Chemical and biological weapons.
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Biological Warfare↗
Biomedical subjects
A H Lockwood
Publications and source records attributed to A H Lockwood.
Verapamil prevents cerebral acidosis during moderate hypoxia and hypotension.
Carotid ligation and moderate hypoxia in rats causes an increase in the glucose metabolic rate in the caudate-putamen and more widespread reductions in pH. Pretreatment of animals with verapamil did not affect the abnormality of glucose metabolism but abolished the associated acidosis. These data suggest that calcium channel blockade may protect the brain from injury during hypoxic hypoxia by preventing the development of acidosis.
Acidosis↗
Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy.
We measured CBF and the CMRglc in normal controls and in patients with severe liver disease and evidence for minimal hepatic encephalopathy using positron emission tomography. Regions were defined in frontal, temporal, parietal, and visual cortex; the thalamus; the caudate; the cerebellum; and the white matter along with a whole-slice value obtained at the level of the thalamus. There was no difference in whole-slice CBF and CMRglc values. Individual regional values were normalized to the whole-slice value and subjected to a two-way repeated measures analysis of variance. When normalized CBF and CMRglc values for regions were compared between groups, significant differences were demonstrated (F = 5.650, p = 0.00014 and F = 4.58, p = 0.0073, respectively). These pattern differences were due to higher CBF and CMRglc in the cerebellum, thalamus, and caudate in patients and lower values in the cortex. Standardized coefficients extracted from a discriminant function analysis permitted correct group assignment for 95.5% of the CBF studies and for 92.9% of the CMRglc studies. The similarity of the altered pattern of cerebral metabolism and flow in our patients to that seen in rats subjected to portacaval shunts or ammonia infusions suggests that this toxin may alter flow and metabolism and that this, in turn, causes the clinical expression of encephalopathy.
Brain↗
Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy.
Cerebral ammonia metabolism was studied in five control subjects and five patients with severe liver disease exhibiting minimal hepatic encephalopathy. The arterial ammonia concentration in the control subjects was 30 +/- 7 mumol/L (mean +/- SD) and 55 +/- 13 mumol/L in the patients (p less than 0.01). In the normal subjects, the whole-brain values for cerebral blood flow, cerebral metabolic rate for ammonia, and the permeability-surface area product for ammonia were 0.58 +/- 0.12 ml g-1 min-1 0.35 +/- 0.15 mumol 100 g-1 min-1, and 0.13 +/- 0.03 ml g-1 min-1, respectively. In the patients, the respective values were 0.46 +/- 0.16 ml g-1 min-1 (not different from control), 0.91 +/- 0.36 mumol 100 g-1 min-1 (p less than 0.025), and 0.22 +/- 0.07 ml g-1 min-1 (p less than 0.05). The increased permeability-surface area product of the blood-brain barrier permits ammonia to diffuse across the blood-brain barrier into the brain more freely than normal. This may cause ammonia-induced encephalopathy even though arterial ammonia levels are normal or near normal and explain the emergence of toxin hypersensitivity as liver disease progresses. Greater emphasis on early detection of encephalopathy and aggressive treatment of minimal hyperammonemia may retard the development of ammonia-induced complications of severe liver disease.
Adult↗
Metabolic encephalopathy: mechanisms affecting limbic function.
Disorders of metabolism are the most common cause of coma of unknown etiology. Hyperammonemia is important as an etiologic factor in the development of hepatic encephalopathy, operating via direct and indirect mechanisms that affect the function of the limbic system. The entry of ammonia into the brain is controlled by blood-brain pH gradients, and cerebral blood flow, coupled with regional variations in the capillary surface area-permeability product. In the brain, ammonium ions may inhibit the generation of action potentials, by substituting for potassium and sodium in current generation, and interfere with the chloride pump, producing a reversible depolarizing shift of the inhibitory post synaptic equilibrium potential toward the equilibrium potential. Ammonia entering the brain is quickly trapped by the ATP-consuming glutamine synthetase reaction leading to energy depletion in the reticular activating system. Ammonia may also interfere with ATP production due to a suspected inhibition of the malate aspartate shuttle, the mechanism for moving reducing equivalents into mitochondria for oxidative phosphorylation. Ammonia also depletes glutamate, causing a potential disruption of glutamatergic neurotransmission. We recently evaluated the effects of chronic portacaval shunts (PCS) and ammonia on regional brain glucose metabolism using the 14C-deoxyglucose technique and found important direct and indirect effects on the limbic system. After a PCS, glucose metabolism was significantly increased in all 20 brain regions that were sampled, with the smallest increase in the cortex and the greatest increase in the reticular activating system. The pattern of glucose metabolism appeared to be different in the two groups, an impression that was confirmed by multivariate statistical analytical techniques.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
Medical problems of musicians.
Surveys of performing musicians indicate that almost half of them experience playing-related medical problems, some of which threaten or end their careers. Overuse injuries involving the muscle--tendon unit are the most common problem, with symptoms ranging from mild pain while the musician is playing to pain severe enough to preclude any use of the affected hand. String players are the most commonly affected, and percussionists the least. The most important predisposing characteristic is the use of repetitive movements during long hours of practice, but awkward body positions mandated by the shape and weight of the instrument, the technical difficulty of the repertoire, and unfamiliar instruments may also play a part. Women are more commonly affected than men. Rest is the cornerstone of therapy. Neural impingement syndromes affecting the median or ulnar nerves or the thoracic outlet affect many musicians. Focal dystonias may involve part or all of a hand or the muscles forming the embouchure (the position of the lips in wind players). These are very resistant to therapy and may terminate or drastically alter a career. Stress, especially performance anxiety, may impede performance. Beta-adrenergic blocking agents prevent the symptoms of performance anxiety and are frequently used by musicians without medical supervision. A recognition of the unique problems of musician-patients has led to the formation of successful specialty clinics in a number of cities.
Female↗
Glucose metabolism and acidosis in the metabolic penumbra of rat brain.
The characterization of tissue acid-base status related to the penumbral zone of increased glucose consumption surrounding a focal cerebral ischemic lesion may suggest therapeutic techniques to maximize tissue survivability from stoke. We measured local cerebral metabolic rate for glucose (1 CMRglc) and an index of brain tissue pH (pHt) concurrently and characterized their interaction in a model of focal cerebral ischemia in rats in a double-label autoradiographic study, using [14C]2-deoxyglucose and [14C]dimethyloxazolidinedione. Computer-assisted digitization and analysis permitted the simultaneous quantification of the two variables on a pixel-by-pixel basis in the same brain slices. Hemispheres ipsilateral to intravascular tamponade-induced middle cerebral artery occlusion showed areas of normal, depressed, and elevated glucose metabolic rate (as defined by an interhemispheric asymmetry index) after 2 hr of ischemia. Regions of increased 1 CMRglc showed moderate acidosis (6.87 +/- 0.05), while regions of normal glucose metabolic rate showed normal pHt (pH +/- SD = 6.98 +/- 0.05) and regions of decreased 1 CMRglc showed severe acidosis (6.69 +/- 0.11). A repeated-measures analysis of variance found these values to differ from each other at the P less than 0.0005 significance level. The finding of moderate acidosis coupled with increased 1 CRMglc in the metabolic penumbra suggests that the excess protons may result from the anaerobic dissociation of ATP synthesis and hydrolysis.
Adenosine Triphosphate↗
Effects of moderate hypoxemia and unilateral carotid ligation on cerebral glucose metabolism and acid-base balance in the rat.
We used our recently developed method for the simultaneous measurement of the local CMRglc (LCMRglc) and composite tissue pH to evaluate the response to unilateral carotid ligation and moderate hypoxia [40.1 +/- 4.8 (SD) mm Hg]. The LCMRglc and tissue pH were measured simultaneously in brain slices using [14C]2-deoxy-D-glucose and [14C]5,5-dimethyl-2,4-oxazolidinedione. The ipsilateral LCMRglc was increased significantly in the caudate-putamen and medical thalamus and was surrounded by a much more extensive zone of acidosis, as shown by significant reductions in the tissue pH, which was affected in parietal cortex, caudate-putamen, lateral septal nucleus, medial geniculate, Ammon's horn, and nucleus reticularis of substantia nigra. In regions with an elevated LCMRglc and acidosis, anaerobic glycolysis combined with ATP hydrolysis are likely to co-exist. In regions characterized by normal glucose metabolism and acidosis, we hypothesize that a direct effect of hypoxia on the sodium/hydrogen ion antiporter may lead to secondary acidosis. Disturbed acid-base balance during hypoxia may have an adverse effect on cerebral function and cause clinical symptoms.
Acid-Base Equilibrium↗
Neurologic complications of renal disease.
Renal failure and its treatment are associated with a number of neurologic complications that must be differentiated from the nervous system complications of the disease leading to renal failure. Uremic encephalopathy is characterized by clinical signs of depressed brain function coexisting with excitation, often in the form of generalized epileptic seizures. Peripheral neuropathy, due to axonal involvement, is common and is characterized by ascending sensory and motor dysfunction. The treatment of renal failure also may lead to the development of neurologic abnormalities in the form of dialysis disequilibrium characterized by headache, nausea, irritability that may progress to seizures, coma, and death, which is caused by the entry of free water into the brain and swelling. Dialysis dementia, caused by the toxic effects of aluminum, is now rare. Renal transplant recipients may develop cerebrovascular disease, infections by opportunistic organisms, or malignant neoplasms, particularly primary lymphoma of the brain. As transplant recipients live longer and more operations are performed, additional complications may be seen in the future.
Brain Diseases↗
Brain extraction of a calcium channel blocker.
Dihydropyridine calcium channel blockers may be effective treatment for acute cerebral ischemia, but the uptake of these drugs into the brain is unknown. A 0.2-ml bolus of [14C]nicardipine hydrochloride and [3H]water was injected into the common carotid arteries of 7 normal and 7 ischemic rats. The corrected first-pass extraction of nicardipine, compared to water, was calculated to be 30.7% into the hemispheres and 42.3% into the hippocampi. The uptake was greater into the ischemic hemispheres (p less than 0.001). These data suggest that dihydropyridines are available to binding sites and calcium channels in neurons.
Animals↗
Cellular signal transduction and the reversal of malignancy.
Animal cells contain only a few defined molecular systems that transduce hormonal and growth signals from the external environment to the intracellular milieu to regulate cellular growth and differentiation. Among the most ubiquitous of these "second messenger" pathways are those utilizing cyclic AMP and phosphatidylinositide turnover. The former activates protein kinase A, while the latter leads to the activation of protein kinase C and mobilization of intracellular calcium. Lesions induced by oncogenes in signal transduction systems may be responsible for the cancerous transformation of cells. In many tumor cell lines, including some transformed by the ras and sis oncogenes, activation of protein kinase A by elevation of cyclic AMP or activation of protein kinase C by addition of phorbol esters can restore many normal aspects of growth and morphology. Such "reverse transformation" is accompanied by the phosphorylation of unique cellular proteins and alterations in the phosphoinositide cycle. Molecular mechanisms by which activation of signal transduction systems can attenuate the malignant phenotype are considered in the context of cellular growth and differentiation.
Animals↗
Simultaneous double-isotope autoradiographic measurement of local cerebral glucose metabolic rate and acid-base status in rat brain.
We developed a double-isotope autoradiographic method for the simultaneous measurement of the local cerebral metabolic rate for glucose (1CMRG) and index of regional acid-base status (rABI) in single brain slices using [2-14C]deoxy-D-glucose (DG) and 5,5-dimethyl-[2-14C]oxazolidine-2,4,dione (DMO). After iv isotope administration, paper chromatography separates plasma DMO from DG activity using a methanol-methylene chloride solvent system. Initial tissue autoradiograms depict regional DMO plus DG and DG metabolite distribution. After 14 days in a well-ventilated hood, 97.5 +/- 0.5% of all DMO is lost from tissue sections by sublimation, and a second autoradiogram depicts DG plus DG metabolite distribution. Retention of brain lipids does not alter beta-particle self-absorption, avoiding problems associated with isotope extraction with solvents. Autoradiograms are digitized and converted to isotope-content images. The second autoradiogram is used for 1CMRG computation. After subtracting the second regional isotope-content value from the first, the DMO content is obtained and used to compute rABI. Application of this method to normal animals yields expected values for 1CMRG and rABI. This method is amenable to whole-slice digitization and creation of functional images of 1CMRG and ABI followed by pixel-by-pixel correlations of the two variables, making this a potentially valuable tool for the investigation of the relationships between glucose metabolism and brain acid-base balance.
Acid-Base Equilibrium↗
Metabolic encephalopathies: opportunities and challenges.
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Ammonia↗
Hepatic encephalopathy: experimental approaches to human metabolic encephalopathy.
Derangements in systemic metabolism are probably the most frequent cause of coma of unknown etiology. Within this group, coma due to liver failure is common. Systematic research into the mechanisms that underlie the development of hepatic coma is a topic that has interested investigators of as many backgrounds as there are theories that seek to explain the development of the disorder. This review seeks to summarize relevant basic science and clinical literature that focuses on potential etiological mechanisms. In the sections on actions of toxins including ammonia, mercaptans, and fatty acids, and descriptions of altered levels of plasma amino acid levels and abnormalities of neurotransmitter pharmacology, a complex pattern of interrelationships emerges. Discussions of ammonia inevitably require analysis of other seemingly unrelated topics, suggesting strongly that hepatic encephalopathy is indeed the multidimensional problem that might be suspected to follow disorders of this central organ of intermediary metabolism and digestion. The recent development of new technical and statistical methodology has started to make it possible to consider the impact of multiple isolated and seemingly unrelated abnormalities on patterns of functional interaction within the brain. These global aspects of brain function form the essential basis for the understanding of this fascinating disorder.
Animals↗
Nuclear weapons and nuclear war: implications for Texas physicians.
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Nuclear Warfare↗
Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy.
The regional cerebral metabolic rate for glucose was measured in normal and portacaval shunted rats and the effects of unilateral carotid infusions of "threshold" amounts of ammonia were assessed. 8 wk after shunting the glucose metabolic rate was increased in all 20 brain regions sampled. Effects on subcortical and phylogenetically older regions of the brain were most pronounced with a 74% increase observed in the reticular formation at the collicular level. Increases in the cerebral cortex ranged from 12 to 18%. Unilateral infusions of ammonia did not affect behavior but altered the electroencephalogram and selectively increased the glucose metabolic rate in the thalamus, hypothalamus, and substantia nigra in half of the animals, a pattern similar to that seen after a portacaval shunt, suggesting hyperammonemia as the cause of postshunt increases in glucose metabolism. Visual inspection of autoradiograms, computed correlation coefficients relating interregional metabolism, and principal component analysis suggest that normal cerebral metabolic and functional interrelationships are altered by shunting. Ammonia stimulation of the hypothalamic satiety centers may suppress appetite and lead to cachexia. Reductions in the ammonia detoxification capacity of skeletal muscle may increase the probability of developing future episodes of hyperammonemia, perpetuating the process. Direct effects of ammonia on specific brain centers such as the dorsomedial hypothalamus and reticular activating system may combine with global disruptions of cerebral metabolic-functional relationships to produce the protean manifestations of portal-systemic encephalopathy.
Acetates↗
Invasiveness in studies of brain function by positron emission tomography (PET).
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Blood Specimen Collection↗
Effects of acetazolamide and electrical stimulation on cerebral oxidative metabolism as indicated by the cytochrome oxidase redox state.
The intravenous administration of acetazolamide to rats caused a prompt oxidation of cytochrome a,a3 that was associated with an increase in the rate at which this cytochrome underwent additional oxidation and reductive recovery after electrical stimulation of the cerebral cortex. These effects were not observed in animals made hypercapnic after ventilation with 5% CO2. The speed with which these and other metabolic and physiological events occur, after administering the drug, suggests that acetazolamide exerts its effects by complex mechanisms and that the site of action may be in the region of the blood-brain barrier, an area rich in carbonic anhydrase, and noradrenergic innervation.
Acetazolamide↗