Guanidine in type B botulism.

On two occasions, guanidine produced clinical and electrophysiological improvement in a 54-year-old man with botulism, type B. However, guanidine was ineffective for autonomic dysfunction. There were no intolerable side effects. Our experience showed that guanidine is also effective in botulism, type B, as adjunctive therapy.

Transient focal ischemia in subhuman primates. Neuronal injury as a function of local cerebral blood flow.

Unilateral, transient (30, 60, and 120 minutes (min)) middle-cerebral-artery (MCA) occlusion was induced via transorbital craniotomy in 11 waking subhuman primates. Local cerebral blood flow (LCBF) was calculated from hydrogen clearance curves obtained through the use of intracerebral platinum microelectrodes. Unilateral MCA occlusion decreased LCBF in the territory of the ipsilateral MCA. Within minutes of the arterial occlusion all monkeys developed contralateral neurologic deficits that began disappearing three hours (h) after reopening the MCA. Regional ischemia, followed by 24 h of reperfusion, produced varying degrees of tissue vacuolation which correlated (r = 0.60, p less than 0.01, n = 49) with the percent reduction in LCBF multiplied by the occlusion time. Neurons were classified according to the structural features of their perikaryon. A plot of neuron types versus percent vacuolation suggested that normal neurons become increasingly scalloped under increasingly severe ischemic conditions. The number of scalloped neurons decreased precipitously in areas of marked sponginess coincident with the appearance of irreversibly damaged neurons. Local tissue edema values exceeding 30% correlated with irreversible injury to all neurons in the same area. Regional cerebral ischemia of increasing severity was acompanied by increasing numbers of lethally injured neurons.

The contribution of reoxygenation to ischemic brain damage.

This study examined the hypothesis that the level of postischemic reperfusion affects the severity of the resulting neuronal necrosis. In rats, tissue PO2% was monitored as an index of flow (reoxygenation) at four cortical sites by chronically implanted platinum electrodes. Twenty minutes of total global cerebral ischemia was followed by 30 min of reoxygenation. The level of reoxygenation was controlled to maintain the PO2 nearly constant at one or more of the cortical electrodes. Tissue from within 400 microns of each of 19 electrode sites among seven rats was evaluated histologically. There was a positive correlation between reoxygenation level and severity of neuronal damage. Perineuronal lucent halo formation, probably representing astrocyte foot process swelling, was negatively correlated with reoxygenation level. This study demonstrates that ischemic neuronal damage was aggravated by increased reoxygenation but that perineuronal swelling, as evidenced by halo formation, was somewhat ameliorated.

Pressure distribution in the pial arterial system of rats based on morphometric data and mathematical models.

The objective of the present work was a theoretical evaluation of pial arterial pressures in normotensive rats and spontaneously hypertensive rats based on the geometry and topography of the pial arterial system as well as on various topological models of the vascular trees. Pial branches of the middle cerebral artery in the diameter range of 30-320 microns were selectively visualized by corrosion compound, and the diameter and length of vascular segments were measured. The vessels were classified into branching orders by the methods of Horsfield and Strahler. The steady-state pressure distribution in the pial arterial system was calculated assuming that the flow at the bifurcations was partitioned in proportion to a given power of the diameters of the daughter branches (diameter exponent). The maximum number of vascular segments along the longest branch varied between 16 and 33. The mean branching ratio was 4.14 +/- 0.23 (SD). The mean diameter of vessels classified into Strahler orders 1-5 were: 50 +/- 12, 71 +/- 19, 106 +/- 22, 168 +/- 22, and 191 +/- 7 microns, respectively. The calculated pressure drop in the pial trees of normotensive rats was approximately twice as large in proximal orders 3 and 4 than in distal orders 1 and 2. The mean pressure in arteries of order 1 ranged from 54.4 to 58.4 mm Hg in the normotensive rat (input pressure: 83 mm Hg), and from 77.2 to 89.0 mm Hg in the spontaneously hypertensive rat (input pressure: 110 mm Hg). The coefficient of variation of terminal pressures in vessels of order 1 increased linearly with the mean pressure drop in the system. The coefficient of variation in terminal pressure had a minimum as a function of the diameter exponent in case of each pial tree. At its minimum, it was higher in all spontaneously hypertensive rats (10.1-22.9%) than in any normotensive rats (6.0-8.5%). The corresponding diameter exponents were in most cases lower in the spontaneously hypertensive rat (1.3-2.5) than in the normotensive rat (2.5-3.0). Topologically consistent models of the pial arterial network predicted significantly less variation in intravascular pressures than was obtained by direct calculations. More idealized models suggested the dependence of coefficient of variation in terminal pressure on the total number of vascular segments contained by the tree. All models predicted the existence of the minimum of coefficient of variation in terminal pressure in function of the diameter exponent.(ABSTRACT TRUNCATED AT 400 WORDS)

Concomitant EEG, lactate, and phosphorus changes by 1H and 31P NMR spectroscopy during repeated brief cerebral ischemia.

Pilots of high-performance aircraft are subject to transient loss of consciousness due to cerebral ischemia resulting from sudden high gravitational stress. To assess the effects of gravitational stress-induced blackout on cerebral metabolism and electrical function, we developed an animal model in which global cerebral ischemia is produced repeatedly at short intervals. Rats were prepared by ligation of subclavian and external carotid arteries and the right carotid artery was cannulated bidirectionally to measure circle of Willis and systemic pressures. Ischemia was induced by inflation of an occluder about the left carotid artery. Interleaved 31P and 1H NMR spectra were acquired on a 4.7-T Biospec system simultaneously with EEG recordings. We report results from 20 experiments of 30-min duration in which rats were subject to 30 1-min ischemia:reflow cycles of 10I:50R, 20I:40R, 30I:30R, and 40I:20R [numbers are seconds of ischemia (I) and reflow (R) during each 1-min cycle]. During ischemia the graded delivery of the ischemic insult permitted direct correlations between 2- to 5- and 7- to 20-Hz EEG activity and progressive changes in pH, lactate, ATP, phosphocreatine (PCr) and Pi. The best correlations were found between EEG activity and pH and PCr; correlation coefficients ranged from 0.93 to 0.95. A loss of EEG activity was observed without significant sustained energy loss in all but the most severe cycle.

Evaluation of lactate production and clearance kinetics by 1H NMR in a model of brief repetitive cerebral ischemia.

Pilots of high-performance aircraft are subject to repeated transient cerebral ischemia during high-gravitational stress maneuvers. Previously we have demonstrated that repeated episodes of transient cerebral ischemia and reflow are cumulative and lactate accumulations appear to be exponential. To evaluate the metabolic events determining the kinetics of lactate accumulation, and therefore the rates of substrate utilization, we have used in vivo 1H nuclear magnetic resonance with a 5-s time resolution to measure lactate production and clearance. The individual rates for each animal were then used to predict the accumulation of lactate in the same animal during 30 episodes of ischemia and reflow. Lactate accumulation was modeled as the balance between a zero-order production process during the ischemic period and a first-order clearance process. The predicted lactate accumulation showed excellent agreement with the observed time course, validating the predictive power of the simple model used. The highly reproducible nature of this model and its accuracy in predicting lactate accumulation should enable more accurate studies of the deleterious effects of lactate accumulation in cerebral ischemia by providing a highly reproducible means for generating a specific level of lactate accumulation.

Cerebral blood flow. A predictor of recovery from ischemia in the gerbil.

Cerebral ischemia was induced in gerbils by bilateral carotid ligation for periods of 10 to 40 minutes. Cerebral blood flow (CBF) was measured by hydrogen clearance. Following ischemia, ultimate clinical and electroencephalogram recovery could be predicted in every case within the first five minutes by recovery could be predicted in every case within the first five minutes by recovery of CBF to at least 100% of the control level. In animals without EEC recovery, the postischemic CBF was always less than 80% of control and progressively declined to zero. Residual flow during ischemia appeared to minimize the likelihood of brain death. The determination of ultimate brain death appeared to coincide with a major circulatory abnormality that is probably microvascular.

Regional cerebral blood flow comparison of right and left hand movement.

Regional cerebral blood flow measurements were made in normal right-handed subjects by the 133 xenon inhalation method at rest and during movement of either hand. Left hand movement evoked a prominent focal flow increase in the right hemisphere in the Rolandic region. During right hand movement, there was a smaller and not statistically significant increase in left hemisphere Rolandic region. This suggests that more effort is required of right-handed subjects to move the left hand than the right, or that motor organization differs for left and right hand movements. Of several flow indices tested, there was little difference among gray matter flow rate, the product of gray matter flow and relative weight, the mean regional flow, and the initial slope index, all reflecting the flow changes with nearly equal sensitivity. The gray matter weight and fractional flow did not change consistently during hand movement.

Age effects on focal cerebral blood flow changes produced by a test of right-left discrimination.

The effects of age on focal cerebral blood flow changes resulting from the cognitive processing during right-left discrimination were examined. The pattern and amount of cortical flow were comparable for young and middle-aged subjects and consisted of flow increases in bilateral frontal, parietal and occipital regions. Task performance was negatively related to activation from left parietal and occipital channels. The frontal activation and the parietal correlation were attributed to the middle-aged subjects experiencing increased emotional arousal and attention to the right-left discrimination task due to hypothesized differences in cognitive effort and style, and/or novelty of formal examination situations.

Focal right temporo-occipital blood flow changes associated with judgment of line orientation.

Focal cerebral blood flow changes for judgment of line orientation were determined using the 133Xe inhalation technique with 18 normal right-handed male subjects. Measurements were made during three conditions in the same session: a line orientation task, a sensorimotor control task, and normal rest. Blood flow changes attributable to the judgment of line orientation were found for the measure f1 at a detector centered over the right temporo-occipital region. For the measure IS this activation was significant in the temporo-occipital region in both hemispheres but significantly greater in the right hemisphere. For f1 the change in blood flow and for IS the percent change in blood flow in the right temporo-occipital region attributable to judgment of line orientation decreased as performance on the line orientation task improved.

Relevance of sensorimotor task components to the interpretation of task related blood flow changes.

This study demonstrated the importance of documenting rCBF changes produced by the sensorimotor components of a cognitive task when making inferences regarding brain-behavior relations. Subjects were ten young, non-smoking adult, right-handed, normal male volunteers. They were administered two tasks having identical cognitive and similar sensory components but different response modalities (oral vs manual). The two tasks produced highly divergent rCBF landscapes. In conjunction with the results from a previous rCBF activation study, these data were used to illustrate the necessity of including sensorimotor control tasks in cognitive activation studies designed to elucidate brain-behavior relations.

Biological and neuropsychological characterization of physostigmine responders and nonresponders in Alzheimer's disease.

To assess the efficacy of oral physostigmine for the treatment of Alzheimer's disease, 20 patients were entered into a clinical trial. All patients underwent a dose-finding phase (two weeks), followed by an open trial (two weeks), and a double-blind crossover phase (two weeks drug, two weeks placebo). Extensive neuropsychological testing (Buschke Selective Reminding procedure, category generation, picture recognition, finger tapping) and measurement of systemic cholinergic parameters were measured during each of these phases. Patients were classified as physostigmine responders and nonresponders based on a priori established criteria. Using these, nine patients were found to respond to physostigmine, while 11 were classified as nonresponders. During baseline conditions, responders when compared to nonresponders were found to have higher concentrations of red blood cell (RBC) choline (Ch) and higher ratios of RBC Ch to plasma Ch. Neuropsychological tests were found to fall into one of three categories. The first group of tests were sensitive to drug effects and differentiated physostigmine responders from nonresponders; the second group was found to predict responsiveness; and the third group was neither predictive nor sensitive to drug effects.

Correlation of cerebral blood flow and EEG during carotid occlusion for endarterectomy (without shunting) and neurologic outcome.

One hundred twenty-nine consecutive carotid endarterectomies performed for atherosclerotic ulcerative stenosis without the use of intraoperative shunting were analyzed prospectively in an effort to determine the significance of intraoperative ischemia. Intraoperative EEG and regional cerebral blood flow measurements were used to monitor these patients. Ten of the patients were excluded because of inadequate data, but none of these 10 patients experienced a complication. Factors analyzed included preoperative risk assessment according to the Mayo Clinic system of Sundt et al., intraoperative regional cerebral blood flow measurements, and intraoperative EEG changes. The overall mortality rate was 2.5%, the major morbidity rate was 2.5%, the minor morbidity rate was 1.7%, and the rate of transient neurologic dysfunction was 1.7%. The patients' preoperative state as determined according to the Mayo Clinic system of Sundt et al. was more useful in identifying patients at risk than was intraoperative EEG and regional cerebral blood flow monitoring.

rCBF for middle-aged males and females during right-left discrimination.

rCBF was measured in 10 male and 10 female normal righthanders with an average age of 44.2 years. For the measures f1 and IS significant occipital lobe activation was produced bilaterally and for the measure IS significant left hemisphere parietal activation was produced also by a visually presented right-left discrimination cognitive activation task over and above the activation produced by a sensorimotor control task. The amount and pattern of blood flow changes were similar for both sexes. Performance of males on the cognitive task was not significantly better than that of females. However, an inverse relationship was found for males but not females between cognitive task performance and percentage increase in IS for all regions showing significant cognitive activation.

The importance of cerebral ischemia during carotid endarterectomy.

The importance of cerebral ischemia produced by carotid clamping during carotid endarterectomy remains controversial. In an effort to determine the importance of cerebral ischemia during carotid endarterectomy, 369 patients undergoing 431 consecutive carotid endarterectomies were studied by Xenon-133 (133Xe) clearance and electroencephalogram (EEG) monitoring. None of the patients was shunted during the procedures. The severity of ischemia as indicated by 133Xe clearance from the ipsilateral hemisphere during 20 to 30 minutes of carotid occlusion did not predict the appearance of complications in this group of patients (chi 2 = 1.417; P = 0.841). There was a highly significant relationship between the depth of cerebral ischemia as demonstrated by 133Xe clearance and the appearance of abnormalities on the EEG (chi 2 = 42.043, P less than 0.0001). In the subgroup of patients developing abnormalities as shown by EEG, there was a negative correlation (chi 2 = 17.495; P less than 0.002) between reduction in blood flow and the appearance of complications, in that the higher the blood flow during occlusion the more likely the patient developing EEG changes would develop complications.

Method for measuring brain tissue pressure. Response to alteration in pCO-2 systemic blood pressure, and middle cerebral artery occlusion.

The authors report a method for measuring total local brain tissue pressure (BTP) using a miniature catheter transducer stereotaxically introduced into the white matter of the cat's cerebrum. Quantitative rapid phasic pressure changes were satisfactorily demonstrated. Due to some drift of baseline of the transducers and inability to perform in vivo calibration, reliable long-term quantitative pressure measurements sometimes could not be studied. The BTP from each cerebral hemisphere and the cisternal pressure (CP) were monitored during alterations of pCO-2 and systemic blood pressure, and distilled H20 injection prior to and after right middle cerebral artery (MCA) ligation. The catheter transducers functioned well on chronic implantation for up to 6 weeks. Compared to the chronically implanted catheters, acutely implanted catheters responded identically except for drift. The response of intracranial pressure and CP to MCA occlusion, alterations in pCO2, and systemic blood pressure were similar. No BTP gradients appeared in response to MCA ligation, hypercapnia, hypertension, or progressive swelling of the resulting infarction.

Transcranial Doppler in acute brain stem infarction.

Two patients with acute brain stem infarctions were examined angiographically and with the transcranial Doppler. One patient had a patent basilar artery but worsened clinically. The second patient had a thrombosis of the left vertebral artery which was dislodged with the angiographic catheter. Thrombolytic therapy was initiated. Serial transcranial Doppler examinations showed persistent patency of the vertebrobasilar system although the patient failed to improve. The usefulness of the transcranial Doppler in the management of acute stroke is discussed in the context of these patients.

Stability of oxygen transmissibility during ischemia.

Simultaneous measurements of oxygen availability (O2a) and partial pressure (PO2) were made by the double noble metal electrode system designed by Erdmann and Krell in an attempt to monitor the oxygen transmissibility (Dk) with respect to time before and after ischemic episodes in the brain cortex. Available current equations can appropriately describe the performance of the electrode in a homogeneous nonconsuming medium, and with some experimental error this electrode system can be used to estimate oxygen transmissibility changes in the brain based on the different characteristics of the O2a (rod-type, flush-ended bare tip) and the PO2 (rod-type, recessed tip) cathodes. Our method monitors the oxygen transmissibility within the diffusion sphere of the bare tip as the ratio of the currents related to O2a and PO2. We find with this system that even prolonged global cerebral ischemia does not alter the oxygen transmissibility of the brain tissue. Therefore, alternation of the oxygen transmissibility can not be a contributing factor to postischemic cerebral malfunction.

A mathematical model of the intracerebral steal phenomenon in regional and focal ischaemia.

The objective of the present work was to mathematically estimate the extent and dynamics of intracerebral steal which may occur in response to cerebral vasodilation in regional and focal cerebral ischaemia. To this end, a spatially distributed mathematical model of regional cerebral blood flow (rCBF) was developed. The model contained a parallel system of intracerebral vascular resistances which were connected in series to a lumped extracerebral artery resistance and, for the focal ischaemia model, also a lumped pial collateral resistance. The rCBF was measured at 30 min of ischaemia in the following models: (1) bilateral carotid occlusion in spontaneously hypertensive rats (SHR), and (2) occlusion of the middle cerebral artery (MCA) in normotensive rats. The measured 3-dimensional rCBF data were used to set up the initial values of intracerebral resistance components. Cerebral vasodilation induced by inhalation of CO2 was simulated in the model by decreasing the values of both intracerebral and collateral resistance. Vascular responsiveness was specified to decrease with the ischaemic rCBF. In addition, a long term change in rCBF and resistance distribution was introduced to account for: (1) gradual rise in intracerebral resistance due to ischaemic oedema, and (2) adaptive decrease in collateral resistance. The following were predicted by the mathematical model. (1) At 60% maximum intracerebral dilatation a small intracerebral steal (5-10%) occurs at flow levels below 30-50 ml/100 g/min in both ischaemic models. (2) In focal ischaemia, the steal can be compensated by the 5% to 20% decrease in the collateral vascular resistance. (3) The rate of collateral adaptation overcomes the rate of intracerebral resistance rise and, therefore, eliminates the intracerebral steal after an adequately long period of time (on the order of a few hours). (4) An inverse steal effect can be demonstrated at the end of vasodilatation, provided that the time constant of collateral adaptation selected is longer (about 5:1) than the time constant of the intracerebral resistance rise. We conclude that the prediction of rCBF response to vasodilatation in cerebral ischaemia requires a knowledge of resting rCBF and of the response characteristics of both intracerebral and pial arterial segments.

A critical evaluation of oxygen disappearance during stop flow in the gerbil brain.

The rate of oxygen disappearance from the gerbil cerebral cortex was measured during bilateral carotid artery occlusion with an oxygen microelectrode at normal tissue PO2 and under hyperbaric oxygenation. The oxygen disappearance rate (ODR) was found to be heavily dependent on the PO2 at occlusion due to the desaturation of hemoglobin-bound oxygen. When the tissue PO2 was elevated to a level high enough to saturate hemoglobin, the ODR reflected the oxygen consumption rate which was calculated to range from 1.6-7.4 cc O2/100 cc tissue-min. for ten barbiturate-anesthetized animals. The fall in PO2 was found not to be totally linear to zero in many cases, but instead consisted of a linear phase followed by a period of decreasing slope. We believe this phase of changing slope represents a diminishing oxygen consumption rate. The exact nature of this decrease is not known but perhaps is an inhibitory response to the accumulation of metabolites as a result of the circulation arrest.