Biomedical subjects
Publications and source records attributed to K M Welch.
We measured platelet levels of norepinephrine (NE), epinephrine (E), and dopamine (DA) in migraine patients. Platelet NE was selectively increased in common migraine. This is attributed to platelet dense body hyposecretion.
We studied the platelet dense body as a model for serotonergic vesicular function. Headache-free migraine sufferers had increased numbers of dense bodies, decreased dense body secretion, a defective link between cytosolic ionized calcium and platelet activation, an abnormal sensitivity to activation by platelet-activating factor and decreased serotonin metabolism in the presence of an unactivated platelet. These findings are interpreted as evidence for low platelet serotonin turnover. Also an abnormality in coupling of secretion to cytosolic ionized calcium caused by a membranal defect results in reduced platelet secretory function. A similar abnormality is postulated for serotonergic vesicles in central neurons. Central serotonergic hypofunction in migraine sufferers may reduce this normally present inhibitory influence on the intrinsic noradrenergic system, the activation of which may initiate the neuronal mechanisms of migraine.
We used transmission electron microscopy to investigate selected aspects of the platelet response (surface activation as well as aggregation) and quantify cytoplasmic organelles within the cytoplasm of platelets obtained from both healthy control women and women diagnosed as having either common or classic migraine. Comparisons between controls and migraineurs showed no differences for: (1) the number of circulating platelets, (2) degree of surface activation, (3) amount of aggregate formation or (4) percent of hyperactive platelet populations. In contrast, platelets of migraine sufferers uniformly contained a significantly greater number of dense bodies compared to control platelets. Although we did not find functional abnormalities for the platelets obtained from migraineurs, we did demonstrate that they were altered structurally.
Two adults presented with new-onset migrainous-type visual disturbances and had angiographically demonstrated filling defects near the torcular Herophili. Neither patient had a visual field deficit nor cerebral computed tomography evidence of an occipital infarction. The association of migraine-like visual phenomena with cerebral venous thrombosis may provide insight into the pathogenesis of migraine.
Brain magnesium was measured in migraine patients and control subjects using in vivo 31-Phosphorus Nuclear Magnetic Resonance Spectroscopy. pMg and pH were calculated from the chemical shifts between Pi, PCr and ATP signals. Magnesium levels were low during a migraine attack without changes in pH. We hypothesize that low brain magnesium is an important factor in the mechanism of the migraine attack.
Brain magnesium was measured in migraine patients and control subjects using in vivo 31-Phosphorus Nuclear Magnetic Resonance Spectroscopy. pMg and pH were calculated from the chemical shifts between Pi, PCr and ATP signals. Magnesium levels were low during a migraine attack without changes in pH. We hypothesize that low brain magnesium is an important factor in the mechanism of the migraine attack.
Platelet serotonin (5 hydroxytryptamine, 5-HT) and norepinephrine (NE) were measured in common and classic migraine patients and healthy controls. Common migraine sufferers had high NE levels and a low 5-HT/NE ratio. Classic migraine patients had a high 5-HT level and a high 5-HT/NE ratio. The data suggest disparate NE and 5-HT metabolism between common and classic migraine.
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To study the pathogenesis of platelet activation in ischemic stroke, ionized calcium ([Cai2+]) was measured in aequorin-loaded gel-filtered platelets in the basal and stimulated state. Basal [Cai2+] was increased in stroke patients maximally 36-72 hours after onset. The increase in [Cai2+] after stimulation with thrombin, collagen, and platelet-activating factor were also greater in stroke patients, but the profiles of these [Cai2+] changes were parallel to control. Cross incubation of control platelets with plasma from stroke patients resulted in raised basal [Cai2+] and caused the release of serotonin from platelets. These results indicate that the higher platelet basal [Cai2+] in stroke patients represents a lowered threshold for activation and that this may be due to a plasmatic factor rather than a primary platelet defect.
We studied platelet function in whole blood, a situation that better reflects the in vivo state, from 85 patients with acute ischemic stroke and from 19 healthy controls. Patients receiving no antithrombotic drugs demonstrated increased platelet dense body secretion without an associated increase in platelet aggregation, thus raising the possibility that dense body secretion may be of separate importance in cerebral infarction. Our results also suggest that dense body secretion may occur independently of aggregation. Heparin and heparin plus warfarin were ineffective in reducing the high level of dense body secretion seen in acute cerebral infarction, whereas treatment with aspirin plus dipyridamole inhibited both dense body secretion and platelet aggregation. It seems worthwhile to investigate the usefulness of antiplatelet drugs in the treatment of acute ischemic stroke wherein clinical outcome is correlated with the extent of suppression of platelet dense body secretion.
We used transmission electron microscopy to count the organelles (dense bodies, alpha granules, and mitochondria) contained within platelets from 11 acute ischemic stroke patients and 12 healthy controls. We randomly selected for evaluation 25 platelet profiles in ultrathin sections cut from three separate blocks. Compared with those from controls, platelets from stroke patients contained significantly fewer alpha granules (p less than 0.001) and mitochondria (p less than 0.02) and showed a trend toward fewer dense bodies. Supportive of our previous studies, the amount of adenosine triphosphate secreted following stimulation by collagen also tended to be greater in platelets from stroke patients. These observations support the presence of increased platelet secretion associated with acute cerebral infarction and raise the possibility that platelet secretion may be of separate importance to the mechanical occlusion of blood vessels by platelet aggregates in the pathogenesis of cerebral infarction.
We investigated the effects of multiple episodes of cerebral ischemia on intracellular brain pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy. Four cats were subjected to two 16-minute episodes of complete global cerebral ischemia 6 hours apart; the second episode occurred under hyperthermic conditions (mean +/- SD body temperature 40.8 +/- 0.4 degrees C). Intracellular pH in these four cats was compared with that in nine cats subjected to a single 16-minute episode of complete global cerebral ischemia under hyperthermic conditions (mean +/- SD body temperature 40.6 +/- 0.2 degrees C). Intracellular pH during hyperthermic recirculation was significantly (p less than 0.03) greater in cats subjected to a previous ischemic event than that in cats subjected to only a single hyperthermic ischemic event. We speculate that the induction of heat shock proteins by an initial ischemic event may protect brain tissue from further ischemic insult.
We developed techniques to assess the utility of a nuclear magnetic resonance (NMR) indicator for cerebral blood flow studies in cats, using Freon-22 for the first candidate. A PIN-diode-switched NMR experiment allowed the acquisition of an arterial as well as a cerebral fluorine-19 signal proportional to concentration vs. time in a 1.89 T magnet. Mean +/- SD blood:brain partition coefficients for Freon-22 were estimated at 0.93 +/- 0.08 for gray matter and 0.77 +/- 0.12 for white matter. Using maximum-likelihood curve fitting, estimates of mean +/- SD resting cerebral blood flow were 50 +/- 19 ml/100 g-min for gray matter and 5.0 +/- 2.0 ml/100 g-min for white matter. Hypercapnia produced the expected increases in gray and white matter blood flow. The physiologic effects of Freon-22, including an increase in cerebral blood flow itself with administration of 40% by volume, may limit its use as an indicator. Nevertheless, the NMR techniques described demonstrate the feasibility of fluorine-19-labeled compounds as cerebral blood flow indicators and the promise for their use in humans.
Platelet activating factor, a potent inducer of in vivo platelet activation and thrombosis, has been shown to be excessively active in acute ischemic stroke patients. Therefore, we studied the effect of aspirin/dipyridamole therapy in inhibiting platelet activating factor-induced platelet activation in acute ischemic stroke patients, 23 taking aspirin/dipyridamole and 21 untreated. Aspirin/dipyridamole-treated patients failed to show suppression of platelet activating factor-induced platelet aggregation even though collagen-induced activation was inhibited, suggesting that platelet activating factor acts by cyclooxygenase-independent mechanisms. Failure to suppress cyclooxygenase-independent mechanisms of platelet activation may explain the limited usefulness of current antiplatelet therapy, aspirin in particular, in stroke prevention. The role of selective platelet activating factor antagonists both in isolation and combined with aspirin needs to be investigated for their usefulness in the treatment and prevention of ischemic stroke.
We heated Wistar rats (n = 10) to 41.5 +/- 0.2 degrees C for 15 minutes, 24 hours before the induction of forebrain cerebral ischemia. We subjected 23 rats to forebrain ischemia without prior heating. Ischemic cell damage in the medial, lateral, and overall CA 1/2 hippocampus, inferior frontal cortex, and dorsal-lateral striatum was significantly (p less than 0.05) less severe in heated animals than in nonheated animals.
We used in vivo phosphorus 31 nuclear magnetic resonance (31P NMR) spectroscopy to study regional high-energy phosphate and phospholipid metabolism in brains of patients with dementia associated with probable Alzheimer's disease (AD) and multiple subcortical cerebral infarctions (MSID). The MSID patients demonstrated elevations of the phosphocreatine (PCr)/inorganic orthophosphate (Pi) ratio in both the temporoparietal and frontal regions. Phosphomonoesters (PME) and the ratio of PME to phosphodiesters were elevated in the temporoparietal region of AD. Pi was also elevated in the frontal and temporoparietal regions of AD. Findings from 31P NMR were accurate in distinguishing MSID from AD. Values of PCr/Pi accurately classified 100% of the MSID patients and 92% of AD. Pi and PME, considered jointly, also accurately classified all MSID and all but 1 AD. Findings from in vivo 31P NMR spectroscopy appear to yield metabolic profiles useful in distinguishing AD from MSID.
Symptomatic common carotid artery occlusion (CCAO) is rare. We studied 17 patients with ischemic cerebrovascular symptoms and unilateral CCAO on angiography to help clarify clinical and radiologic features. Mean age was 62 years; 65% were women. Predominant symptoms and signs included visual-ipsilateral monocular or retrochiasmal symptoms (88%), motor weakness (88%), sensory disturbance (59%), dizziness/lightheadedness (53%), and syncope (24%). Dysarthria, headache, or involuntary limb shaking occurred less frequently. Positionally related symptoms occurred in approximately two-thirds of the patients. TIAs were often multiple and preceded a stroke or occurred without subsequent stroke in 82%. Hemispheric TIAs contralateral to the CCAO occurred in 41%. Ten patients (59%) suffered stroke, seven (70%) of which were ipsilateral to the CCAO. Vascular risk factors included cigarette use (76%), hypertension (71%), diabetes mellitus (41%), and hyperlipidemia (41%); 82% had two or more risk factors. Known cardiac disease was present in 59%. CCAO was present at the origin of the vessel in most patients. Most had atherosclerotic narrowing of multiple extracranial large vessels. During follow-up, none of the patients had a spontaneous second infarct; five had TIAs, including two with amaurosis fugax, all in the CCAO territory. More restricted external carotid collaterals may, in part, explain the higher frequency of ipsilateral stroke and contralateral TIAs than reported for internal carotid occlusion.
We studied 15 patients with angiographically documented intraluminal clot in the vertebrobasilar (VB) circulation and ischemic stroke. Progressive brainstem signs were the most common presentation; the neurologic deficit was maximum at stroke onset in 4. Seven experienced their first symptoms during sedentary activities. Thirteen of the initial 15 CTs revealed infarcts in the VB territory, 7 with multiple foci. Intraluminal clot was present in the vertebral artery in 7 patients (2 bilateral), basilar artery in 7, posterior cerebral artery in 5, and superior cerebellar artery in 1. Multiple clots were seen in 5 patients. Stroke risk factors were present in the majority of cases. Although cardiac source embolism was the most common single etiology (4 patients), most patients had other causes including migraine, coagulopathy associated with malignancy and nephrotic syndrome in systemic lupus erythematosus, vertebral artery dissection with local embolism, delayed irradiation arteriopathy, and a fusiform, ectatic basilar artery. Six (40%) died within 5 months of follow-up. Intraluminal clot in the posterior circulation is a marker for multiple stroke mechanisms, not all of which are embolic. Intraluminal clot should prompt investigations into occult risk factors when no cause appears obvious.