Search PubMed⌕ Search

Biomedical subjects

J M Findlay

Publications and source records attributed to J M Findlay.

At least 91 records · Page 5Linked to original sources
PubMed1991

Etiology of cerebral vasospasm in primates.

A primate model was used to determine whether oxyhemoglobin (OxyHb), methemoglobin (MetHb), or bilirubin is likely to be responsible for cerebral vasospasm following subarachnoid hemorrhage (SAH). Forty cynomolgus monkeys were randomly assigned to one of five groups. On Day 0, each animal underwent angiography followed by right craniectomy and placement of an Ommaya reservoir with its catheter adjacent to the right middle cerebral artery (MCA). The animals received intrathecal injections twice a day for 6 days of one of the following solutions: mock cerebrospinal fluid (CSF); OxyHb; MetHb; bilirubin; or supernatant fluid from an incubated mixture of autologous blood and mock CSF. On Day 7, angiography was repeated and the animals were killed. Comparison of angiograms obtained on Day 0 and Day 7 of the experiment showed significant vasospasm of the right MCA and the right anterior cerebral and internal carotid arteries in the animal groups that had received OxyHb or supernatant fluid. There was a smaller reduction in diameter of the same vessels in the bilirubin group (not statistically significant), while no effects were observed in the groups receiving MetHb or mock CSF. Electron microscopy of the right MCA's gave results consistent with the angiographic findings. One monkey in the OxyHb group developed a delayed-onset right MCA infarction. These data suggest that OxyHb is the cause of cerebral vasospasm following SAH.

Animals↗
PubMed1991

Surgical manipulation of primate cerebral arteries in established vasospasm.

It is generally believed that surgery in the face of angiographic vasospasm is dangerous due to an increased incidence of postoperative cerebral ischemia. One theory is that arterial narrowing is exacerbated by surgical manipulation of vasospastic vessels during aneurysm dissection and clipping. This theory was tested in a primate model of cerebral vasospasm and the results reported. Six monkeys underwent baseline cerebral angiography, followed by induction of subarachnoid hemorrhage (SAH) on both sides of the circle of Willis. An equal amount of fresh autologous blood clot was placed around each internal carotid, anterior cerebral, and middle cerebral artery. Six days later, angiography was repeated and the right craniectomy was reopened for clot evacuation and surgical manipulation of the right cerebral arteries, including placement of a temporary aneurysm clip on the right middle cerebral artery. The left cerebral arteries were not exposed or manipulated, and served as controls. Twenty-four hours later angiography was repeated, then the animals were killed. Equal and significant vasospasm (greater than 40% reduction in vessel caliber compared to baseline, p less than 0.05) was seen in the middle cerebral arteries on both sides of the circle of Willis in all animals 6 and 7 days after SAH. There was no significant change in the severity of vasospasm on Day 7 compared with Day 6 in the right cerebral arteries. Increased risk of postoperative cerebral ischemia for surgery in the peak vasospasm period may be due to mechanisms other than increased arterial narrowing precipitated by surgical manipulation.

Animals↗
PubMed1991

Current concepts of pathophysiology and management of cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

Approximately 10 in 100,000 persons suffer rupture of a saccular intracranial aneurysm annually, and roughly 60% of these will survive the initial catastrophe in reasonable neurological condition. Of the many ensuing complications of aneurysmal subarachnoid hemorrhage, the most frustrating continues to be a form of delayed-onset cerebral arterial narrowing known as vasospasm. Because it is caused by thick subarachnoid blood clots coating the adventitial surface of cerebral arteries, the distribution and severity of vasospasm correlates closely with location and volume of subarachnoid hematoma as visualized on computed tomography (CT). Critical vasospasm causes cerebral ischemia and infarction: the "second stroke." It is now know that vasospasm represents sustained arterial contraction rather than structural thickening of the vessel wall with lumen encroachment. A large body of evidence points to oxyhemoglobin, released from lysing erythrocytes, as the principal component of blood clot responsible for this contraction. The precise mechanism by which oxyhemoglobin causes prolonged vascular smooth muscle cell constriction has not yet been established, but possibilities include secondary generation of vasoactive free radicals, lipid peroxides, eicosanoids, bilirubin, and endothelin. Vasospasm treatments are directed at preventing or reversing arterial narrowing, or at preventing or reversing cerebral ischemia. Several treatments from the latter category, namely, hypertensive, hypervolemic hemodilutional therapy and the calcium channel blocker nimodipine, have proven moderately effective and are in widespread clinical use. It has also been possible to mechanically dilate vasospastic vessels with transluminal angioplasty improving cerebral blood flow to ischemic brain. However we are still in need of an effective agent to prevent arterial narrowing, and several hopeful candidates in this category of treatment are clot lytic agent tissue plasminogen activator (rt-PA) and an inhibitor of iron-dependent peroxidation, 21-aminosteroid U74006F (tirilazad mesylate).

Humans↗
PubMed1990

The effect of timing of intrathecal fibrinolytic therapy on cerebral vasospasm in a primate model of subarachnoid hemorrhage.

The effect of intrathecal tissue plasminogen activator administered at times from 0 to 72 hours after subarachnoid hemorrhage on the development of cerebral vasospasm in primates was examined. Thirty monkeys were randomly assigned into one of five equal groups: a control group that underwent subarachnoid hemorrhage alone, and 0-, 24-, 48-, and 72-hour treatment groups that received 0.75 mg of tissue plasminogen activator at those times after baseline cerebral angiography and subarachnoid hemorrhage on the right side. Seven days later angiography was repeated and the animals were killed. One animal in the 72-hour group developed a delayed ischemic deficit on Day 7 after subarachnoid hemorrhage. In the control and 72-hour groups significant vasospasm occurred in most of the major, right cerebral arteries (P less than 0.05), but no significant vasospasm developed in the 0-, 24-, and 48-hour groups. Although a large subarachnoid clot remained in the control animals, most clot had been dissolved in all treatment groups. Lysing of subarachnoid hematoma with intrathecal tissue plasminogen activator within 72 hours of subarachnoid hemorrhage is effective in preventing vasospasm in primates.

Animals↗
PubMed1990

A dosage study of the effect of the 21-aminosteroid U74006F on chronic cerebral vasospasm in a primate model.

The efficacy of the 21-aminosteroid U74006F was investigated using different dosages in a restricted, randomized, placebo-controlled trial. Forty cynomolgous monkeys were divided into five groups of eight. There were two groups given treatment with placebos, one being saline and the other the vehicle in which U74006F was delivered. There were three U74006F treatment dosage groups: 0.3, 1.0, and 3.0 mg/kg. Each monkey underwent baseline cerebral angiography followed by right-sided craniectomy and subarachnoid placement of a clot around the middle cerebral artery (MCA). Treatment was administered intravenously every 8 hours for 6 days. Seven days after experimental subarachnoid hemorrhage, angiography was repeated, and the animals were killed. In both saline or vehicle placebo treatment groups, significant vasospasm (VSP) occurred on the clot side in the extradural internal carotid artery (C3), the intradural internal carotid artery, the precommunicating segment of the anterior cerebral artery (A1,) and the MCA (P less than 0.01). After U74006F treatment, significantly less VSP developed in the A1 on the clot side (0.3 mg/kg U74006F treatment group) and the MCA (all U74006F treatment groups, P less than 0.05). When the percentages of change from the baseline for the vessel diameters on the clot side were compared, VSP was attenuated in the A1 (P less than 0.05) and MCA (P less than 0.001) of all U74006F treatment groups as compared with the placebo treatment groups. Only 0.3 mg/kg of U74006F significantly prevented VSP in C3 (P less than 0.01). Although the 0.3 mg/kg dosage appeared to have the most favorable effect, no significant differences were observed among the three dosage groups. Electron microscopy of the MCA on the clot side in the animals treated with U74006F still showed luminal convolutions and morphological changes in the endothelial cells. These changes appeared less prominent in those MCAs with milder VSP. If these results in primates are applicable to humans, U74006F would be useful in reducing VSP after aneurysmal subarachnoid hemorrhage.

Animals↗
PubMed1989

Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: dosage study in a primate model and review of the literature.

Because of the naturally low fibrinolytic activity of CSF many erythrocytes entrapped in subarachnoid blood clot undergo hemolysis in situ, releasing vasogenic oxyhemoglobin (OxyHb) in high concentrations around the basal cerebral arteries. In order to promote more rapid clearance of erythrocytes from the basal subarachnoid cisterns we are currently investigating intrathecal thrombolytic therapy with human, recombinant, tissue plasminogen activator (rt-PA) in a primate model of subarachnoid hemorrhage (SAH) and cerebral vasospasm (VSP). In the present study 16 monkeys were divided into 4 groups of 4, and each group received a different dose of sustained-release gel rt-PA at the time of experimental SAH. Cerebral angiography seven days later showed that whereas no VSP occurred in the groups receiving 0.5 or 0.75 mg of rt-PA, mild to moderate VSP occurred in the groups receiving 0.125 or 0.25 mg of rt-PA. Analysis of the combined 2 smaller dosage groups revealed significant (P less than 0.05) reduction of lumen caliber in the clot-side internal carotid (C3 and C4), proximal anterior cerebral (A1) and middle cerebral (MCA) arteries. Gross subarachnoid clot remained in all of the animals in the 0.125 and 0.25 mg dose groups, in 2 of the animals in the 0.5 mg dose group, and none of the animals in the 0.75 mg dose group. It was concluded that 0.75 mg of gel rt-PA is sufficient to completely lyse a 4.25 ml SAH and prevent VSP in our primate model. The literature on fibrinolysis and erythrocyte clearance in cerebrospinal fluid (CSF) is reviewed.

Animals↗
PubMed1989

Preparation and characterization of a [14C]cellulose suitable for human metabolic studies.

In six normal subjects administered 5 microCi of an oral dose of a commercially available 14C-labelled cellulose, significant amounts of 14CO2 were detected in expired air within 30 min, suggesting that other 14C-labelled non-cellulosic material was present. Chemical and microscopical examination confirmed that starch was the principal contaminant. The commercial preparation was purified using amyloglucosidase (EC 3.2.1.3) digestion following gelatinization of the starch by autoclaving. Subsequent administration of the purified cellulose to a further six normal subjects decreased the expired air 14CO2 during the subsequent 10 h from 13.0 (SD 4.0) to 4.1 (SD 1.9)%. Administration of the purified product to a further group of four normal subjects, before and after a regimen of increased dietary fibre, showed a cumulative increase in expired 14CO2 over 24 h from 7.9 (SD 1.1) to 12.1 (SD 2.6)% on fibre. In six ileostomy subjects the cumulative excretion of 14CO2 was greatly decreased compared with normal controls (3.0 (SD 1.14) and 10.5 (SD 3.9)% respectively). In constipated subjects expired 14CO2 continued beyond 48 h, in contrast to normal subjects where expired 14CO2 at this time was negligible.

Adult↗
PubMed1989

Arterial wall changes in cerebral vasospasm.

A right-sided subarachnoid hemorrhage (SAH) was created in 12 monkeys. Only the right (clot-side) cerebral arteries developed angiographic vasospasm (VSP), which was maximal 7 days after SAH. Eight animals were killed at this time and the remainder at 14 days. At the time of killing the middle cerebral arteries (MCAs) were harvested, and four normal, left (non-clot-side) MCAs were vasoconstricted in vitro with prostaglandin F2 alpha. All MCAs were studied with scanning and transmission electron microscopy. Right MCAs in maximal VSP 7 days from SAH were undistinguishable on scanning electron microscopy from normal arteries vasoconstricted in vitro: both groups demonstrated a mean 57% reduction in vessel caliber and a 5-fold increase in vessel wall thickness compared to normal, nonvasoconstricted left MCAs. On transmission electron microscopy, however, arteries in SAH-induced VSP showed degenerative changes in the tunica intima and media. These changes were still evident at 14 days, despite considerable resolution of VSP. These findings, as well as those from other pathological studies of animal and human cerebral arteries in VSP, suggest that the arterial narrowing and vessel wall thickening seen within several weeks of SAH is due primarily to medial contraction, but unlike simple vasoconstriction, is associated with degenerative ultrastructural changes in the endothelium and vascular smooth muscle cells which may denote a temporarily irreversible state.

Animals↗
PubMed1989

A trial of the 21-aminosteroid U74006F in a primate model of chronic cerebral vasospasm.

The efficacy of U74006F in the prophylaxis of chronic cerebral vasospasm (VSP) was evaluated in a randomized, double-blind, placebo-controlled trial. Forty cynomolgus monkeys were divided by restricted randomization into 2 treatment groups of 20. Five animals from each treatment group were randomized into subgroups 1 and 2. The animals of subgroup 1 were studied pathologically. Brain biopsies of the animals in subgroup 2 were performed and studied with high-performance liquid chromatography (HPLC). The remaining 20 animals supplemented the number studied angiographically. Significant VSP (P less than 0.05) was detected in the majority of vessels from the clot site (right) of both treatment groups. Electron microscopy results showed positive correlation with the angiographic data. When comparing the effects of U74006F to those of the placebo at day 7, there was a significant difference (P less than 0.05) in the degree of VSP in the right extradural internal carotid and right middle cerebral arteries. This resulted from a greater degree of VSP in placebo animals. Two animals developed delayed ischemic deficits, one from each group. The infarct of the U74006F animal was smaller than the infarct in the placebo animal. Although overall changes in phosphagen levels did not reach statistical significance, HPLC analysis of the cortical biopsies did show a decrease in the ATP/ADP +/- AMP ratio of 54% in placebo animals and only 7% in animals receiving U74006F. The middle cerebral arteries of 2 animals were also studied with HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Safety and efficacy of intrathecal thrombolytic therapy in a primate model of cerebral vasospasm.

To test the safety of a large intrathecal dose of human recombinant tissue plasminogen activator (rt-PA), 6 cynomolgous monkeys were given 10 mg of rt-PA (mean, 2.7 mg/kg) through an Ommaya reservoir after craniectomy and dissection of the basal cisterns. Bleeding occurred briefly at the incision in 2 animals; otherwise the clinical condition of all 6 remained normal throughout the postoperative period. Systemic fibrinolysis did not occur, and gross and microscopic examination of the brain and meninges revealed no abnormality. Next, we evaluated the efficacy of unilateral administration of rt-PA suspension (0.5 mg) plus slow-release gel rt-PA (1.25 mg) in lysing a bilateral subarachnoid clot and preventing vasospasm in a randomized, placebo-controlled trial. Sixteen monkeys were divided randomly into 2 equal groups, each of which underwent baseline cerebral angiography, followed by frontotemporal craniectomy and induction of subarachnoid hemorrhage on the left side and then on the right. Before closure on the right side either rt-PA or an equal volume of placebo was injected into the subarachnoid space. On day 7 angiography was repeated, and the animals were killed under anesthesia for necropsy. One of the animals in the placebo group developed a cerebral infarction on day 5. In the placebo group significant vasospasm occurred in all major right and left-sided anterior cerebral vessels (P less than 0.01). No vasospasm occurred in the rt-PA-treated animals. Whereas gross subarachnoid clot was found in all animals in the placebo group (mean clot weight 1.13 g), only a small fragment of clot was found in a single rt-PA-treated animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pharmacological studies on relaxation of spastic primate cerebral arteries in subarachnoid hemorrhage.

Chronic cerebral vasospasm was induced in 16 monkeys by direct placement of a clot of autologous blood over the arteries of the circle of Willis on the right side. The middle cerebral arteries (MCA's) on the clot side all showed angiographic vasospasm, which was maximal 7 days after subarachnoid hemorrhage. Animals were sacrificed at this time and vascular responses to acetylcholine (ACh), histamine, and the calcium ionophore A23187 were studied in MCA rings from the clot (spastic) side and the non-clot (control) side. In control preparations with an intact endothelium, which had been precontracted by prostaglandin F2 alpha (PGF2 alpha), histamine and A23187 produced significant relaxation. The same concentrations of histamine and A23187 did not relax vascular tissues in which the endothelium had been mechanically removed. Acetylcholine did not produce a significant endothelium-dependent relaxation of primate MCA rings, but did relax rings of primate common carotid artery. Pretreatment with chlorpheniramine (an H1-receptor antagonist) prevented histamine-induced relaxation; however, cimetidine (an H2-receptor antagonist) had no inhibitory action. It thus seems that histamine mediates relaxation of intact MCA's mostly by an H1-receptor-mediated release of endothelium-derived relaxing factor (EDRF). Relaxations induced by histamine and A23187 in MCA's from the clot side were substantially reduced. Moreover, the small component of ACh-induced relaxation was also abolished. Endothelium-independent relaxation induced by glyceryl trinitrate (GTN) occurred in arteries from both the control and the clot sides. Constrictions induced by KC1 and PGF2 alpha were reduced on the clot side of the MCA's. These results suggest that subarachnoid hemorrhage influences both the generation of EDRF and the constriction of affected arteries. The small contraction which was elicited in spastic arteries was fully relaxed by GTN.

Acetylcholine↗
PubMed1988

Sphenoethmoidal sinusitis complicated by cavernous sinus thrombosis and pontocerebellar infarction.

An unusual case of sphenoethmoidal sinusitis complicated by cavernous sinus thrombosis, meningitis and pontine and cerebellar infarction is described. The patient presented with advanced intracranial complications which in retrospect caused delay in recognition and treatment of the underlying sphenoethmoidal sinusitis. Surgical drainage of the sinusitis was ultimately required. The pathogenesis of these complications is discussed, and the topic of sphenoid sinusitis reviewed in order to emphasize the numerous neurological manifestations of this disease.

Aged↗
PubMed1988

Human saccadic eye movements in the absence of the geniculocalcarine projection.

This paper describes the results of an investigation into the spatial and temporal properties of the saccadic eye-movement system in a subject with a 'blind' hemifield caused by accidental damage to the left geniculostriate projection. The results show that blind hemifield stimulation can elicit goal-directed saccades of short latency provided the contrast of the visual stimulus is above the threshold required for saccade generation at the corresponding stimulus eccentricity. Signal processing associated with blind hemifield pathways shows reduced sensitivity by comparison with the normal hemifield and greater dependence on stimulus size, eccentricity and mode of presentation. Higher contrast levels are always needed for blind field stimulation and larger variance in mean saccadic amplitudes and latencies is normally observed. Large stimulus eccentricities which would normally require corrective saccades exhibit a different response pattern to that observed in normal vision. The results show that the centre of gravity effect and the generation of rapid, 'express-saccades' observed in normal vision are not inevitable outcomes of midbrain processing of visual information. The subject's performance reveals strategic patterns of eye-movement responses which maximize the use of his normal hemifield. Visual performance in the control of saccadic eye-movement responses appears to be optimum when the detection of the visual stimulus is associated with both the geniculostriate and the midbrain pathways. Experiments designed to test for the effects of light scatter into the normal hemifield show that the subject's saccadic eye-movement performance following visual stimulation of the blind hemifield cannot be attributed either to the amount or the pattern of light scatter into the normal hemifield. The implications of present findings on the results of other studies of eye-movements in subjects with scotomas associated with cortical lesions are also examined.

Adult↗
PubMed1988

Microcystic spinal cord degeneration causing posttraumatic myelopathy. Report of two cases.

Two cases of progressive myelopathy occurring years after incomplete cervical spinal cord injury are presented. In both patients, the clinical features, as well as the "bull's-eye" appearance of the delayed computerized tomography (CT) myelography study and the circumscribed low density of the magnetic resonance image, were consistent with posttraumatic syringomyelia, but surgical exploration including intra-operative spinal sonography failed to reveal a syrinx. Although arachnoiditis was present in both patients, the striking abnormality found at surgery was the softened appearance and the microcystic degeneration of the cord. The microcystic spinal cord degeneration found in these cases represents a previously undescribed cause of late deterioration after spinal cord injury that may mimic the clinical, CT-myelographic, and magnetic resonance features of posttraumatic syringomyelia.

Adult↗
PubMed1988

Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH.

The safety and efficacy of the thrombolytic agent tissue-type plasminogen activator (tPA) in the elimination of subarachnoid clot and prevention of chronic vasospasm were evaluated in a blind randomized placebo-controlled trial. Twenty-four monkeys were randomly assigned to one of two groups of 12. Each group underwent baseline cerebral angiography and coagulation analysis followed by right-sided craniectomy and experimental subarachnoid hemorrhage (SAH). An Ommaya reservoir was inserted with its catheter placed into the subarachnoid space. Twenty-four hours later one group (the tPA group) received 0.5 mg of tPA in 0.5 ml of buffer injected into the reservoir every 8 hours for three doses, while the second group (the placebo group) received the same volume of normal saline. On Day 7, angiography was repeated and the animals were sacrificed. One animal from the placebo group developed a delayed ischemic neurological deficit on Day 5 after SAH. Moderate to severe vasospasm (greater than 30% reduction in vessel caliber) was present on Day 7 in the internal carotid and middle cerebral arteries of the animals in the placebo group (p less than 0.01), while in the tPA group only mild narrowing of the anterior cerebral artery was seen. No significant change in coagulation status occurred in either group. All animals in the placebo group had a large amount of subarachnoid clot remaining at the time of sacrifice, but 11 of the 12 animals in the tPA group were completely free of clot. The results of electron microscopic studies of the cerebral arteries correlated with angiography, and there was no histological evidence of brain inflammation associated with the intrathecal use of tPA.

Animals↗
PubMed1987

Fenestration of the supraclinoid internal carotid artery.

A twenty-eight year old woman presenting with subarachnoid hemorrhage was found at angiography to have a left anterior cerebral-anterior communicating artery aneurysm. Also identified was a fenestration of the right supraclinoid internal carotid artery with an associated accessory middle cerebral artery. This appears to be the second reported case of fenestration of the intracranial internal carotid artery. Fenestrations of cerebral vessels and their possible embryologic origins are briefly reviewed.

Adult↗
PubMed1987

Visual computation and saccadic eye movements: a theoretical perspective.

A simple instance of parallel computation in neural networks occurs when the eye orients to a novel visual target. Consideration of target-elicited saccadic eye movements opens the question of how spatial position is represented in the visual pathways involved in this response. It is argued that a point-for-point retinotopic coding of spatial position (the 'local sign' approach) is inadequate to account for the characteristics of the response. An alternative approach based on distributed coding is developed.

Form Perception↗