Increased levels of cytosolic phospholipase A2 in dyslexics.

Research findings are increasingly reporting evidence of physiological abnormalities in dyslexia and sites for dyslexia have been identified on three chromosomes. It has been suggested that genetic inheritance may cause phospholipid abnormalities in dyslexia somewhat similar to those found in schizophrenia. A key enzyme in phospholipid metabolism, Type IV, or cytosolic, phospholipase A2 (cPLA2), releases arachidonic acid (AA), a 20-carbon fatty acid, which is the major source of production of prostaglandins and leukotrienes. An entirely new assay, which for the first time has enabled determination of the amount of the enzyme rather than its activity, was used to measure cPLA2 in dyslexic-type adults and controls and the two groups were found to differ significantly, the dyslexic-types having more of the enzyme. A report elsewhere of schizophrenics having even greater amounts of the enzyme suggests that dyslexia may be on a continuum with schizophrenia, as may be other neurodevelopmental disorders - which have also been described as phospholipid spectrum disorders.

Repeated automated assessment of abstinent male alcoholics: essential fatty acid supplementation and age effects.

A double-blind trial carried out with alcohol-dependent males randomly allocated to n-6 essential fatty acid (EFA) supplementation or placebo capsules over a 6-month period incorporated a battery of automated neuropsychological tests. Results from problem-solving and perceptual motor speed tests are used. The effect that EFA supplementation had on recovery over 6 months of abstinence is shown, as well as the tests in which younger (aged 20-39) alcohol-dependent males differ from the older (aged 40-59) subjects.

The role of essential fatty acids in alcohol dependence and tissue damage.

Evidence for the role of essential fatty acids in alcohol dependence is reviewed. If alcohol-induced tissue damage is associated with impaired fatty acid and phospholipid metabolism, supplements of essential fatty acids might be beneficial in the treatment of alcoholics. The evidence for this effect is examined.

Essential fatty acids, mean cell volume and nuclear magnetic resonance brains of ethanol dependent human subjects.

The relationships between essential fatty acids, mean cell volume and a measure of membrane fluidity from nuclear magnetic resonance scans, T1, are assessed and appear to contradict what would be expected. Our findings indicate poorly functioning membranes and high water content of tissues.

The use of two automated neuropsychological tests, Cogfun and the Perceptual Maze Test, with alcoholics.

Forty-eight male detoxified alcoholics completed the automated neuropsychological tests, Cogfun II and the Perceptual Maze Test. On both tests, the younger group of patients performed better than the older group. No differences were found between short- and long-term drinkers, although there was some indication that older long-term drinkers performed less well than younger long-term drinkers. Control subjects performed significantly better than alcoholic subjects. Thus characteristics found by others using conventional psychometric tests were also apparent when using new, automated tests, and baselines were established from which to measure change over the passage of time.

Localized changes in blood-brain barrier permeability following the administration of antineoplastic drugs.

The effects of four antineoplastic drugs on the permeability of the blood-brain barrier to Evans blue-albumin and to horseradish peroxidase were studied in cats. Extravasation of tracer in brain tissue was observed only rarely following the injection of methotrexate, cyclophosphamide, or vincristine. However, 5-fluorouracil (15 mg/kg) caused localized Evans blue-albumin exudation in various gray and white matter areas in 8 of 13 cats to which the Evans blue was administered 7 hr after the drug injection. Electron microscopy revealed that 5-fluorouracil stimulated pinocytotic vesicular transport of peroxidase across brain capillary endothelial cells and possibly that it widened endothelial tight junctions. Barrier leakage was not observed when time periods longer than 7 hr elapsed between 5-fluorouracil injection and tracer administration, and extravasation occurred only once after a shorter time interval. These results suggest that changes in blood-brain barrier permeability observed 7 hr after 5-fluorouracil administration are reversible and of fairly short duration. Such changes may be relevant to the development of secondary intracranial tumors following antineoplastic chemotherapy.

Prostaglandin-induced effects in the primate cerebral circulation.

The effects of intracarotid infusions of prostaglandins E2 and F2alpha on cerebral blood flow (CBF) and oxygen consumption (CMRO2), and on extracranial blood flow, have been studied in anaesthetisex baboons. The 133Xe clearance method was used for measuring CBF, whilst extracranial blood flow was assessed by both the local tissue injection of 133Xe and external carotid artery flowmetry. Both PGF2alpha and PGE2 (10(-7) and 10(-6) g/kg/min) reduced both CBF and CMRO2. Spasm of the internal carotid artery with PGE2 was noted at the higher dose. Following osmotic opening of the blood-brain barrier by the hypertonic urea technique, the effects of small doses of PGE2 and CBF and CMRO2 were greatly potentiated. PGE2 greatly increased extracranial blood flow. Hence, both PGE2 and PGF2alpha reduce CBF and CMRO2, whilst PGE2 greatly increases extracranial blood flow.

Response of the cerebral circulation in baboons to changing perfusion pressure after indomethacin.

An earlier study has demonstrated that indomethacin, a prostaglandin synthesis inhibitor, blocks the cerebrovascular response to hypercapnia. This response is believed to be mediated by a lowering of pH in the cerebral interstitial fluid. Should autoregulation of cerebral blood flow (CBF) to changing perfusion pressure also be mediated by a changing interstitial pH (the "metabolic" theory), then indomethacin should impair autoregulation. This hypothesis was tested in anesthetized baboons. CBF was measured by the intracarotid 133Xe clearance technique; the preparation and the indomethacin protocol were identical to those of our previous investigation. Arterial pressure was increased by the intravenous infusion of angiotensin and decreased by controlled hemorrhage. Indomethacin was given by continuous infusion into the internal carotid artery. Although it reduced resting CBF, the cerebrovascular response to changing perfusion pressure was unchanged. Because indomethacin affects the response to changing CO2 but not that to changing perfusion pressure, the mechanisms for these two reactions presumably are different and it is improbable that changing interstitial pH is responsible for autoregulation in the cerebral circulation.

The role of baroreceptors and chemoreceptors in the regulation of the cerebral circulation.

1. Ten experiments, each using two dogs, were performed to evaluate the effect of chemoreceptor and baroreceptor activity on the cerebral circulation. 2. The carotid bifurcation areas were vascularly isolated bilaterally and perfused with arterial blood from a second animal. 3. Bilateral vagotomy interrupted stimuli from the aortic group of receptors. 4. Administration of 5% carbon dioxide to the donor animal resulted in an increase in cerebral (cortical) blood flow in the recipient. 5. A change in the arterial perfusion pressure from the donor resulted in a reciprocal change in the cerebral blood flow of the recipient. These changes were abolished by sectioning the sinus nerves.

Factors affecting the cerebrovascular response to noradrenaline in the dog.

1 Noradrenaline infused into the internal carotid artery of the dog (0.01-1 mug kg(-1) min(-1)) constricts the blood vessels of the cortex. This constriction is mediated by the action of noradrenaline on alpha-adrenoceptors of the cerebral arteries.2 Intravenous (1 mug kg(-1) min(-1)) or intra common carotid arterial (0.01-1 mug kg(-1) min(-1)) infusions of noradrenaline cause an increase in cortical blood flow that can be dissociated from changes in blood pressure.3 The effect of intravenous noradrenaline on the cortical blood vessels and metabolism is blocked by high PaCO(2) levels, or by the prior administration of (+/-)-propranolol. (+)-Propranolol is without such effect.4 Following section of both vagi and both sinus nerves, intravenous noradrenaline fails to cause an increase in cortical blood flow.5 In another series of animals the area of the carotid bifurcation was vascularly isolated and perfused with blood from a second dog. Chemoreceptor and baroreceptor activity was shown to be intact.6 Administration of 5% CO(2) to the donor dog caused an increase in cerebral blood flow in the recipient dog.7 Administration of intravenous noradrenaline (1.0 mug kg(-1) min(-1)) to the donor animal caused an increase in cerebral blood flow, cerebral O(2) and glucose utilization of the recipient.8 Administration of 5% CO(2) and intravenous (-)-noradrenaline (1.0 mug kg(-1) min(-1)) caused a further increase in flow and metabolism.9 This evidence suggests that the cerebrovasodilatation observed following intravenous noradrenaline is reflex and is triggered by chemoreceptor activity.10 The evidence also suggests that the antagonism of the cortical dilatory effects of intravenous noradrenaline by raised PaCO(2) in the intact animal must be at a site different from the peripheral chemoreceptors.

Effect of ornithine alpha ketoglutarate on disturbances of brain metabolism caused by high blood ammonia.

The administration of ammonium salts to free ventilated dogs causes an increase in the anaerobic consumption of glucose. Prior and simultaneous administration of the drug ornithine alpha ketoglutarate not only attenuates the rise in blood ammonia but also favourably affects these changes in brain metabolism.