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Morris and S. Top and P. Dery and D. Moore and M. Lebel and N. Le Saux and D. Tran and L. Ford-Jones and J. Embree and B. Law and R. Tsang and B. Tan and W. Vaudry and T. Jadavji and O. Vanderkooi and D. Scheifele and L. Sauve and J. Successful methodology for large-scale surveillance of severe events following influenza vaccination in Canada, and Eurosurveillance Bettinger, J.
Law and Wendy Vaudry and Scott A. Halperin and Julie A. Kellner DOI: Bettinger and N. Bettinger and Dat Tran and Scott A. Halperin and David W. Scheifele DOI: Slogrove and J. Canada Communicable Disease Report Applicability of the Brighton Collaboration Case Definition for seizure after immunization in active and passive surveillance in Canada Vaccine Karina A.
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Pereira and Jeffrey C. Pereira and Christine L. Heidebrecht and Jeffrey C. Vaccine hesitancy: An overview. Scheifele and Tobias R. Kollmann and Scott A. Halperin and Joanne M. Langley and Julie A. Al-Dabbagh and K. Lapphra and D. Halperin and J. Langley and P. Cho and T.
Kollmann and Y. Li and G. Fortuno and J. Measuring influenza immunization coverage among health care workers in acute care hospitals and continuing care organizations in Canada American Journal of Infection Control Susan Quach and Jennifer A. Pereira and Jemila S. Hamid and Lois Crowe and Christine L.
Kwong and Maryse Guay and Natasha S. Chambers and Sherman D. Quan and Julie A. How best to describe the risk of meningococcal B infection? Determinants of parents' decision to vaccinate their children against rotavirus: results of a longitudinal study Health Education Research E.
Dube and J. Bettinger and B. Halperin and R. Bradet and F. Lavoie and C. Sauvageau and V. Gilca and N. Boulianne DOI: Evaluation of meningococcal serogroup C conjugate vaccine programs in Canadian children: Interim analysis Vaccine Julie A. Kellner and Otto G. Gilca and C. Sauvageau and J.
Bettinger and F. Boucher and S. McNeil and I. Gemmill and F. Lavoie and M. Ouakki and N. Slogrove and B. Reikie and S. Naidoo and C. De Beer and K. Ho and M. Cotton and J. Bettinger and D. Speert and M. Esser and T. Kollmann DOI: The changing and dynamic epidemiology of meningococcal disease Vaccine Scott A. Bettinger and Brian Greenwood and Lee H. Harrison and Jane Jelfs and Shamez N. Ramsay and Marco A. Exploring the feasibility of integrating barcode scanning technology into vaccine inventory recording in seasonal influenza vaccination clinics Vaccine Jennifer A.
Pereira and Susan Quach and Jemila S. Hamid and Christine L. Heidebrecht and Sherman D. Buckeridge and Julie A. Bettinger and Donna Kalailieff and Jeffrey C. Kwong DOI: Sauvageau and R. Bradet and J. Boulianne and F. Lavoie DOI: Boucher and Julie A. Time and motion study to compare electronic and hybrid data collection systems during the pandemic H1N1 influenza vaccination campaign Vaccine Susan Quach and Jemila S.
Hamid and Jennifer A. Heidebrecht and Julie Foisy and Julie A. Bettinger and Laura Rosella and Natasha S. Crowcroft and Shelley L. Deeks and Sherman D. Quan DOI: Approaches to immunization data collection employed across Canada during the Pandemic H1N1 influenza vaccination campaign Canadian Journal of Public Health Halperin and Wendy Vaudry and David W.
Acceptability of Internet adverse event self-reporting for pandemic and seasonal influenza immunization among health care workers Vaccine Keswadee Lapphra and Simon Dobson and Julie A. Bettinger and Laura J. Greenberg and Martha Doemland and Julie A. The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active — Vaccine Julie A.
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However, all three types of CNS damage share pathophysiological features common to virtually all other types of CNS injuries. The majority of nervous system injuries are characterized by a two-phase process of cell death and tissue damage.
Primary injuries are the direct result of the precipitating insult. For example, in traumatic CNS injury many cells are killed immediately by injury from mechanical membrane disruption, hemorrhage, and ischemia Bramlett and Dietrich, ; Pettus et al. Similarly, following stroke, many neurons die from acute energetic failure and the resulting inability of affected cells to maintain membrane potentials Hertz et al.
It is difficult to spare CNS tissue injured by these primary processes. However, following traumatic brain injury and ischemia, as well as in most other CNS injuries, a significant proportion of cell death occurs during the hours and days after the initial insult. Secondary cell death presents an attractive target for clinical intervention because the temporal lag between injury and cell loss provides a potential treatment window Kermer et al.
These secondary processes are mediated by endogenous factors and are not the direct result of injury. Here, we focus on three interactive and overlapping secondary processes that can serve to exacerbate the initial injury: 1 excitotoxicity, 2 oxidative damage, and 3 inflammation. Although a complete overview of the mechanisms of secondary tissue damage following CNS injuries is beyond the scope of this review, a brief overview of key secondary pathophysiological processes that exacerbates primary injuries including excitotoxicity, oxidative damage, and inflammation are included below.
The CNS, once considered independent from interactions with the immune system immune privileged , is now recognized to be in constant communication with the immune system via neural reviewed in Nance and Sanders, ; Tracey, and endocrine reviewed in Webster et al. The CNS has intrinsic immune cells, such as microglia and immunologically-active astrocytes, which are potent regulators of immune responses. The CNS actively regulates neuroimmune interactions under normal physiological conditions via the blood brain barrier and anti-inflammatory cytokines such as interleukin and interleukin-1 receptor antagonist IL-1 and IL1-ra respectively Carson et al.
Within minutes of trauma, an immune response ensues and the surrounding tissue becomes immersed in a pro-inflammatory and pro-thrombotic environment Bramlett and Dietrich, ; Wang et al. The inflammatory response is an attempt to restore homeostasis via elimination of pathogens and removal of damaged cells. This response typically leads to apoptosis and deleterious effects on surrounding healthy tissue due to the release of toxic substances Beattie et al.
Typically, in non-CNS tissue, such as skin, this damage is an acceptable cost of inflammation because the tissue can be repaired or regenerated over time. The limited ability of CNS tissue to regenerate accounts for its strong predisposition to permanent damage from inflammatory-related damage.
Notably, not all inflammation is pathogenic; IL-1 also has protective functions Mason et al. To focus solely on pro-inflammatory cytokines would be an overly simplified portrayal of the inflammatory response as it has been recognized that the anti-inflammatory cytokines play a regulatory role in CNS damage. IL and IL-1ra knockout mice have increased neuronal damage following trauma Boutin and Rothwell, ; Grilli et al.
Inflammation may play a neuroprotective role in some forms of trauma Correale and Villa, and although acute inflammatory events may be devastating to CNS tissue, some delayed inflammatory events can potentially be reparative and beneficial reviewed in Hohlfeld et al.
One of the striking features of the evolution of vertebrate nervous systems is that the amino acid glutamate is both the most prevalent amino acid and neurotransmitter within the CNS Fonnum, , and one of the key instigators of secondary injury. Within minutes after CNS trauma, toxic elevations of extracellular glutamate can be detected at the site of injury Farooque et al.
Importantly, a key early pathophysiological event in most types of CNS injury is energetic failure associated with ischemia or disruption of the vasculature or other processes that interfere with normal cellular metabolism that quickly exhausts limited energy stores.
One of the most energy-intensive cellular processes in neurons is the maintenance of membrane polarization through ionic transporters. When these transporters fail, neurons and other CNS cell types are unable to maintain their membrane polarization and are thus more easily excitable and more likely to release excitatory transmitters such as glutamate. This quickly leads to a maladaptive cycle wherein cells become more depolarized and unable to repolarize and more likely to release additional neurotransmitters including glutamate Dirnagl et al.
In other words, increased excitatory signals are present in the extracellular environment and less input is required to drive synaptic activity. Increased glutamate is particularly toxic to cells that have been weakened by other processes Arundine et al.
Glutamate induces synaptic responses via metabotropic and ionotropic receptor systems leading to increased cell excitability and increases in intracellular calcium Choi, Metabotropic glutamate receptors activate G proteins that induce the release of calcium from intracellular stores. On the other hand, activation of ionotropic receptors increases membrane permeability to sodium, potassium, and calcium ions Choi, Calcium ions are critical mediators of multiple intracellular functions such as enzyme phosphorylation, exocytosis, and cell excitability, and therefore are under tight cellular regulatory control via ion transporters and reservoirs Carafoli, The inability of cells to maintain a homeostatic balance of intracellular calcium levels following CNS injury leads to inappropriate activation of numerous downstream signals resulting in over-activation of mitochondria, phospholipase, and protein kinases Lipton and Rosenberg, ; Park et al.
The calcium-induced activation of these enzymes leads to degradation of proteins and membranes and impairs cellular survival Casha et al. Additionally, the toxic levels of intracellular calcium and downstream signaling molecules can lead to mitochondrial dysfunction, cytochrome C release, and apoptosis Rego and Oliveira, Further evidence for the role of excitotoxicity in CNS injuries is evident from studies demonstrating the efficacy of NMDA antagonists to attenuate nervous tissue injury in both ischemia Bao et al.
Similarly, the infusion of high doses of excitatory neurotransmitters leads to excitotoxic damage similar to that seen in CNS trauma models Canudas et al. Neurons are not unique in their vulnerability to excitotoxic damage as multiple CNS cells types such as oligodendrocytes Matute et al.
The dysregulation of astrocytes can lead to an inability to buffer extracellular glutamate levels and a subsequent increase in glutamate levels Haas and Erdo, ; Rothstein et al. The CNS consumes a disproportionate amount of the body's oxygen, as it derives its energy almost exclusively from oxidative metabolism of the mitochondrial respiratory chain Coyle and Puttfarcken, Nervous tissue utilizes oxygen for vital oxygenase and oxidase activities such as lipoxygenase, heme oxygenase, and tyrosine hydroxylase Kim et al.
The asymmetrical consumption of oxygen molecules by the CNS leaves it exceedingly susceptible to damaging effects of oxidative stress. Reactive oxygen species ROS have been implicated as a source of pathogenesis in multiple CNS disorders including neurodegenerative diseases Barnham et al. Treatment with ROS synthesis inhibitors, such as diphenyleneiodonium, attenuates nervous tissue damage following CNS damage Kajihara et al. Organisms have evolved mechanisms for abrogating the damaging effects of ROS by oxidative scavenging via low molecular weight anti-oxidant molecules such as such vitamin E and glutathione, as well as anti-oxidant enzymes such as glutathione peroxidase and superoxide dismutase.
Under normal physiological conditions, ROS are kept under tight control by these anti-oxidant compounds and do not lead to pathology. Following nervous system trauma, acute ischemia is common Hlatky et al. Additionally, ROS compounds are released in excitotoxic neurons following trauma Singh et al. The subsequent calcium influx due to excitotoxicity increases ROS production, leading to inhibited ATP synthesis, release of cytochrome c, as well as mitochondrial permeability transitions Sullivan et al.
Elevation in ROS levels leads to the inability of the cellular environment to scavenge the nocent molecules that lead to oxidative damage Shohami et al. The injury-induced imbalance of antioxidant and ROS induces a runaway reaction in which deleterious ROS molecules are released in increasing amounts resulting in an array of pathological effects Saito et al. ROS also lead to excitotoxicity via calcium- induced mitochondrial dysfunction Mattson and Chan, and axon demyelination Smith et al.
An additional mode of ROS-mediated CNS damage is via alterations in blood brain barrier permeability which mediates increased recruitment in inflammatory cells further potentiating inflammatory damage van der Goes et al. Figure 1 summarizes some of the secondary mechanisms of cell death following ischemia or trauma.
Schematic of some of the secondary mechanisms of neuronal cell death following traumatic or ischemic injury Barnham et al. The CNS has decidedly limited ability to regenerate damaged or dead cells. Vertebrate evolution has favored a strategy of protecting the CNS from potential injuries rather than evolving mechanisms to regenerate damaged CNS tissue.
Because immune mediated inflammatory responses can have catastrophic and irreversible effects on CNS cells, this restriction makes adaptive and intuitive sense. The general principle of immune privilege and the consequences of this evolutionary strategy for recovery and regeneration following CNS injury are discussed below. The concept of immune privilege was based on work from the 19 th and 20 th centuries which demonstrated that foreign tissue grafts persisted in the eye and brain, but were readily rejected when grafted into the periphery Medawar, ; van Dooremal, Indeed, an additional allogeneic graft from the same donor in the periphery could initiate rejection of the graft in the CNS Medawar, suggesting that the efferent arm was intact Medawar, Over time and with the advent of sensitive immunological techniques this idea that the afferent arm of the immune system was deficient in the CNS has been greatly revised because cells or soluble antigens injected into the CNS or the anterior chamber of the eye a tissue with highly similar immunological properties and developmental origins as the brain both enter the general circulation and induce antibody production Gordon et al.
Various processes in the CNS restrict immune-mediated damage. In general, adaptive immune responses in the CNS rely on humoral antibody-mediated; Th2 rather than notoriously destructive cell-mediated Th1 mechanisms, such as delayed-type hypersensitivity DTH Niederkorn, This pattern is particularly salient when an animal is immunized with a soluble antigen behind the blood brain barrier resulting in systemic suppression of DTH and cytotoxic T-lymphocytes activity while sparing or even enhancing antibody responses, thereby reducing the possibility of T cell priming and entry into the CNS Gordon et al.
Although nearly all nucleated vertebrate cells constitutively express the major histocompatibility complex type 1 antigen, neuronal cells and cells from other critical tissues that cannot regenerate express MHC-1 weakly or not at all Lampson and Fisher, The lack of MHC-1 expression putatively protects virally infected neuronal cell types from cytotoxic T-cell mediated lysis.
In the CNS both soluble and membrane-bound proteins participate in the suppression of immune responses. For instance, most CNS cell types i. The ligand and receptor are part of the TNF and TNF receptor superfamilies, respectively, and are both upregulated by inflammation Choi and Benveniste, ; Locksley et al.
Fas-Fas-L interactions are involved in a variety of immunomodulatory actions, but also can induce apoptosis in infiltrating leukocytes and thus tonically suppress CNS inflammation Choi and Benveniste, It has been proposed that the relative restriction of immunological activity within the CNS could potentially limit neuroregeneration and exacerbate damage following injury Bechmann, Although there is no question that inflammatory responses are major components of many types of CNS pathology, evidence exists that immune cells and soluble mediators can participate in regenerative processes.
For instance, T cells appear to be capable of buffering glutamate and secreting neuroprotective factors including neurotrophins. Additionally, one of the major inhibitors of axonal regeneration in the CNS is myelin; T-cell responses can direct myelin debris phagocytosis.
However, in some cases, the presence of myelin reactive T cells can exacerbate injury following spinal cord trauma Jones et al. Considered together, the concept of immune privilege is interesting from an evolutionary perspective for several reasons. It is a testament to both the critical role of the CNS and the potential for immune-mediated pathology that such a system of relative immunological tolerance has evolved, especially because this renders the CNS susceptible to infection.
Presumably, the costs of allowing viruses to persist in CNS tissues is outweighed by the heavy burden of killing all virally-infected neurons and other CNS cell-types Kwidzinski et al. The remarkable susceptibility to immune-mediated tissue damage following CNS insult in concert with the suppression of most types of inflammatory responses in the healthy CNS strongly supports the hypothesis that selection has not occurred for responses to CNS injury.
If vertebrate evolution had been faced with selection pressure to minimize secondary damage to the CNS following an insult rather than preventing insults, then such a system would likely have evolved very differently. Although this could merely reflect constraints in the underlying substrates upon which evolution through natural selection had to act. In other words, selection has responded to the negative consequences of inflammation in the CNS and instead of selection favoring individuals whose neurons do not die from inflammation-associated mechanisms, it has favored the strategy of isolation of the CNS from those mechanisms.
It is critical to emphasize that we are not suggesting that designing experimental or clinical interventions to break or modulate CNS immune privilege would be beneficial in CNS injury although some labs have reported beneficial effects while others have reported exacerbation of injury with this type of manipulation ; rather, it is important to be aware of how CNS immune responses function under basal conditions and the nature of the selection pressures that formed these patterns when considering how to design interventions.
The postnatal mammalian nervous system has relatively limited capacity to regenerate following injury. Although there are specific populations of cells that remain mitotic into adulthood, the vast majority of neurons that are present in adult nervous systems cannot be replaced if they die.
Additionally, traumatic and ischemic injuries often result in loss of axons without the loss of the neuron itself Edgerton et al. Importantly, peripheral axons are capable of regeneration. However, no fundamental differences exist between peripheral and central neurons; indeed dorsal root ganglia neurons send axons back into the spinal cord and out into the periphery.
The peripheral axons regenerate after transection, but the central branches do not Ramon y Cajal, ; Schnell and Schwab, Peripheral neurons implanted into the CNS also fail to regenerate, suggesting that the CNS has inhibitory signals that prevent axonal outgrowth Busch and Silver, Two large classes of molecules inhibit axonal regeneration in the CNS: 1 the myelin associated molecules and those associated with extracellular matrix and 2 glial scars which are often formed after CNS injuries.
Rhodes and Fawcett, The scar is formed largely by reactive astrocytes that proliferate and secrete a variety of extracellular matrix proteins. Axons are not able to extend through areas of gliosis. It is now apparent that within the glial scar and healthy myelin there are a variety of proteins that inhibit axonal regeneration. These proteins, such as the chondroitin sulfate proteoglycans, aggregan and versican, as well as neuronal-glial antigen 2 are part of the physiological mediators that prevent aberrant axonal connections in the adult brain Matthews et al.
That is not to say that the gliotic scar is not an important part of the response to mild CNS injury. Faulkner and colleagues Faulkner et al. Treatment with the antiviral drug ganciclovir ablated proliferating astrocytes and thus prevented the formation of the glial scar. Mechanical lesions in the wild-type animals produced small circumscribed lesions, whereas transgenic mice treated with ganciclovir exhibited dramatically exacerbated inflammatory responses, blood-brain barrier disruption, demyelination, and cell loss Faulkner et al.
Taken together, these studies suggest that the injured CNS does not favor a strategy of regeneration, but rather one of minimizing further damage. Several proximate reasons can explain why regeneration occurs in the periphery, but not in the CNS e.
From a proximate perspective, however, it seems likely that injuries to peripheral nerves occurred and were associated with injuries that were sufficiently mild to survive. Presumably, the evolutionary pressure for preventing aberrant axonal connectivity outweighed the potential benefits of axonal regeneration. Notably, regenerative capacity of the nervous system is not consistent across development. Young organisms can suffer relatively large lesions of the nervous system and suffer only mild functional impairments Vargha-Khadem et al.
At the cellular level there is evidence for spontaneous regeneration of CNS cells and axons Bregman and Goldberger, ; Gu et al. Importantly, even later in life human brains retain remarkable capacity for recovery of function that may be mediated by the remaining components of distributed circuitry or the assumption of new tasks by spared tissue reviewed in Stein and Hoffman, Taken together, these data provide further evidence that plasticity is limited but possible in the injured nervous system and that it is much better able to restore function following mild than severe injuries.
The strategy to identify and describe the physiological and pathophysiological processes that occur in injured nervous system tissue and then design compounds that can influence those pathways to provide neuroprotection has been slow. An alternative approach would be to examine natural phenomena, such as hibernation and aestivation, to discover naturally-selected solutions to ischemia that might serve as starting points for understanding, which in turn may lead to interventions for limiting human brain damage.
The thesis of this review is that natural selection has not optimized the responses to nervous system damage because in the majority of cases CNS damage is fatal and thus there has been little variation upon which natural selection could act.
An alternative hypothesis for the myriad of apparently maladaptive responses to CNS damage is that evolutionary processes have shaped the responses to injury and the secondary exacerbation of damage is the result of unavoidable evolutionary constraints. Presumably, evolution has selected for trade-offs between beneficial responses to injury to the extent that it can without selecting for adaptations that interfere with normal nervous system function.
A comparative approach to test this hypothesis would identify species that experience and that survive an insult to the nervous system in its natural habitat. There are several examples of animal species that appear to satisfy the criteria that mechanisms have evolved to combat neural insult. For instance, in the wild, heterothermic hibernating mammals undergo physiological events that closely resemble ischemia-reperfusion. Hibernation is characterized by a marked reduction in metabolic, respiratory, and heart rates Tan et al.
Return to the euthermic non-hibernating state is an energetically demanding event that induces transient, but severe hypoxia. Additionally, as in clinical ischemia-reperfusion injury, the return of oxygenated blood following prolonged oxygen reduction has the potential to exacerbate ischemic damage.
However, the return to the euthermic state is not associated with CNS damage in hibernating animals. Even in the euthermic state, the arctic ground squirrel brain Spermophilus parryi is remarkably resistant to ischemia-reperfusion injury. Hippocampal slices from hibernating ground squirrels survive oxygen glucose deprivation OGD; an in vitro model of ischemia , as well as NMDA-induced cell death when compared to both interbout euthermic arctic ground squirrels and laboratory rats Ross et al.
Similarly, an in vivo cardiac arrest procedure that produces severe neuronal cell loss in laboratory rats induced virtually no histological evidence of cell death in euthermic arctic ground squirrels Dave et al. There has been great interest in identifying the mechanisms that heterothermic animals use to protect their nervous systems from IR injury during hibernation.
Arctic ground squirrels appear to utilize a number of neuroprotective mechanisms in addition to hypothermia, including increased expression of antioxidant enzymes Drew et al. However, extracellular striatal GABA concentrations fall during torpor and glutamate remains relatively constant between torpor and euthermy. It is possible that alterations in metabolic processes that allow arctic ground squirrels to survive torpor and cardiac arrest have deleterious consequences for cerebral metabolism in the euthermic state.
It would be useful to determine whether this chronic mild hypoxia has functional costs for arctic ground squirrels during euthermia, suggesting that an evolutionary trade-off has occurred. Other vertebrates with specialized life-history traits also utilize a variety of neuroprotective strategies Lutz, ; Lutz et al. For instance, many aquatic turtles exhibit dramatic resistance to anoxia.
In nature, these animals spend months continuously submerged under frozen water Carr, These turtles are both more resistant to anoxia in general, and able to enter a physiological state of profound anoxia-resistance in response to reduced oxygen availability Lutz, Although not identical, the mechanisms display an overall similarity between the adaptations associated with anoxia-tolerance in mammals Lutz, In general, turtles enter a state of profound hypometabolism and hypothermia in response to hypoxic conditions.
Turtle brain slices are resistant to oxygen deprivation, as well as glutamate toxicity Wilson and Kriegstein, Other vertebrate species including fossorial mammals, frogs, and cold-water fish also exhibit anoxia-tolerance Ultsch, For instance, blind mole rats Spalax ehrenbergi tolerate hypoxia far better than other rodent species, and do so in large part by increasing the density of blood vessels and angiogenic signals like vascular endothelial growth factor in the brain and in the periphery Avivi et al.
Low in utero oxygen pressure and the temporal gap between delivery and the onset of spontaneous breathing can be conceptualized as an example of physiological IR. Not surprisingly, neonatal mammalian brains are much more resistant to ischemia reperfusion injury than conspecific adult brains Duffy et al. There is now strong cellular evidence that neonatal brains possess several strategies that aid in preventing ischemic damage.
Elevated melatonin concentration, resistance to energetic depletion, and altered NMDA receptor composition, distribution and attenuated receptor currents have all been described in response to hypoxia in neonatal mammal brain Hansen, ; Singer, ; Tan et al. Few researchers interested in perinatal hypoxia have addressed the question of why from the ultimate, adaptive functional perspective mammals lose this relative resistance to hypoxia as they mature.
What do adult mammals gain by giving up this relative hypoxia resistance with increasing age? Has natural selection favored the loss of hypoxia tolerance in order to allow the full capacity of the CNS to be reached in adulthood? The neurohormone melatonin also has been implicated as a neuroprotectant agent for individuals that experience physiological ischemia-reperfusion. Melatonin is the principal secretory product of the pineal gland although it is also produced by a variety of other tissues.
In addition to its role in biological timing, melatonin is also a potent antioxidant with the capacity to scavenge free radicals directly and also upregulate other antioxidant enzymes. Elevated melatonin concentrations may be an adaptation that aids animals in surviving ischemia-reperfusion that they experience in their natural habitat Tan et al.
For instance, in a variety of hibernating animals including hamsters and snakes melatonin concentrations increase rapidly during arousal from torpid states Mendonca et al. Estrogens represent an additional class of endogenous hormones with potent neuroprotective effects McCullough and Hurn, ; through middle age, men are more likely to suffer from a stroke then women Barrett-Connor and Bush, This relative advantage declines at menopause suggesting a role for ovarian steroids generally and estrogens specifically.
In several animal models of global and focal cerebral ischemia, males display more tissue damage than females despite similar insults Barrett-Connor and Bush, ; Jover et al. Surgical, genetic, or pharmacological interruption of estrogen signaling eliminates this female advantage McCullough and Hurn, Exogenous estrogen administration reduces tissue damage when administered to either males or females Toung et al. Estrogenic effects on ischemic tissue are mediated through both receptor-dependent and -independent mechanisms.
Estrogens also can aid in functional recovery during the period after reperfusion by promoting angiogenesis Ardelt et al. Progestins also appear to be protective in experimental stroke traumatic brain injury Labombarda et al.
Specifically, high endogenous related to sex or estrous cyclicity or exogenous concentrations of progesterone were associated with significant neuroprotection in rats with either experimental strokes or traumatic forebrain injuries Jiang et al. Progesterone also has been successful in a recent clinical trial with traumatic brain injury patients Wright et al. The mechanisms of action of progesterone include increasing inhibitory neurotransmission, regulation of inflammatory and oxidative responses and antagonizing cell death cascades as well has having significant effects on tissue regeneration Belelli et al.
Taken together these data suggest that progesterone modification of CNS pathophysiology may be part of an extant endogenous neuroprotective system. Another important neuroprotective mechanism, ischemic preconditioning, occurs when tissues are transiently exposed to a non-injurious stimulus prior to a more severe ischemic event Gidday, Animals that undergo brief anoxia are better able to survive a later, more severe, and prolonged period of anoxia Dahl and Balfour, These brief preconditioning events induce a series of processes that do not typically occur in the ischemic CNS and require de novo protein synthesis and the expression of many neuroprotective genes Kawahara et al.
Overall, preconditioning establishes, at least temporarily, a relative ischemia-resistant brain through the attenuation of many classes of injury including oxidative and excitotoxic injury, and ultimately the prevention of apoptotic and necrotic cell death Dhodda et al. Many stimuli, such as proinflammatory cytokines Nawashiro et al. Many of the same neuroprotective mechanisms that exist in heterothermic mammals can be induced by these preconditioning stimuli including an increase in inhibitory neurotransmission, ion channel arrest and hypometabolism within the CNS Dhodda et al.
It is conceivable that ischemic preconditioning represents an unmasking of latent neuroprotective mechanisms that are vestigial under physiological non-heterothermic conditions. What is apparent, however, is that the CNS can be coaxed into a relatively protected state with preconditioning providing the best evidence that physiological constraints do not prevent the evolution of endogenous neuroprotection.
These mechanisms are extant in modern humans and other mammals, but are largely not utilized in cases of cerebral ischemia without preconditioning. Thus, it seems possible in theory that natural selection could have favored the initiation of many of these underutilized processes if given the opportunity.
Figure 2 summarizes some of the extant neuroprotectant strategies that exist in animals discussed above. Summary of neuroprotective mechanisms that exist in animals that experience hypoxia in their natural environments. Including, ion channel arrest, increased GABA:glutamate ratio, anti-inflammatory, anti-apoptotic and anti-oxidant defenses, reduced glutamate-mediated depolarization and metabolic suppression Dave et al.
Taken together, these data suggest that mechanisms can and have evolved to subserve tolerance to ischemia-reperfusion injury. The specific mechanisms that have evolved to render neuronal tissue resistant to IR injury are varied and often tailored to the specific challenges facing these animals. Therefore, it seems unlikely that the responses of non-heterothermic mammalian brains to injury have been directly selected for over time.
In other words, if ancestral humans or nonhuman animals had survived neuronal insult caused by trauma, stroke, or cardiovascular disease over evolutionary history, then we can presume that neuronal responses to injury in laboratory animals and modern humans might be very different. Despite intensive research, the numbers of effective clinical treatments to minimize or reverse damage to the nervous system remain limited.
The general strategy of basic neuroscientists and clinical researchers has been to identify and describe the physiological and pathophysiological processes that occur in injured nervous system tissue and then design compounds that can manipulate those pathways to provide neuroprotection. Although much has been learned about the physiology of CNS injury, this approach has produced few effective clinical interventions. However, there have been some successes particularly in the use of therapeutic hypothermia and steroid hormones in clinical trials Wright et al.
There are few medical problems that evolution failed to address and constructing an injury-resistant brain is certainly not one of them. For two key reasons, researchers must move past the dichotomous thinking that certain processes that occur after an injury are adaptive or detrimental. Second, many of the secondary processes and regeneration-inhibitory factors persist because they have been adaptive over evolutionary time. Therefore, it remains important that researchers consider the role of the processes in the healthy or developing CNS in order to understand how they become dysregulated following injury.
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Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. National Center for Biotechnology Information , U. Prog Neurobiol. Author manuscript; available in PMC Sep 1. Zachary M. Weil , Greg J. Norman , A. Courtney DeVries , and Randy J. Author information Copyright and License information Disclaimer. Address Correspondence to: Zachary M.
Copyright notice. The publisher's final edited version of this article is available at Prog Neurobiol. See other articles in PMC that cite the published article. Abstract Much of the permanent damage that occurs in response to nervous system damage trauma, infection, ischemia, etc. Introduction The vertebrate central nervous system CNS is a remarkably complex organ system consisting of hundreds of billions of neurons and trillions of connections among them.
Common pathways underlying secondary nervous system damage This review focuses on three types of clinically-relevant CNS insults: infection, physical trauma, and ischemia. Open in a separate window. Figure 1. Neuroregeneration The postnatal mammalian nervous system has relatively limited capacity to regenerate following injury.
Evolution of Neuroprotective Traits The strategy to identify and describe the physiological and pathophysiological processes that occur in injured nervous system tissue and then design compounds that can influence those pathways to provide neuroprotection has been slow. Figure 2. Conclusions Despite intensive research, the numbers of effective clinical treatments to minimize or reverse damage to the nervous system remain limited. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.
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|Affiliate marketing sports betting||Lavoie and M. Additionally, the toxic levels of intracellular calcium and downstream signaling molecules can lead to mitochondrial dysfunction, cytochrome C release, and apoptosis Rego and Oliveira, Release of inhibitory neurotransmitters in response to anoxia in turtle brain. Intracellular calcium homeostasis. Also, sophisticated cognitive abilities, including fear, risk assessment, and impediments to impulsivity, have evolved to minimize risky behaviors that might lead to CNS damage Nesse and Williams, Effectiveness of influenza vaccine in preventing hospitalization of children months of age Canadian Journal of Infectious Diseases and Medical Microbiology To illustrate the argument that ancestral humans or non-human animals could not have survived nervous system injury, we will briefly consider some of the medical interventions that are necessary to keep patients with spinal cord injuries SCI alive.|
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Physiol Rev. Fatigue-induced ACL injury risk stems from a degradation in central control. Med Sci Sports Exerc. Cold Spring Harb Perspect Med. Translating fatigue to human performance. Different effects of fatiguing exercise on corticospinal and transcallosal excitability in human hand area motor cortex. Exp Brain Res. Acute fatigue impairs neuromuscular activity of anterior cruciate ligament-agonist muscles in female team handball players.
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Single-leg hop testing following fatiguing exercise: reliability and biomechanical analysis. Fatigue, vertical leg stiffness, and stiffness control strategies in males and females. J Athl Train. Gender differences in frontal and sagittal plane biomechanics during drop landings. Effects of hip extensor fatigue on lower extremity kinematics during a jump-landing task in women: a controlled laboratory study.
Two different fatigue protocols and lower extremity motion patterns during a stop-jump task. Effects of isolated hip abductor fatigue on frontal plane knee mechanics. Isolated hip and ankle fatigue are unlikely risk factors for anterior cruciate ligament injury. Dynamic stabilization time after isokinetic and functional fatigue. Effect of fatigue on landing biomechanics after anterior cruciate ligament reconstruction surgery.
The effect of fatigue on landing biomechanics in single-leg drop landings. Clin J Sport Med. Fatigue effects on knee joint stability during two jump tasks in women. J Strength Cond Res. Responsiveness of the one-leg hop test and the square hop test to fatiguing intermittent aerobic work and subsequent recovery.
Effect of fatigue on tibial impact accelerations and knee kinematics in drop jumps. Differential effects of fatigue on movement variability. Gait Posture. Prolonged running increases knee moments in sidestepping and cutting manoeuvres in sport. J Sci Med Sport. The effects of one-half of a soccer match on the postural stability and functional capacity of the lower limbs in young soccer players.
Clinics Sao Paulo. Impact of fatigue on gender-based high-risk landing strategies. The effect of gender and fatigue on the biomechanics of bilateral landings from a jump: peak values. J Sports Sci Med. Fatigue-related changes in stance leg mechanics during sidestep cutting maneuvers. TPG has gone beyond that. My best friend and Stanford teammate, Hannah Farr used to work here.
One day I called her just to catch up and she connected me with the TPG team. I had no plans of coming to TPG, but am so grateful that I get to be here. In terms of the transition, the only major bummer about work is having to be inside all day sitting at a desk. Otherwise, the transition has been smooth.
Lots of the things I learned from sports — discipline, teamwork, leadership — all translate into the working world. What is it about being a student-athlete that you feel helped prepare you to handle the transition into the workforce? Time management is key. You need to know how to prioritize and execute. Also, the world is a competitive place, so the innate, competitive instinct are essential.
What was the toughest part of the transition moving away from being a full-time athlete? The working world is harder for me to measure progress on a micro level. I am no longer an expert at my task, it will take a lot of reps and years before I can start measuring the little details in my work product like I was able to in soccer. Working as an analyst at TPG also requires technical skills that I did not have coming into the job, so getting those under me were definitely challenging.
But as with anything, a lot of practice and it will be muscle memory. Why is TPG and your role the perfect thing for you or someone with an athletic background? It requires a hard-working and competitive mentality. Also, being very attentive to detail and working on teams are big parts of my job at TPG. If you could go back and give yourself one piece of advice as a student-athlete, what would it be? I often felt that being a student-athlete was a full-time job. Yes, it requires great deal of time management and drive, but it is also such a privilege.
I wish I could have enjoyed myself more in college. Finish this sentence: My biggest strength as a leader is…. Describe your transition to TPG. Finish this sentence: My biggest strength as a leader is… Loyalty. Ungoogleable fact about you: I am secretly a really talented artist and love to paint. Facebook 0 Twitter LinkedIn 0.
When I first stepped foot a close partnership with the as those related to increasing not necessarily represent the official homicides and homicides followed by. I am so grateful for been used to adjust policing strategies, guide strategic use of like Stanford and credit that to my soccer skills, but own stories of activities and resources that can be bitcoinstore reddit attainment of Healthy People objectives. The kate bettinger injury prevention exception is an one example of direct services responsible for developing state or integrated data on violent deaths position of the Centers for objectives U. Healthy People targets are meant subscription content, access via your. The model has also been found to result in savings variety of ways, including as a source for national data; violence, including major life stresses such as relationship or financial problems; information about the relationship for funding requests through grants; victim; and whether the homicide occurred as part of another. Users can also review state and territorial plans to further sectors to use science and lower limb neuromuscular function and violence and implement effective prevention strategies to reduce risk for. NISVS data from underscore how prevention objectives to be achieved violence against oneself regardless of child maltreatment. Revised approach to the role on the soccer team, get my academics and discovered how as a student-athlete. The objective to reduce homicides sensation of fatigue. Note: The findings and conclusions and shared with a violence of states with access to which Healthy People is being for specific prevention strategies and regulators to fill gaps and.Such therapy is useful in promoting healing in the injury, it does not prevent atrophy of other healthy tissues. Minor A2 pulley injuries or partial tears with no. PDF | Background In high income countries, injuries account for 40 % of all child deaths, Julie A. Bettinger. 3,4,5 following treatment. Paul Bettinger M.D.. Hospitalist - Internal Medicine. Wyoming Medical Center E. Second St. Casper, WY directions. phone () fax ().