne substances that stimulate different signalling pathways. This discovery reinforces the concept that inter-organ communication, and maintenance thereof, is key. As such, greater understanding of mechanisms and elucidation of treatment strategies is imperative to improve clinical outcomes particularly in patients with comorbidities. For instance, autonomic imbalance between sympathetic and parasympathetic nervous system regulation can initiate cardiovascular autonomic neuropathy that compromises cardiac stability and function. Neuromodulation therapies that directly target the intrinsic cardiac nervous system or other elements of the nervous system hierarchy are currently being investigated for treatment of different maladies in animal and human studies.

Contribution of Myocyte Apoptosis to Myocardial Injury in an in Vivo Rabbit Preparation of Ischemia-Reperfusion

Objective: Exposure of the heart to repeated, brief episodes of coronary occlusion/reperfusion prevents lethal myocyte injury. Necrosis and apoptosis, two seemingly distinct mechanisms of cell death caused by ischemia could contribute independently to progressive loss of myocardium. Studies suggest that ischemic conditioning (IC) lessens myocyte injury by decreasing apoptosis. The goal of this study was to examine cell death in rabbit hearts subject to ischemia-reperfusion injury without (nIC) or with pretreatment by IC. Methods: In the control study, anesthetized, male rabbits (n = 4/group) underwent 30-min regional coronary occlusion (CO) and either 3, 6 or 24h reperfusion (REP). In the IC study, rabbits were pretreated by IC (2 cycles of 5-min CO and 10-min REP) before 30-min CO and subsequent REP. Additional groups were evaluated with 60, or 120-min CO followed by up to 96 h REP. Agarose electrophoresis was used to detect DNA laddering and poly (ADP-ribose) polymerase (PARP;chromatin bound nuclear DNA repair enzyme) was assessed in myocardial biopsies. Results: Genomic DNA from nIC and IC hearts showed no oligonucleosomal fragmentation. In addition, we did not detect any cleavage of PARP;however, myocardial PARP levels decreased when CO and REP durations were prolonged. Conclusion:Absence of genomic DNA fragmentation or PARP cleavage in an in vivo preparation of ischemia-reperfusion injury does not support the view that apoptosis contributes markedly to post-ischemic tissue necrosis.

Role of mitogen- and stress-activated kinases in inflammatory arthritis

Lysophosphatidic acid(LPA) is a pleiotropic lipid mediator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fibroblast-like synoviocytes(FLS) from patients with rheumatoid arthritis. LPA activates several proteins within the mitogen activated protein(MAP) kinase signaling network, including extracellular signal-regulated kinases(ERK) 1/2 and p38 MAP kinase(MAPK). Upon docking to mitogen- and stress-activated kinases(MSKs), ERK1/2 and p38 MAPK phosphorylate serine and threonine residues within its C-terminal domain and cause autophosphorylation of MSKs. Activated MSKs can then directly phosphorylate c AMP response element-binding protein(CREB) at Ser133 in FLS. Phosphorylation of CREB by MSKs is essential for the production of pro-inflammatory and anti-inflammatory cytokines. However, other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, and high mobility group nucleosome binding domain 1 may also regulate gene expression in immune cells involved in disease pathogenesis. MSKs are master regulators of cell function that integrate signals induced by growth factors, pro-inflammatory cytokines, and cellular stresses, as well as those induced by LPA.

The implication of neurovascular unit signaling in controlling the subtle balance between injury and repair following ischemic stroke

Neurovascular unit（NVU）：Brain microvasculature has a close structural and functional relationship with brain parenchyma,an aspect governed by the NVU（Hermann and El Ali,2012）.The concept of it was introduced by the Stroke Progress Review Group who defined it as triad of neurons.

Impact of Acute Ischemia-Reperfusion Injury on Left Ventricular Pressure-Volume Relations in Dogs

Objective: Ischemic conditioning (IC) limits myocyte necrosis after acute myocardial ischemia-reperfusion;however, controversy persists regarding its potential to attenuate LV contractile dysfunction. Pressure-volume (P-V) loop analysis, via the load-insensitive conductance catheter method, was used to evaluate LV contractility, diastolic function, and ventriculo-arterial coupling. The goal of this study was to evaluate the ability of IC to improve post-ischemic recovery of LV contractile function. Methods: Twelve anesthetized dogs were randomly distributed to either the IC or the non-IC group;all dogs were subject to 60-min acute coronary occlusion followed by 180-min reperfusion. IC consisted of 4 repeated cycles of 5-min occlusion and 5-min reperfusion of the left main coronary artery. LV P-V relations were constructed under steady-state conditions (by inferior vena cava occlusion) at the beginning and end of the experiments;P-V loops were acquired at different time points before and during ischemia-reperfusion. Results: During ischemia and reperfusion, dP/dtmax decreased significantly compared to baseline in both groups;dP/dtmin, an indicator of the rate of LV relaxation rate was not affected for either group. Significant changes in several parameters of LV function including LVEF, SW, tPFR, ESV, and EDV caused by ischemia were also identified;none of these negative effects were resorbed, even in part, during reperfusion. Conclusions: Diminished LV contractile efficiency during systole and diastole produced by ischemia-reperfusion did not improve with IC pre-treatment despite significant endogenous protection against tissue necrosis.

Towards Mutuality in the Canada-China Relationship:The Experience of the Department of Surgery at Laval University since the 1980s

The Department of Surgery at Laval University has been a key player in the development of Canada-China cooperation since the 1980s.The projects initiated and developed by Jean Couture and Guojin Liu to address cancer issues,and specifically breast cancer,were heralded as outstanding successes.In the meantime,the Department of Surgery at Laval University trained numerous Chinese scholars,students,and post-doctoral fellows who became leaders in their fields of expertise.A few of these scholars and students settled in Canada,but the vast majority returned home.Since 2007,a highly specialized research program related to surgical implants with the College of Textiles at Donghua University has been opening new avenues in medical textiles to develop expertise through student training,to launch bridges between textile engineers and clinicians,and to provide the industry with a unique expertise.The final goal is to improve the accessibility and affordability of health care delivery in both Canada and China.China is now a key player in related research and no longer requires foreign assistance.Since it can easily find multiple partners,Canada must be alert to building on its legacy and maintaining its privileged position.China is now a place for Canadian champions.

Targeted therapy for capillary-venous malformations

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK,an endothelial transmembrane receptor signaling through PIK3CA.Venous malformations are associated with pain,bleedings,thrombosis,pulmonary embolism,esthetic deformities and,in severe cases,life-threatening situations.No authorized medical treatment exists for patients with venous malformations.Here,we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes.We showed that these malformations only partially signal through AKT proteins.We compared the efficacy of different drugs,including rapamycin,a mTORC1 inhibitor,miransertib,an AKT inhibitor and alpelisib,a PI3Kαinhibitor at improving the lesions seen in the mouse model.We demonstrated the effectiveness of alpelisib in preventing vascular malformations’occurrence,improving the already established ones,and prolonging survival.Considering these findings,we were authorized to treat 25 patients with alpelisib,including 7 children displaying PIK3CA(n=16)or TEK(n=9)-related capillary venous malformations resistant to usual therapies including sirolimus,debulking surgical procedures or percutaneous sclerotherapies.We assessed the volume of vascular malformations using magnetic resonance imaging(MRI)for each patient.Alpelisib demonstrated improvement in all 25 patients.Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated.MRI showed a decrease of 33.4%and 27.8%in the median volume of PIK3CA and TEK malformations respectively,over 6 months on alpelisib.In conclusion,this study supports PI3Kαinhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

Timely completion of multiple life-saving interventions for traumatic haemorrhagic shock: a retrospective cohort study

Background:Early control of haemorrhage and optimisation of physiology are guiding principles of resuscitation after injury.Improved outcomes have been previously associated with single,timely interventions.The aim of this study was to assess the association between multiple timely life-saving interventions(LSIs)and outcomes of traumatic haemorrhagic shock patients.Methods:A retrospective cohort study was undertaken of injured patients with haemorrhagic shock who presented to Alfered Emergency&Trauma Centre between July 01,2010 and July 31,2014.LSIs studied included chest decompression,control of external haemorrhage,pelvic binder application,transfusion of red cells and coagulation products and surgical control of bleeding through angio-embolisation or operative intervention.The primary exposure variable was timely initiation of≥50%of the indicated interventions.The association between the primary exposure variable and outcome of death at hospital discharge was adjusted for potential confounders using multivariable logistic regression analysis.The association between total pre-hospital times and pre-hospital care times(time from ambulance at scene to trauma centre),in-hospital mortality and timely initiation of≥50%of the indicated interventions were assessed.Results:Of the 168 patients,54(32.1%)patients had≥50%of indicated LSI completed within the specified time period.Timely delivery of LSI was independently associated with improved survival to hospital discharge(adjusted odds ratio(OR)for in-hospital death 0.17;95%confidence interval(CI)0.03–0.83;p=0.028).This association was independent of patient age,pre-hospital care time,injury severity score,initial serum lactate levels and coagulopathy.Among patients with pre-hospital time of≥2 h,2(3.6%)received timely LSIs.Pre-hospital care times of≥2 h were associated with delayed LSIs and with in-hospital death(unadjusted OR 4.3;95%CI 1.4–13.0).Conclusions:Timely completion of LSI when indicated was completed in a small proportion of patients and reflects previous research demonstrating delayed processes and errors even in advanced trauma systems.Timely delivery of a high proportion of LSIs was associated with improved outcomes among patients presenting with haemorrhagic shock after injury.Provision of LSIs in the pre-hospital phase of trauma care has the potential to improve outcomes.