This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells "at risk," these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis. Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl-, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH. In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interfers with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++. A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.

Pathophysiology and treatment of focal cerebral ischemia: Part I: Pathophysiology

The cation conductance activated upon hyperpolarization of the membrane beyond the resting value appears to represent an ubiquitous type of membrane channel. Our understanding of the respective membrane current, termed Ih, in neurons has matured from that of a "queer" current toward that of a highly regulated mechanism that is particularly important in determining integrative behavior near rest and providing the pacemaker depolarization during rhythmic-oscillatory activity.

QUEER CURRENT AND PACEMAKER: The Hyperpolarization- Activated Cation Current in Neurons

✓ The mechanisms that give rise to ischemic brain damage have not been definitively determined, but considerable evidence exists that three major factors are involved: increases in the intercellular cytosolic calcium concentration (Ca++i), acidosis, and production of free radicals. A nonphysiological rise in Ca++i due to a disturbed pump/leak relationship for calcium is believed to cause cell damage by overactivation of lipases and proteases and possibly also of endonucleases, and by alterations of protein phosphorylation, which secondarily affects protein synthesis and genome expression. The severity of this disturbance depends on the density of ischemia. In complete or near-complete ischemia of the cardiac arrest type, pump activity has ceased and the calcium leak is enhanced by the massive release of excitatory amino acids. As a result, multiple calcium channels are opened. This is probably the scenario in the focus of an ischemic lesion due to middle cerebral artery occlusion. Such ischemic tissues ca...

Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment.

tance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermiainduced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (<30°C), moderate hypothermia does not induce arrhythmias; indeed, the evidence suggests that arrhythmias can be prevented and/or more easily treated under hypothermic conditions. Conclusions: Therapeutic hypothermia is a highly promising treatment, but the potential side effects need to be properly managed particularly if prolonged treatment periods are required. Understanding the underlying mechanisms, awareness of physiological changes associated with cooling, and prevention of potential side effects are all key factors for its effective clinical usage. (Crit Care Med 2009; 37[Suppl.]:S186 –S202)

https://emcrit.org/wp-content/hypoarts/polderman%20mechs%20of%20hypothermia.pdf

Mechanisms of action, physiological effects, and complications of hypothermia.

Around 1970, Fleckenstein postulated that cardiac muscle damage following ischemia or excessive stimulation with catecholamines was due to calcium entry and mitochondrial calcium overload (e .g . , REF. 1). Somewhat later, a similar hypothesis was advanced to explain cell necrosis in dystrophic skeletal muscle.2 It soon emerged that lethal calcium influx could occur, not only via voltage-sensitive calcium channels (VSCCs), but also via those operated by agonists (AOCCS).~ Subsequently, Schanne et al.4 suggested that liver cell damage due to a variety of toxins was mediated by calcium influx (see also REF. 5). These various hypotheses of calcium-related cell necrosis thus have in common the assumption that cell calcium homeostasis is upset by enhanced influx inlo the cell, the routes of entry varying with the condition. Brain damage usually occurs in one of two forms: selective neuronal vulnerability, affecting groups of neurons with a characteristic distribution within the brain, and infarction or pan-necrosis, affecting not only neurons but also glial cells and vascular elements. When it was originally thought that selective neuronal vulnerability in ischemia, hypoglycemia, and status epilepticus is a calcium-related phenomenon, it was tacitly assumed that calcium entered through VSCCs in the apical dendrites of vulnerable (burst-firing) neurons.6 It was soon reported that, following a transient ischemic insult, both net calcium accumulation and neuronal necrosis may be considerably delayed (see REF. 7). Since calcium accumulation seemed to precede light microscopical evidence of cell necrosis, the hypothesis was advanced that increased calcium cycling across damaged membranes causes gradual mitochondrial overload and, after varying delays, cell necrosis.8 However, although this may be one of the mechanisms involved, the gen'eral consensus is that some of the most important consequences of a disordered calcium homeostasis are activation of lipases, proteases, and endonucleases (see REFS. 6,9-12 and, for corresponding data on liver tissue, 13,14). Although doubts have been raised that calcium is an obligatory mediator of anoxic (or toxic) cell death, 1 5 , 1 6 recent results strongly indicate that necrosis of neurons, exposed to anoxia or excitotoxins, is calcium-mediated.'7-'9 In fact, it now seems likely that anoxic neuronal damage, at least in part, represents an excitotoxic lesion caused by enhanced

Calcium, Excitotoxins, and Neuronal Death in the Braina

Our objectives were to study the loss of heat from ischemic brain and to devise a method of maintaining brain temperature. Reversible forebrain ischemia was induced by carotid clamping and exsanguination in 30 anesthetized and artificially ventilated rats. Rectal, skull, and brain temperatures were measured, confirming previous findings that brain temperature falls by 4-5 degrees C during 15 minutes of ischemia unless measures are taken to maintain head temperature by external heating. Temperature gradients developed within the ischemic brain, superficial tissues being cooler than deep ones. These temperature gradients were reversed when skull temperature was maintained at core body (rectal) temperature by external heating. With rectal and skull temperatures maintained at 38 degrees, 37 degrees, 35 degrees, or 33 degrees C, brain temperatures nonetheless decreased by approximately 1 degree C during ischemia. This decrease in brain temperature could be prevented by placing the rat in a Plexiglas box with circulating air at temperatures close to that of the body core and a relative humidity of approximately 100%. We also found that, unless special precautions are taken, a temperature gradient develops between the brain and body core during recirculation.

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.21.5.758

Preservation of brain temperature during ischemia in rats.

https://lup.lub.lu.se/search/ws/files/5200662/1484091.pdf

Schizophrenia in Medline 1950-2006: a bibliometric investigation.

Most reviews of patients who have had subarachnoid bleeding are concerned mainly with the mortality and its relation to the incidence of aneurysms and recurrent haemorrhage (e.g. Tappura 1962). Permanent sequelae in survivors have received relatively little attention in the literature. A complication that has attracted more attention in rccent years is hydrocephalus (Sfrauss e f al . 1932, Folfz & Ward 1956, Shulman e f al. 1963), probably because of the improved methods now available for the treatment of this condition. This paper deals with the frcquency and symptoms of hydrocephalus as a complication of subarachnoid haemorrhage.

Sequelae after spontaneous subarachnoid haemorrhage, with special reference to hydrocephalus and korsakoff's syndrome

The growth of the literature on eating disorders during four decades is described, especially the development of literature on bulimia. The study is based on a database, ED40, that contains more than 14,000 references to articles on ED from 1960 to 1999. The references were imported from Medline(R) and PsycINFO(R). A broad search method included articles on the physiology of hunger and satiety. The main data, of the analysis are the total number of references per year, and the percentage of references per year that contain certain words or phrases. Over the 40 years an almost 27-fold increase has occurred in the number of references in ED40, while the increase in Medline is about 4-fold. A study of the relative increase shows a recent stagnation of the growth in the ED literature. The clinical emergence of bulimia nervosa and some epidemiological findings are discussed in relation to the increase of literature on bulimia. Copyright (C) 2002 John Wiley & Sons, Ltd and Eating Disorders Association. (Less)

Literature on eating disorders during 40 Years: increasing number of papers, emergence of bulimia nervosa

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