I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Background and Purpose—The authors present an overview of the current evidence and management recommendations for evaluation and treatment of adults with acute ischemic stroke. The intended audienc...

/pdf/guidelines-for-the-early-management-of-patients-with-acute-19udbft6e7.pdf

Guidelines for the Early Management of Patients With Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

To develop a simple, relatively noninvasive small-animal model of reversible regional cerebral ischemia, we tested various methods of inducing infarction in the territory of the right middle cerebral artery (MCA) by extracranial vascular occlusion in rats. In preliminary studies, 60 rats were anesthetized with ketamine and different combinations of vessels were occluded; blood pressure and arterial blood gases were monitored. Neurologic deficit, mortality rate, gross pathology, and in some instances, electroencephalogram and histochemical staining results were evaluated in all surviving rats. The principal procedure consisted of introducing a 4-0 nylon intraluminal suture into the cervical internal carotid artery (ICA) and advancing it intracranially to block blood flow into the MCA; collateral blood flow was reduced by interrupting all branches of the external carotid artery (ECA) and all extracranial branches of the ICA. In some groups of rats, bilateral vertebral or contralateral carotid artery occlusion was also performed. India ink perfusion studies in 20 rats documented blockage of MCA blood flow in 14 rats subjected to permanent occlusion and the restoration of blood flow to the MCA territory in six rats after withdrawal of the suture from the ICA. The best method of MCA occlusion was then selected for further confirmatory studies, including histologic examination, in five additional groups of rats anesthetized with halothane. Seven of eight rats that underwent permanent occlusion of the MCA had resolving moderately severe neurologic deficits (Grade 2 of 4) and unilateral infarcts averaging 37.6 +/- 5.5% of the coronal sectional area at 72 hours after the onset of occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversible middle cerebral artery occlusion without craniectomy in rats.

— A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2-deoxy-D-[14C]glucose ([14C]DG) as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose-6-phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2-chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.

The method has been applied to normal albino rats in the conscious state and under thiopental anesthesia. The results demonstrate that the local rates of glucose consumption in the brain fall into two distinct distributions, one for gray matter and the other for white matter. In the conscious rat the values in the gray matter vary widely from structure to structure (54-197 μmol/100 g/min) with the highest values in structures related to auditory function, e.g. medial geniculate body, superior olive, inferior colliculus, and auditory cortex. The values in white matter are more uniform (i.e. 33–40 μmo1/100 g/min) at levels approximately one-fourth to one-half those of gray matter. Heterogeneous rates of glucose consumption are frequently seen within specific structures, often revealing a pattern of cytoarchitecture. Thiopental anesthesia markedly depresses the rates of glucose utilization throughout the brain, particularly in gray matter, and metabolic rate throughout gray matter becomes more uniform at a lower level.

The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat.

Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.

Role of free radicals and catalytic metal ions in human disease: an overview.

COMPLETE ARREST of the cerebral circulation leads within seconds to cessation of neuronal electrical activity and within a few minutes to deterioration of the energy state and ion homeostasis. Depletion of high energy phosphates, membrane ion pump failure, efflux of cellular potassium, influx of sodium, chloride and water, and membrane depolarization occur swiftly. If such chaos persists for longer than 5-10 minutes, irreversible cell damage is likely. Such is the inevitable sequence of events if blood flow to the brain is arrested. If, however, the ischemia is incomplete the outcome is more difficult to predict and is largely dependent on residual perfusion and oxygen availability. It is in large measure the outcome of incomplete cerebral ischemia, which is of particular interest in cerebrovascular disease. With occlusion of a cere-bral vessel and signs of acute stroke, ischemia is hardly ever total. Some residual perfusion persists in the ischemic area dependent on collateral vessels and local perfusion pressures. Recent evidence indicates that immediate failure of basic functions such as synaptic transmission, ion pumping and energy metabolism in the ischemic brain, is critically dependent on residual blood flow, and that these functions fail at certain critical flow thresholds. It appears, further, that the development of infarction is critically correlated to residual per-fusion, and there is a lethal threshold of residual blood flow below which tissue infarction develops after a certain time. Such knowledge provides the theoretical background for application of the instrumentation now being developed for repeated non-invasive 3-dimensional imaging of residual flow in the ischemic brain. By these means one hopes it will become possible to conduct treatment and to evaluate prognosis in the acute stroke patient by reproducible repeatable measurement in man. In man, flattening of the EEG occurs immediately if hemispheric flow falls below 0.16-0.17 ml-g^min 1 as evidenced by measurements of cerebral blood flow and EEG during clamping of one carotid artery in end-arterectomy. 1-* The critical relationship between cere-bral electrical activity and blood flow which such clinical observation suggested has been amply proven in exDerimental studies. Svmon and Branston and co-workers' demonstrated that the evoked somato-sensory potential recorded in baboon cortex was abolished at local flows below about 0.15 ml'gr^mirr 1. This flow level could be regarded as critical in the sense that electrical function in the cortex was abolished below but sustained above this level. It has, therefore, been referred to as the flow threshold of electrical …

Thresholds in cerebral ischemia - the ischemic penumbra.

All cells in living organisms have a limited life span, and when the time set by their biological clocks has run out, they will die , their highly orga­ nized macromolec ular structure will disintegrate, and the low-molec ul ar degrad ation products be­ come part of the disorder of the surroundings . In thermodynamic terms, this series of events consti­ tutes what has been c alled the entropic doom. We know little about those molec ul ar mechanisms that limit the life span of cells in the absence of dise ase. For the clinician, therefore, the important task is to prevent or tre at dise ases that jeopardize the proper functioning and viability of cells whose biologic al clocks have not yet run out . Measures instituted to prevent brain cell death have a special importance . This i s partly due t o the fact that w e equate human life with the functioning of the brain. However, this importance also resides in the v ulnerability of brain cells to conditions that allow cells of most other tissue to survive , and to continue or res ume their activitie s . The clinically most important conditions leading to brain cell death are those associated with cere­ brovascul ar dise ase, particularly stroke, and with head trauma. We will begin, though, by rec alling the traditional view of the occ urrence and loc alization of neuronal damage in four conditions that lead to more disseminated alterations, e specially since they have been considered to c ause nerve cell injury of a

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1981.18

Cell Damage in the Brain: A Speculative Synthesis

It has been commonly assumed that calcium, which normally serves important functions as a membrane stabilizer, metabolic regulator, and sec­ ond messenger, also can mediate anoxic and toxic cell death (Schanne et aI., 1979; Farber, 1981; Trump et aI., 1981). It is then postulated that when the plasma membrane becomes unduly permeable to calcium, the free cytosolic concentration (Ca2+) rises to toxic levels. As applied to the brain, this hypothesis predicts that loss of cellular calcium ho­ meostasis underlies selective neuronal vulnerability in ischemia, hypoglycemia, and epileptic seizures (Siesj6, 1981; Meldrum, 1983; Raichle, 1983; for further literature, see Siesj6 and Wieloch, 1985; Siesj6, 1988). It should be clearly understood that ischemia, particularly if dense, causes all cells to loose their calcium homeostasis. The hypothesis predicts, therefore, that some cells are more vulner­ able than others because they have a higher density of calcium channels in their plasma membranes. Presumably, this could lead to untolerable local in­ creases in calcium concentration. In a recent extension of the calcium hypothesis, it was speculated that increased calcium cycling across ischemia-damaged membranes leads to a sustained rise in Ca2 + j and slow calcium overload of mitochondria, thereby causing delayed neuronal death (Deshpande et aI., 1987; see also Martins et aI., 1988). Dux et aI. (1987), inducing transient isch­ emia in the gerbil, recently assessed the time course of mitochondrial calcium deposits in glia cells and in pyramidal cells of the hippocampus CAl sector and

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1989.20

Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis.

✓ 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.

The density and distribution of brain damage after 2-10 min of cerebral ischemia was studied in the rat. Ischemia was produced by a combination of carotid clamping and hypotension, followed by 1 week recovery. The brains were perfusion-fixed with formaldehyde, embedded in paraffin, subserially sectioned, and stained with acid fuchsin/cresyl violet. The number of necrotic neurons in the cerebral cortex, hippocampus, and caudate nucleus was assessed by direct visual counting. Somewhat unexpectedly, mild brain damage was observed in some animals already after 2 min, and more consistently after 4 min of ischemia. This damage affected CA4 and CA1 pyramids in the hippocampus, and neurons in the subiculum. Necrosis of neocortical cells began to appear after 4 min and CA3 hippocampal damage after 6 min of ischemia, while neurons in the caudoputamen were affected first after 8-10 min. Selective neuronal necrosis of the cerebral cortex worsened into infarction after higher doses of insult. Damage was worst over the superolateral convexity of the hemisphere, in the middle laminae of the cerebral cortex. The caudate nucleus showed geographically demarcated zones of selective neuronal necrosis, damage to neurons in the dorsolateral portion showing an all-or-none pattern. Other structures involved included the amygdaloid, the thalamic reticular nucleus, the septal nuclei, the pars reticularis of the substantia nigra, and the cerebellar vermis.

Bo K. Siesjö

Papers

Thresholds in cerebral ischemia - the ischemic penumbra.

Cell Damage in the Brain: A Speculative Synthesis

Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis.

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

The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia