Reperfusion injury

The restoration of blood flow to ischemic tissues causes additional damage, which is termed reperfusion injury. All tissues are susceptible to reperfusion injury, but this susceptibility varies between tissues. Reperfusion has wide clinical relevance. It influences the outcome of patients after myocardial infarction, stroke, organ transplantation, and cardiovascular surgery. Advances in the treatment of reperfusion injury have created an opportunity for plastic surgeons to apply these treatments to flaps and reimplanted tissues. The main putative mechanisms identified in animal models involve leukocyte-endothelium interactions, reactive oxygen species, and the complement system. However, it has become evident that these fundamental biological systems are controlled by many interrelated pathways. Attempts to bypass this complexity have led to a search for the early "upstream" initiating events, rather than the "downstream" cascading events. This contrasts with current clinical efforts that are directed toward hypothermia, intraarterial flushing, and preconditioning. This article outlines the molecular and cellular events that occur during reperfusion injury and then reviews the efforts that have been made to exploit this knowledge for clinical advantage.     

Traumatic brain injury

There is an increasing incidence of military traumatic brain injury (TBI), and similar injuries are seen in civilians in war zones or terrorist incidents. Indeed, blast-induced mild TBI has been referred to as the signature injury of the conflicts in Iraq and Afghanistan. Assessment involves schemes that are common in civilian practice but, in common with civilian TBI, takes little account of information available from modern imaging (particularly diffusion tensor magnetic resonance imaging) and emerging biomarkers. The efficient logistics of clinical care delivery in the field may have a role in optimizing outcome. Clinical care has much in common with civilian TBI, but intracranial pressure monitoring is not always available, and protocols need to be modified to take account of this. In addition, severe early oedema has led to increasing use of decompressive craniectomy, and blast TBI may be associated with a higher incidence of vasospasm and pseudoaneurysm formation. Visual and/or auditory deficits are common, and there is a significant risk of post-traumatic epilepsy. TBI is rarely an isolated finding in this setting, and persistent post-concussive symptoms are commonly associated with post-traumatic stress disorder and chronic pain, a constellation of findings that has been called the polytrauma clinical triad.     

Reperfusion injury

Several lines of evidence point to a major role of oxygen free radicals in the pathogenesis of cell death or dysfunction in a variety of disease processes. Recent studies from this as well as other laboratories have demonstrated that oxygen free radicals play a major role in the pathogenesis of post-ischemic reperfusion injury in the heart. We have recently developed methods for direct measurement of radical species and/or specific byproducts of radical injury. Timely administration of oxygen radical scavengers reduced the quantity of free radicals generated following reperfusion and in addition improved recovery of post-ischemic ventricular function and metabolism. In a regionally ischemic model the free radical scavenger recombinant human superoxide dismutase also administered at the time of reflow was shown to limit infarct size. In this article we review the biophysical and molecular mechanisms of oxygen free radical generation that are viewed as contributing to post-ischemic reperfusion injury. We also discuss the mechanisms by which the body defends against free radical attack and the interrelationships of free radical injury to other mechanisms of tissue injury.     

Lung injury in acute pancreatitis: mechanisms underlying augmented secondary injury

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are common complications of acute pancreatitis (AP). ALI/ARDS contribute to the majority of AP-associated deaths, particularly in the setting of secondary infection. Following secondary pulmonary infection there can be an exacerbation of AP-associated lung injury, greater than the sum of the individual injuries alone. The precise mechanisms underlying this synergism, however, are not known. In this review we discuss the main factors contributing to the development of augmented lung injury following secondary infection during AP and review the established models of AP in regard to the development of associated ALI.     

An axonal strain injury criterion for traumatic brain injury

Computational models are often used as tools to study traumatic brain injury. The fidelity of such models depends on the incorporation of an appropriate level of structural detail, the accurate representation of the material behavior, and the use of an appropriate measure of injury. In this study, an axonal strain injury criterion is used to estimate the probability of diffuse axonal injury (DAI), which accounts for a large percentage of deaths due to brain trauma and is characterized by damage to neural axons in the deep white matter regions of the brain. We present an analytical and computational model that treats the white matter as an anisotropic, hyperelastic material. Diffusion tensor imaging is used to incorporate the structural orientation of the neural axons into the model. It is shown that the degree of injury that is predicted in a computational model of DAI is highly dependent on the incorporation of the axonal orientation information and the inclusion of anisotropy into the constitutive model for white matter.     

Surgical repair of corneal injury

Operations on the cornea relating to trauma are discussed, and included are tangential flaps, corneal injuries, old adherent leukoma, and optical iridectomy. Variations from the usual technique and the immediate surgical closure of corneal wounds are emphasized.     

Blood cells and ischemia-reperfusion injury

Ischemia-reperfusion insults are common clinical problems which involve most notably the heart (myocardial infarction) and brain (stroke). However, these and other organs are susceptible to damage following warming after cold injury, trauma, shock, and/or preparation for transplantation. Although the mechanisms responsible for reperfusion damage following ischemia and reperfusion are unknown, they are the focus of intense interest and investigation. This review briefly addresses our recent research related to the potential contributions of blood cells to the development of ischemia-reperfusion injury.     

Rationalizing vaccine injury compensation

Legislation recently adopted by the United States Congress provides producers of pandemic vaccines with near-total immunity from civil lawsuits without making individuals injured by those vaccines eligible for compensation through the Vaccine Injury Compensation Program. The unusual decision not to provide an alternative mechanism for compensation is indicative of a broader problem of inconsistency in the American approach to vaccine-injury compensation policy. Compensation policies have tended to reflect political pressures and economic considerations more than any cognizable set of principles. This article identifies a set of ethical principles bearing on the circumstances in which vaccine injuries should be compensated, both inside and outside public health emergencies. A series of possible bases for compensation rules, some grounded in utilitarianism and some nonconsequentialist, are discussed and evaluated. Principles of fairness and reasonableness are found to constitute the strongest bases. An ethically defensible compensation policy grounded in these principles would make a compensation fund available to all individuals with severe injuries and to individuals with less-severe injuries whenever the vaccination was required by law or professional duty.     

Blast injury research models

Blast injuries are an increasing problem in both military and civilian practice. Primary blast injury to the lungs (blast lung) is found in a clinically significant proportion of casualties from explosions even in an open environment, and in a high proportion of severely injured casualties following explosions in confined spaces. Blast casualties also commonly suffer secondary and tertiary blast injuries resulting in significant blood loss. The presence of hypoxaemia owing to blast lung complicates the process of fluid resuscitation. Consequently, prolonged hypotensive resuscitation was found to be incompatible with survival after combined blast lung and haemorrhage. This article describes studies addressing new forward resuscitation strategies involving a hybrid blood pressure profile (initially hypotensive followed later by normotensive resuscitation) and the use of supplemental oxygen to increase survival and reduce physiological deterioration during prolonged resuscitation. Surprisingly, hypertonic saline dextran was found to be inferior to normal saline after combined blast injury and haemorrhage. New strategies have therefore been developed to address the needs of blast-injured casualties and are likely to be particularly useful under circumstances of enforced delayed evacuation to surgical care.     

Heat injury prevention--a military perspective

Heat-related injuries, and specifically exertional heat stroke, are a significant occupational risk in the armed forces, especially for those soldiers who are rapidly deployed from a temperate climate region to hot climate regions. Traditionally, adaptation to heat was considered as a matter of physiological adaptation. It is clear today that these injuries are mostly avoidable when applying proper education and behavioral adaptations. Education on behavioral adaptation for the prevention of heat injuries should be targeted at the individual and the organization level. This article summarizes the issue of proper preventive measures that should be taken to avoid, or at least minimize, the risk of exertional heat related injuries during military operations and training.     

Understanding secondary injury

Secondary injury is a term applied to the destructive and self-propagating biological changes in cells and tissues that lead to their dysfunction or death over hours to weeks after the initial insult (the "primary injury"). In most contexts, the initial injury is usually mechanical. The more destructive phase of secondary injury is, however, more responsible for cell death and functional deficits. This subject is described and reviewed differently in the literature. To biomedical researchers, systemic and tissue-level changes such as hemorrhage, edema, and ischemia usually define this subject. To cell and molecular biologists, "secondary injury" refers to a series of predominately molecular events and an increasingly restricted set of aberrant biochemical pathways and products. These biochemical and ionic changes are seen to lead to death of the initially compromised cells and "healthy" cells nearby through necrosis or apoptosis. This latter process is called "bystander damage." These viewpoints have largely dominated the recent literature, especially in studies of the central nervous system (CNS), often without attempts to place the molecular events in the context of progressive systemic and tissue-level changes. Here we provide a more comprehensive and inclusive discussion of this topic.     

Polyaminen and brain injury

Summary The cerebral ODC/polyamine system is disturbed by brain injury. The main modifications are important increases in ODC activity and putrescine concentration, with minor variations in spermidine and spermine concentrations. A great diversity of stimuli such as cerebral ischemia or overstimulation of the central nervous system by chemical or non-chemical agents can induce polyamine disturbances. Both the contribution of polyamines to the brain damage and their involvement in the repair mechanisms triggered after brain insults have been proposed.     

Avoiding injury and surviving injury: two coexisting evolutionary strategies in lizards

Congenital morphological differences between injured and intact individuals in a population may reflect adaptations to avoid injury, to survive injury, or both. We explore the possible occurrence of such adaptations, analysing the relationship between tail state (original, O; regenerated, R) and morphology (20 scale characters) in 23 taxa of Lacertidae. In some taxa, such as Acanthodactylus opheodurus , morphologies of O and R lizards differed significantly. In these, usually O individuals were morphologically typical (modal), while R individuals were extreme; in others, the contrary occurred. Indices of pattern similarity detected fewer differences between O and R lizards than those based on absolute values. We developed unbiased estimates of classification rates of discriminant analysis. The order of inclusion of characters in the discriminant functions of males and females of the same species differed more than the order for the same sex in other species. Some morphological differences between O and R lizards seem adaptive or linked by pleiotropy to adaptive traits. Congenital morphological differences between O and R lizards are probably more frequent than detected because we show that age and geographical heterogeneity of our samples are confounding factors to O–R differences. R-morphologies might reflect microevolution in favour of paedotypic forms, possibly possessing greater regenerating capacities than relatively more peratypic forms.  © 2003 The Linnean Society of London, Biological Journal of the Linnean Society , 2003, 78 , 307–324.     

Exercise-induced injury to skeletal muscle

Strenuous or unaccustomed exercise can cause injury to skeletal muscle. This paper reviews our understanding of the mechanisms of exercise-induced injury. Measurements of exercise-induced injury have included muscle soreness, increased serum levels of intracellular enzymes, increased lysosomal enzyme activities, structural changes in muscle fibers, and prolonged decreases in force development that cannot be attributed to fatigue. Injury can be induced by exercise of small muscle groups, which suggests that it involves processes localized in skeletal muscles. Exercise of relatively short duration can result in injury, which indicates that long durations of exercise and associated metabolic changes are not necessary for injury to occur. Exercise that involves lengthening contractions results in greater evidence of muscle injury than exercise involving isometric or shortening contractions. Lengthening contractions are associated with higher levels of force and lower metabolic costs per muscle fiber than isometric or shortening contractions. These results suggest that changes in muscle metabolism are not responsible for exercise-induced injury to skeletal muscle. Exercise-induced injury is more likely the result of mechanical disruption of muscle fibers.     

HIV-related neuronal injury

Perhaps as many as 25–50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? this article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp 120 also appear to release arachidonic acid and its metabolites. In addition, interferon-γ (IFN-γ) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-α and IL1-β, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca²⁺ channels andN-methyl-d-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.     

Neurosurgery: head injury

The Scientific Board of the California Medical Association presents the following inventory of items of progress in neurosurgery. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, research workers, or scholars to stay abreast of these items of progress in neurosurgery that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another.The items of progress listed below were selected by the Advisory Panel to the Section on Neurosurgery of the California Medical Association and the summaries were prepared under its direction.     

Noncoding RNAs in acute kidney injury

Acute kidney injury (AKI), caused by various stimuli including ischemia reperfusion, nephrotoxic insult, and sepsis, is characterized by abrupt decline of kidney function. Till now, the molecular mechanisms for AKI have not been fully explored and the effective therapies are still lacking. Noncoding RNAs (ncRNAs), a group of biomolecules function at RNA level, are involved in a wide range of physiopathological processes including AKI. MicroRNAs (miRNAs) are the most extensively studied ncRNAs in AKI. Evidence indicated that miRNAs are altered significantly in various types of AKI. Gain-and-loss-of-function studies demonstrated that miRNAs, such as miR-24, miR-126, miR-494, and miR-687, may bind to the 3′-untranslated region of their target genes to regulate inflammation, programmed cell death, and cell cycle in the injury and repair stages of AKI, indicating their therapeutic potential in AKI. In contrast, functions of long noncoding RNAs and circular RNAs in AKI are hot topics but still largely unknown. Additionally, ncRNAs packaged in exosome can be detected in circulation and urine, they may serve as specific biomarkers for AKI. This review summarized the alteration and functional role of ncRNAs and their therapeutic potential in AKI.     

Therapeutic interventions after spinal cord injury

Spinal cord injury (SCI) can lead to paraplegia or quadriplegia. Although there are no fully restorative treatments for SCI, various rehabilitative, cellular and molecular therapies have been tested in animal models. Many of these have reached, or are approaching, clinical trials. Here, we review these potential therapies, with an emphasis on the need for reproducible evidence of safety and efficacy. Individual therapies are unlikely to provide a panacea. Rather, we predict that combinations of strategies will lead to improvements in outcome after SCI. Basic scientific research should provide a rational basis for tailoring specific combinations of clinical therapies to different types of SCI.     

Neutrophil mediated myocardial injury

• 1.1. Activated polymorphonuclear neutrophils (PMN) were shown to exacerbate ischemic myocardial injury and their activation is modulated by complement system, platelet activating factor, arachidonic acid metabolites, adenosine and nitric oxide.
• 2.2. Mechanisms of injurious PMN effect on ischemic myocardium are related to both mechanical and biochemical processes.
• 3.3. Activated PMN aggregate and adhere to endothelium that results in capillary plugging and subsequent impairment of coronary blood flow as well as participating in the development of endothelial cell edema.
• 4.4. PMN-related biochemical damage of ischemic myocardium is a result of the release of cytotoxic free oxygen radicals and proteolytic enzymes as well as vasoconstrictor leukotriene B4 and leukotoxin.