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Biomedical subjects

E F Ellis

Publications and source records attributed to E F Ellis.

At least 73 records · Page 4Linked to original sources
PubMed1989

Increased plasma PGE2, 6-keto-PGF1 alpha, and 12-HETE levels following experimental concussive brain injury.

Previous investigations have shown that brain prostaglandin levels are transiently elevated following experimental fluid percussion brain injury. Associated with these increased prostaglandin levels there is free radical production and abnormalities in cerebral arteriolar function. The purpose of this study was to determine whether experimental fluid percussion brain injury in cats is associated with increased systemic levels of prostaglandins and the lipoxygenase product, 12-HETE. Blood samples were collected before and at various periods of time after 2.7 atm of fluid percussion brain injury was produced in adult cats. Prostaglandin and 12-HETE analysis was performed by radioimmunoassay after extraction of the plasma samples. The control levels for 6-keto-PGF1 alpha, PGE2, and 12-HETE were 477 +/- 42, 2,372 +/- 431, and 13,328 +/- 1,769 pg/ml, respectively. Following injury all three eicosanoids reached peak plasma levels by 1-5 min after injury. The percentile increases for all eicosanoids were similar and increased from 70 to 110%. The increases were sustained at up to 30 min postinjury and by 1 h after injury were at control levels. As in previous studies, hypertension following injury was maximal by 1 min postinjury and blood pressure had returned to near normal levels by 5 min postinjury. These studies demonstrate prolonged systemic increases in eicosanoids following injury. Since free radical production and vascular damage occur concomitantly with eicosanoid production, the prolonged increases in these products suggest that there is an attainable therapeutic window following injury during which administration of free radical scavengers may decrease radical damage and reduce the consequences of injury.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1989

Laser-Doppler assessment of brain microcirculation: effect of systemic alterations.

There is a need for new technical approaches whereby the cerebral microcirculation can be easily and continuously assessed. The objective of this study was to determine whether laser-Doppler (LD) flowmetry can be utilized to assess changes in cerebral cortical blood flow and to determine whether changes in blood perfusion measured by LD flowmetry correlate with simultaneously measured changes in flow measured by H2 clearance in cats or with changes in pial arteriolar diameter measured with a microscope in rabbits equipped with a closed cranial window. In the rabbit experiments a 0.84-mm-diam LD probe was inserted through a cranial window port, and in the cat experiments the probe was fixed adjacent to the H2 probe. The probe was fixed at a distance of 1-2 mm from the cortical surface, where it and its associated electronics detect changes in blood cell velocity and blood volume within a tissue volume of approximately 1 mm3. Volume and velocity are multiplied to provide a flow signal. When cerebral blood flow in cats was decreased by hyperventilation-induced hypocapnia and increased by norepinephrine-induced hypertension, the percent changes in LD flow and H2 clearance flow changed linearly (r = 0.94, slope = 0.97). When arterial PCO2 was increased from 28 to 48 mmHg in the rabbit experiments, the pial arterioles dilated 19 +/- 4% (mean +/- SE) and LD flow increased by 74 +/- 9%, LD flow changes which would be predicted by a third power relationship of diameter to flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Laser-Doppler assessment of brain microcirculation: effect of local alterations.

The objective of this study was to determine whether changes in blood perfusion measured by laser-Doppler (LD) flowmetry correlate with simultaneously measured changes in pial arteriolar diameter after local application of vasoactive agents on the brain surface. A closed cranial window was implanted in anesthetized rabbits. A 0.84-mm-diam LD probe was inserted through one window port and fixed at a distance of 1-2 mm from the cortical surface. The probe detects changes in perfusion within a tissue volume of approximately 1 mm3. The diameter of pial arterioles in the area adjacent to the LD probe was simultaneously measured with a microscope and image-splitting device. Topical application of bradykinin (80 nM to 8 microM), which stimulates the formation of dilator prostaglandins and O2 radicals, induced a dose-dependent arteriolar dilation and increase in LD flow. Topical application of 33 microM 2-chloroadenosine, a stable analogue of adenosine, induced the same degree of pial arteriolar dilation as 8 microM bradykinin but produced a much larger increase in LD flow, probably due to its greater tissue penetration and stability. At 5 min after bradykinin washout the arterioles had nearly returned to their control diameter, whereas LD flow was still increased. Similarly, there was a discrepancy between LD flow and diameter changes after washout of 2-chloroadenosine. We conclude that LD flowmetry is a useful technique for continuous assessment of cortical blood flow in response to topically applied agents.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Chloroadenosine↗
PubMed1989

Brain kininogen following experimental brain injury: evidence for a secondary event.

Previous studies have shown that following experimental brain injury cerebral arterioles dilate and display endothelial lesions and reduced responsiveness to hypocapnia. These abnormalities are caused by cyclo-oxygenase-dependent free radical generation. There is evidence that the kallikrein-kinin system may in part stimulate the cyclooxygenase-dependent damage since bradykinin is a powerful stimulator of prostaglandin formation and it has recently been shown that a specific kinin receptor blocker decreases the arteriolar abnormalities caused by injury. In order to further examine the hypothesis that the kallikrein-kinin system is important in inducing damage, rat brain tissue was examined for kininogen, the precursor of kinins, at 10 minutes and 1, 3, 6, 15, 24, 48, and 72 hours after injury. A fluid-percussion brain injury device was attached over the right cerebral cortex of rats and a 1.6-atmosphere pressure injury was administered. The kininogen content was determined by a radioimmunoassay procedure in tissues which were free of intravascular blood. After injury, bleeding was confined mainly to the right hemisphere. The kininogen content in the right hemisphere was significantly elevated by one hour after injury, continued to rise until 15 hours after injury, then was significantly decreased by 2 days after injury. In the left hemisphere, kininogen was significantly elevated at 1 hour postinjury, returned toward control levels over the 3- to 6-hour period after injury, then was again elevated at 15 hours after injury. These studies also show that brain water and cerebrovascular permeability were greater at 15 hours postinjury than at earlier time points. The data further support a role for the kallikrein-kinin system in brain injury and, when considered with the results of other studies, suggest that a secondary event is occurring in the 12- to 24-hour period after neural injury. The authors hypothesize that this secondary event is related to endothelial and vascular repair and may be important for the return of normal cerebrovascular function.

Animals↗
PubMed1988

In vivo effects of theophylline on diaphragm, bicep, and quadricep strength and fatigability.

Aminophylline has been demonstrated to increase in vitro contractility in skeletal muscle, including diaphragm. In vivo studies report significant increases in diaphragm contractility in patients with chronic obstructive pulmonary disease but only small increases in control subjects. The present study determined the effects of aminophylline on strength and fatigability in the diaphragm, the biceps brachii, and the quadriceps of normal individuals. Seven healthy subjects were tested with placebo and drug conditions on separate days in a randomized, double-blind fashion. Mean theophylline levels of 15 +/- 2 mg/L SD were maintained by constant intravenous infusion. Strength of the diaphragm was measured as maximum inspiratory pressure. Strength of the biceps and quadriceps were measured isometrically during arm flexion (90 degrees) and leg extension (115 degrees) against an electronic load cell. Fatigue was measured as the decrease in tension during a 30-second contraction and during a 6-minute period of alternating 5-second maximal contraction and 5-second rest. Therapeutic levels of theophylline had no effect on strength or fatigability during a maximal contraction in any muscle group studied.

Adult↗
PubMed1988

Asthma: current therapeutic approach.

This article discusses the goals of asthma therapy, treatment of the acute exacerbation, and day-to-day management. The importance of early pharmacologic intervention is emphasized. In 1988, the need to hospitalize a child with asthma often represents failure of ambulatory management.

Acute Disease↗
PubMed1988

Kinins induce abnormal vascular reactivity.

Previous studies have shown that after experimental neural trauma or acute hypertension the brain produces superoxide anion radicals, and brain arterioles display endothelial lesions, dilation, and loss of normal reactivity in response to a decrease in CO2 tension. Because these abnormalities are prevented by pretreatment with free radical scavengers or inhibitors of the cyclooxygenase component of prostaglandin (PG) H synthase, arachidonic acid metabolism by PGH synthase with concomitant formation of tissue injuring oxygen radicals causes the vascular damage. The purpose of the present experiments was to determine whether kinins, which are known to stimulate arachidonate metabolism and to induce cerebral arteriolar dilation via production of superoxide anion, may be involved in initiating the cerebrovascular abnormalities produced by neural trauma in cats. The diameter and reactivity of untreated in vivo pial arterioles on one cerebral cortex was compared with the diameter and reactivity of pial arterioles on the contralateral cortex, which were pretreated topically with a competitive receptor antagonist, which is specific for kinins. Before fluid percussion neural trauma was induced, arterioles on both cerebral hemispheres constricted normally to a decrease in CO2 tension. After injury, the arterioles on the untreated cortex dilated and did not constrict in response to a decrease in arterial CO2 tension, whereas the arterioles pretreated with the kinin antagonist dilated less and displayed normal reactivity to CO2. These experiments demonstrate that a specific kinin receptor stimulates PGH synthase-dependent, free radical-mediated cerebrovascular injury. Given the ubiquitous distribution of the kallikrein-kinin system, we propose that kinins may be an important common mediator of systemic vascular injury and abnormal vascular reactivity.

Animals↗
PubMed1987

Brain 12-HETE formation in different species, brain regions, and in brain microvessels.

We used gas chromatography/mass spectrometry to measure brain 12-HETE (12-Hydroxy-5,8,10,14-eicosatetraenoic acid) formation from endogenous arachidonic acid in different species and different brain regions and in isolated brain microvessels. When blood-free brain slices were incubated for 20 minutes we found that the rabbit and cat brain incubates contained little 12-HETE when compared to rat and mouse brain incubates. Further in vitro studies of various rat brain regions showed a generally even distribution of 12-HETE. When isolated rat or rabbit microvessels were incubated and analyzed, we found 1 and 0.25 micrograms, respectively, of 12-HETE/mg of microvessel protein. Also, rabbit brain had limited or no capacity to actively metabolize tritiated 12-HETE. In summary, these studies show substantial species variation with respect to brain formation of 12-HETE and indicate that the vasculature is a potentially significant contributor to the 12-HETE found in whole brain tissue.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1987

Effect of a fish-oil-supplemented diet on inflammation and immunological processes in rats.

The effect of a diet enriched in fish-oil-derived fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DCHA) in inflammation and immunological processes in rats has been investigated. Rats on a normal chow diet were given 500 mg/kg/day EPA and 333 mg/kg/day DCHA by gavage over a period of 50 days. Control groups received water, oleic acid or safflower oil. Acute and chronic phases of inflammation induced by antigenic challenge with bovine serum albumin were examined in the rat air-pouch model. In rats receiving fish-oil-derived fatty acids, there was a reduced production of the arachidonic acid metabolites, prostaglandin E2 and leukotriene B4, in the exudate in the chronic phase of inflammation, but not in the acute phase. This was associated with an increased infiltration of leukocytes, especially monocytes and macrophages, in the chronic inflammatory phase. The fish-oil-supplemented diet showed no effect on the volume of inflammatory exudate, the amount of protein in the exudate and connective tissue proliferation. Carrageenin-induced paw edema in the animals was not influenced by the diet. There was no effect of the dietary fish oil on production of antibodies to bovine serum albumin in the rats. However, the diet appeared to suppress a delayed-type skin reaction in the animals. These studies suggest that fish-oil-derived fatty acids may modulate chronic inflammation and a cellular-mediated immunological reaction by reducing the synthesis of arachidonic acid metabolites.

Animals↗
PubMed1986

PGH synthase and lipoxygenase generate superoxide in the presence of NADH or NADPH.

Purified PGH synthase when acting on arachidonic acid in the presence of reduced nicotinamide-adenine dinucleotide or reduced nicotinamide-adenine dinucleotide 3'-phosphate generated superoxide in burst-like fashion. In eight experiments using different batches of enzyme, the mean +/- SE rate of superoxide generation from 100 U of enzyme measured as the superoxide dismutase-inhibitable reduction of cytochrome c was 5.06 +/- 0.19 nmol/min in the first minute and 0.35 +/- 0.03 nmol/min subsequently. Optimum rates of superoxide were seen at concentrations of reduced nicotinamide-adenine dinucleotide in excess of 80 microM and reduced nicotinamide-adenine dinucleotide 3'-phosphate in excess of 100 microM. Using prostaglandin G2 or linoleic acid as substrate rather than arachidonate also resulted in superoxide generation. When prostaglandin H2 was used as substrate, no superoxide was generated. The rate of superoxide generation was markedly inhibited by cyclooxygenase inhibitors. Superoxide generation was also observed during the action of lipoxygenase on either linoleic or arachidonic acid in the presence of reduced nicotinamide-adenine dinucleotide or reduced nicotinamide-adenine dinucleotide 3'-phosphate but not in their absence. Indomethacin had no effect on superoxide generation from lipoxygenase. We conclude that PGH synthase and lipoxygenase produce superoxide via a side-chain reaction dependent on the presence of suitable reducing cosubstrate. This mechanism is analogous to that described for peroxidases in general.

Arachidonic Acid↗
PubMed1986

Carrageenan-induced brain inflammation. Characterization of the model.

Administration of the mucopolysaccharide, carrageenan (CAR), into the hind paw of the rat or mouse induces a local inflammation characterized by increased arachidonic acid metabolism, increased vascular permeability, edema, and neutrophil extravasation. Carrageenan-induced hind-paw inflammation is inhibited by prostaglandin synthesis inhibitors, and this assay predicts the clinical success of anti-inflammatory agents in reducing peripheral inflammation. The purpose of this study was to determine if intraventricular injection of CAR would induce brain inflammation similar to that evoked by CAR in peripheral tissues. The present study demonstrates that CAR injection into the ventricles of the mouse brain does in fact induce an inflammatory response very similar to that caused by injection of CAR into the peripheral tissues. The brain response to CAR was dose-dependent, with the maximum increase in cerebrovascular permeability to iodine-125-labeled human serum albumin and percent brain water occurring after injection of 50 micrograms CAR. As is seen in CAR-induced inflammation of the hind paw, the maximum increase in brain vascular permeability occurred 4 hours after CAR injection. Histological analysis of brains 4 hours after CAR administration showed global neutrophil extravasation into the subarachnoid space and evidence of focal neuronal swelling. Methotrexate-induced neutropenia, however, failed to diminish the permeability response to CAR. Gas chromatographic and mass spectrometric measurements of brain prostaglandins 4 hours after CAR injection revealed a significantly increased level of 6-keto-prostaglandin F1 alpha. These results indicate that a significant increase in prostacyclin, the pro-inflammatory arachidonic acid metabolite, during CAR-induced brain inflammation is likely. These studies suggest that CAR-induced brain inflammation may be a useful model on which to test the efficacy of anti-inflammatory agents in the brain, as well as providing information concerning the mediators and mechanisms by which the brain may sustain inflammatory injury.

Animals↗
PubMed1986

Effect of dexamethasone, indomethacin, ibuprofen, and probenecid on carrageenan-induced brain inflammation.

A model of brain inflammation has recently been developed in mice using intraventricular injection of carrageenan (CAR). This model is characterized by increased brain water and vascular permeability, by neutrophil extravasation, and by evidence of increased pro-inflammatory arachidonic acid metabolites. The purpose of the current experiments was to determine the mechanism(s) by which CAR induces brain inflammation and to determine the utility of the CAR model in testing systemically administered therapeutic agents for their capacity to inhibit brain inflammation. Dexamethasone inhibited the increased brain water but not the increased vascular permeability produced by CAR. Indomethacin, an inhibitor of prostaglandin formation, suppressed peripheral inflammation produced by local injection of CAR but not brain inflammation produced by intraventricular CAR injection. Subsequent studies with carbon-14-labeled indomethacin showed that indomethacin penetrates peripheral tissues but is excluded from normal brain or brains inflamed by injection of CAR. Ibuprofen, another prostaglandin synthesis inhibitor, also had no effect on brain inflammation. Probenecid, an organic acid transport inhibitor, completely inhibited CAR-induced brain inflammation and also slowed brain elimination of intraventricularly administered prostaglandins. These experiments suggest, but do not conclusively prove, that increased prostaglandin formation contributes to brain inflammation. Also, the results with indomethacin and CAR-induced brain inflammation indicate that CAR-induced inflammation may be a useful model for screening for the ability of anti-inflammatory agents to cross the blood-brain barrier and exert their effect on brain inflammation.

Animals↗
PubMed1986

Fluorescence polarization immunoassay for theophylline modified for use with dried blood spots on filter paper.

We used dried blood spots successfully as alternative specimens for quantifying concentrations of theophylline in the circulation by a modified fluorescence polarization immunoassay (FPIA) with the Abbott TDx instrument. The method described is simple, rapid, and acceptably precise. More importantly, it can provide results comparable with those of the conventional serum assay. Results for 64 pairs of dried blood spots (y) and serum (x) specimens analyzed by the respective FPIA methods yielded the following regression parameters: y = 0.94x + 0.71, r = 0.988, and Sxy = 0.92. A major advantage of FPIA is that it requires only basic laboratory skills. When coupled with the use of dried blood spots, this system can be effective in remote theophylline monitoring, particularly suited for domiciliary care.

Blood Specimen Collection↗
PubMed1985

Theophylline toxicity.

The adverse effects of theophylline were recognized soon after its introduction into clinical medicine. Reports of major toxic reactions to theophylline, particularly in children, discouraged its use and led to homeopathic dosing recommendations that had little therapeutic effect. Concomitant with the renaissance in theophylline use during the past decade, reports of theophylline toxicity have increased. The epidemiology of theophylline intoxication has changed in recent years, and today most instances of serious toxicity are due to intentional overdosage, as in a suicide attempt. The adverse effects of theophylline involve the gastrointestinal, nervous, cardiovascular, and urinary systems. In addition, significant metabolic derangements are noted in patients with severe intoxication. Treatment of theophylline intoxication involves attention to fluid and electrolyte balance and initiation of measures to remove theophylline from the body (gastric lavage or emesis, repeated charcoal administration by mouth, and charcoal hemoperfusion in serious cases).

Asthma↗
PubMed1985

Effect of leukotrienes, 12-HETE, histamine, bradykinin, and 5-hydroxytryptamine on in vivo rabbit cerebral arteriolar diameter.

To determine the possible role that leukotrienes (LTs) may play in the regulation of cerebral blood flow, the responses of cerebral arterioles to LTs and 12-hydroxyeicosatetraenoic acid (12-HETE) were studied in vivo in rabbits equipped with a cranial window for direct observation of the microcirculation. Topical application of LTC4, LTD4, or 12-HETE (1.6 X 10(-9)-3.1 X 10(-6) M) neither constricted nor dilated the pial arteries. LTB4 produced only a 5% vasoconstriction at 3.0 X 10(-6) M. However, bradykinin induced dose-dependent arteriolar vasodilation and histamine and 5-hydroxytryptamine induced dose-dependent arteriolar vasoconstriction. Although some LTs have potent vasoconstrictor activity in peripheral tissues and 5-lipoxygenase products have been hypothesized to be mediators of vasospasm after subarachnoid hemorrhage, LTB4, LTC4, LTD4, and 12-HETE apparently are unable to induce significant constriction of the cerebral arterioles in the anesthetized rabbit.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗