Biomedical subjects

B K Weir

Publications and source records attributed to B K Weir.

At least 55 records · Page 3Linked to original sources

PubMed1992

Mechanism of cerebral vasospasm following subarachnoid hemorrhage in monkeys.

This paper reviews our recent studies on the mechanism of cerebral vasospasm following subarachnoid hemorrhage (SAH) in monkeys. Middle cerebral artery (MCA) vasospasm was maximal at 7 days, resolving by 14 days, and absent at 28 days after SAH. Arterial fibrosis was not detected during vasospasm, although there was intimal hyperplasia with fibrosis 28 days after SAH. On scanning electron microscopy, smooth muscle cells from vasospastic arteries had corrugated cell membranes and appeared similar to cells contracted pharmacologically, suggesting that vasospastic smooth muscle is contracted. Morphometric analysis of arteries obtained 7 days after SAH showed no significant increases in arterial wall area of vasospastic arteries compared with normal MCAs. The results suggest vasospasm in monkeys is not due to hypertrophy, hyperplasia, or fibrosis in the arterial wall. Vasospasm may be mainly vascular smooth muscle contraction, which damages the arterial wall, leading to secondary structural changes in the arterial wall which occur after angiographic vasospasm.

Animals↗

PubMed1992

[Cerebral vasospasm. Experimental study].

We have studied chronic vasospasm (V.S.) on a primate model (Cynomolgus monkey). The conclusion of several studies are: V.S. is related to the presence of adherent clots along cerebral arteries and when severe may lead to cerebral infarction. Clots removal within 48 h. following subarachnoid hemorrhage reduces V.S. intensity. Free radicals and iron dependent lipidic peroxidation have been involved in cerebral ischemia development. A new aminosteroid (U 74006 F) can act as a free radical phagocyte and antagonize iron dependent lipid oxidation. Histological V.S. changes are less important after S.A.H. with 74006F treatment. Oxyhemoglobin high concentration from red blood cells (R.B.C.) hemolysis has been reported to be responsible for V.S. Therefore induction of R.B.C. release from the clots before hemolysis occurs could prevent from high concentration of oxyhemoglobin. Plasminogen activator can prevent V.S. when used during 72 h. following subarachnoid hemorrhage.

Aneurysm, Ruptured↗

PubMed1991

Development of a large-animal human brain tumor xenograft model in immunosuppressed cats.

A large-animal model was developed to facilitate the noninvasive investigation of the effect on the human glioma-derived D-54 MG (glioblastoma multiforme) continuous cell line of a variety of therapeutic regimens. Twenty random-bred male cats were inoculated intracerebrally with 1 x 10(7) D-54 MG tumor cells after being initiated on one of three preparatory regimens of cyclosporin A p.o. Reproducible success of D-54 MG xenotransplantation (100%, 6 of 6 cats) was achieved only after pretreatment with 120 mg cyclosporin A p.o. (24-30 mg/kg) daily for greater than or equal to 10 days prior to tumor implantation. High-performance liquid chromatography-derived whole blood cyclosporin A 12-h trough levels of greater than or equal to 640 ng/ml were seen in successful implants. Lesions ranging from 2 to 20 mm in diameter were seen in cats sacrificed 27-44 days after implantation with no growth seen in control animals. Histopathological examination revealed the tumors to be well-circumscribed anaplastic intracerebral tumors with some invasion into surrounding host parenchyma. Perivascular lymphocytic cuffing was observed, but intratumoral lymphocytic infiltration was minimal. Gadolinium-EDTA-enhanced nuclear magnetic resonance imaging provided accurate tumor localization in T1-weighted images (TE 26 ms; TR 600 ms). Biochemical tests of kidney, liver, and hematological function were within normal limits, although 10% (2 of 20) of the animals developed gingival hyperplasia, and 5% (1 of 20) developed intussusception. The reproducible growth of the D-54 MG human glioblastoma cell line in a large-animal model eliminates many of the limitations associated with the standard nude mouse/rat model, thereby providing a novel test bed for a variety of imaging modalities as well as for drug immunoconjugate localization and toxicity studies.

Animals↗

PubMed1991

Glutathione levels and chemosensitizing effects of buthionine sulfoximine in human malignant glioma cells.

Biopsy samples and cultured cells derived from them were obtained from 39 patients with malignant glioma and were analyzed for 1) glutathione (GSH) content; 2) sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or nitrogen mustard (HN2) treatment and 3) the effect of buthionine sulfoximine (BSO) treatment on BCNU and/or HN2 cytotoxicity. The average GSH concentration of biopsy specimens was lower than those of cultured cells (2.36 +/- 0.44 vs. 11.42 +/- 2.32 nmol/10(6) cells). While some of the tumor specimens were sensitive to either BCNU or HN2, the majority were resistant to both. However, 8 of 23 tumors tested showed enhanced sensitivity to BCNU following treatment with BSO. Five of 17 tumors were similarly sensitized to HN2 by BSO. These results suggest that BSO chemosensitization may be of value for certain patients and that screening assays may help identify treatment-sensitive individuals.

Adolescent↗

PubMed1991

Scanning electron microscopy of normal and vasospastic monkey cerebrovascular smooth muscle cells.

Normal cytoarchitecture of smooth muscle cells of monkey cerebral arteries was studied using scanning electron microscopy after removal of adventitial connective tissue by hydrolysis with HCl. Cerebral arteries were also examined after contraction in vitro with prostaglandin F2 alpha (PGF2 alpha). Anterior cerebral arteries were studied after exposure for 6 days in vivo to whole blood, oxyhemoglobin, methemoglobin, bilirubin, mock cerebrospinal fluid, or supernatant fluid from an incubated mixture of autologous blood and mock cerebrospinal fluid. Normal smooth muscle cells were spindle-shaped and oriented circumferentially around the vessel. They were often grouped into bundles of 5 to 10 cells; bundles were recognizable because cells within them were joined by multiple intercellular contacts. Groups of smooth muscle cells oriented longitudinally were present outside the circular layers of cells. The adventitial surface of muscle cells was smooth apart from fine longitudinal striations in some areas. Arteries contracted with PGF2 alpha had markedly convoluted and folded cell membranes. Muscle cells of vasospastic arteries and of arteries exposed to oxyhemoglobin and supernatant fluid appeared identical to cells contracted with PGF2 alpha. The outer surface of cells of arteries exposed to bilirubin, methemoglobin, and mock cerebrospinal fluid were normal. Marked similarity between vasospastic smooth muscle cells and smooth muscle cells from arteries contracted with PGF2 alpha suggest that smooth muscle contraction occurs during "vasospasm" due to whole blood and to intrathecal injection of oxyhemoglobin.

Animals↗

PubMed1991

Morphometric analysis of monkey cerebral arteries exposed in vivo to whole blood, oxyhemoglobin, methemoglobin, and bilirubin.

Whether vasospasm results from smooth muscle contraction or from arterial wall infiltration by cells and other material is subject to debate. Computer-assisted image analysis was used to measure lumen area, total wall area, and area of tunica media plus tunica intima of cross-sections of monkey right middle cerebral arteries (MCAs), exposed in vivo for 6 days to whole blood (n = 4), oxyhemoglobin (OxyHb, n = 5), methemoglobin (MetHb, n = 5), bilirubin (n = 5), mock cerebrospinal fluid (CSF, n = 6), and supernatant fluid from an incubated mixture of autologous blood and mock CSF (n = 5). Five control (left) MCAs from each group and 4 MCAs contracted in vitro with potassium chloride were measured. Significant angiographic vasospasm occurred in groups receiving whole blood, supernatant fluid, and OxyHb (p less than 0.05). There was significant correlation (r = 0.58, p less than 0.05) between right MCA diameter on angiography and diameter calculated from lumen area. When compared to effects of mock CSF, OxyHb significantly increased total wall area. When right and left MCAs were compared within groups, total wall area increased in every group with significant increases in groups exposed to mock CSF, OxyHb, and bilirubin (p less than 0.05). No changes developed in area of tunica media plus tunica intima, whether comparing right versus left MCAs within groups or right MCAs between groups. Contraction in vitro did not significantly increase total wall area or area of tunica media plus tunica intima. Light microscopy demonstrated inflammatory debris in the tunica adventitia of arteries from every group. This study shows that whole blood, OxyHb, and supernatant fluid, which contains OxyHb, cause vasospasm. Increases in total wall area are not sufficient to account for luminal narrowing, and therefore, changes such as cell proliferation and arterial wall fibrosis in the intima or media apparently do not contribute primarily to arterial narrowing of vasospasm but could be related to persistence of narrowing. Vessel wall thickening, which does occur, is caused by increased tunica adventitia area only and is nonspecific in that it develops after injection of substances not associated with vasospasm. The data are consistent with the hypothesis that oxyHb causes vasospasm (both angiographic and morphologic) by inducing muscle contraction in the media.

Animals↗

PubMed1991

A review of hemoglobin and the pathogenesis of cerebral vasospasm.

We believe that current experimental and clinical evidence can be most satisfactorily interpreted by assuming that oxyhemoglobin is the cause of cerebral vasospasm that follows subarachnoid hemorrhage. We review the pathogenetic mechanisms by which oxyhemoglobin affects cerebral arteries. The relative importance of each of these mechanisms in the genesis of vasospasm, the biochemical pathways of oxyhemoglobin-induced smooth muscle contraction, and the intracellular actions of oxyhemoglobin on smooth muscle and on other cells in arteries are still not definitely established.

Cerebral Arteries↗

PubMed1991

Effect of 21-aminosteroid U-74006F on lipid peroxidation in subarachnoid clot.

The present study was undertaken to investigate the effect of U-74006F on malondialdehyde (a by-product of lipid peroxidation) in subarachnoid clot. Eighteen cynomolgus monkeys were divided into three groups of six each. There were two U-74006F-treated groups, receiving doses of 0.3 or 1.0 mg/kg, and a placebo-treated group. Each monkey underwent baseline cerebral angiography followed by right-sided craniectomy and placement of subarachnoid clot around the middle cerebral artery (MCA). Treatment was administered intravenously every 8 hours for 6 days. Seven days after the experimental subarachnoid hemorrhage (SAH), angiography was repeated and the animals were killed. In the placebo-treated group, significant vasospasm occurred in the MCA on the side of the clot (p less than 0.01). After U-74006F treatment at both dosages, significantly less vasospasm developed in the clot-side MCA (p less than 0.01). The content of malondialdehyde was measured by both the thiobarbituric acid test and high-performance liquid chromatography (HPLC). Comparing the two methods, HPLC proved to be more accurate than the thiobarbituric acid test, especially for measurement of low concentrations of malondialdehyde. In the placebo-treated group, the malondialdehyde content was significantly increased in the Day 7 clot (p less than 0.05). In contrast, malondialdehyde content in freshly prepared clot was very low. In the 0.3-mg/kg U-74006F group, the malondialdehyde content of clot was significantly less at Day 7 compared to clot from the placebo-treated group (p less than 0.05). Although the malondialdehyde content of clot from the 1.0 mg/kg U-74006F-treated group was less than that of placebo, it was not significantly so. Malondialdehyde was not detected in the actual vessel wall of the MCA of any group. These results suggest that lipid peroxidation in subarachnoid clot may play a role in the pathogenesis of vasospasm and that the salutary effects of U-74006F in vasospasm may be mediated by a reduction of lipid peroxidation in SAH.

Animals↗

PubMed1991

Lysis of intraventricular hematoma with tissue plasminogen activator. Case report.

A 42-year-old woman suffered a severe intracerebral and intraventricular hemorrhage from a ruptured anterior cerebral artery aneurysm. Evacuation of the frontal hematoma and clipping of the aneurysm was performed but the intraventricular blood clot persisted, causing ventricular dilatation and high intracranial pressure (ICP) 24 hours after surgery despite external ventricular drainage. Over this period of time the patient's clinical condition improved from Grade V to Grade IVb (World Federation of Neurological Surgeons classification). The intraventricular hematoma was lysed with a total of 8 mg recombinant tissue plasminogen activator injected directly into the ventricles on the 1st and 2nd postoperative days, resulting in rapid normalization of ventricular size and ICP. The patient has since made a substantial recovery and has been able to return home.

Adult↗

PubMed1991

Intracisternal recombinant tissue plasminogen activator after aneurysmal subarachnoid hemorrhage.

Fifteen patients undergoing surgery within 48 hours of aneurysm rupture were administered recombinant tissue plasminogen activator (rt-PA) directly into the basal subarachnoid cisterns after minimal surgical clot removal and aneurysm clipping. Preoperatively, 13 patients had diffuse or localized thick subarachnoid blood clots on computerized tomography (CT), and two had diffuse thin clots. The rt-PA was given as a single intraoperative injection of 7.5 mg (one patient), 10 mg (nine patients), or 15 mg (five patients). Postoperative cisternal drainage was employed in three patients. All patients except one demonstrated partial to complete cisternal clot clearance on CT scans within 24 hours after surgery. The patient who showed no clot reduction was the only patient in this series to develop symptomatic vasospasm and was the only fatality, dying 8 days after rupture. No vasospasm was seen on follow-up cerebral angiography in six of the 14 responding patients, and mild-to-moderate arterial narrowing was seen in at least one major cerebral artery in the remaining eight patients. Severe angiographic vasospasm was not seen, although the patient who died did not undergo repeat angiography. There was one major complication early in the series which seemed clearly related to treatment, and that was a large extradural hematoma occurring within several hours of craniotomy. Intrathecal fibrinolytic treatment appears effective in clearing subarachnoid clot and reducing vasospasm, and may be associated with acceptable risks if given to patients with large-volume subarachnoid hemorrhages at high risk for severe vasospasm.

Adult↗

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

Rapid growth of residual aneurysmal neck during pregnancy. Case report.

The pregnant state has an apparently stimulatory effect on the tendency for aneurysms to grow. A patient is reported whose symptomatic aneurysm was clipped during pregnancy. The small amount of residual aneurysm underwent remarkable continued growth during the last trimester of the pregnancy. The implications for management of such cases are discussed.

Adult↗

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

Hemoglobin causes release of inositol trisphosphate from vascular smooth muscle.

To test the hypothesis that oxyhemoglobin causes contraction of vascular smooth muscle by production of inositol 1,4,5-trisphosphate which results in a release of intracellular calcium, smooth muscle cells were exposed to oxyhemoglobin and inositol trisphosphate was measured. Oxyhemoglobin, but not methemoglobin which has much less contractile action, stimulated inositol trisphosphate production. The time course was consistent with an early role for this compound in the contraction produced by hemoglobin. The increase in production of inositol trisphosphate was inhibited by pertussis toxin and also by neomycin, an inhibitor of phospholipase C, although the actions of the latter compound cannot be attributed only to an inhibition of the enzyme responsible for the production of inositol trisphosphate.

Animals↗

PubMed1990

Hemifacial spasm and craniovertebral anomaly.

Two patients with congenital anomaly of the craniovertebral junction causing disabling hemifacial spasm (HFS) are presented. In one patient, complete cessation of the HFS occurred for a period of two years following simple bony decompression of the craniovertebral junction raising unanswered questions as to the exact pathogenesis of HFS. Eventually both patients required microvascular decompression at the root entry zone of the facial nerve.

Adult↗

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↗