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Twelve children with fibromyalgia and complaints of chronic dizziness were evaluated with both clinical office maneuvers of vestibular function and laboratory tests composed of electronystagmography and sinusoidal harmonic acceleration rotary chair testing. All test results were normal for spontaneous nystagmus with or without visual fixation, oculocephalic reflex, dynamic visual acuity, head-shaking nystagmus, Quix test, and Dix-Hallpike maneuver. Electronystagmography test results were essentially normal for saccades, gaze, Dix-Hallpike, pendular tracking, and caloric evaluation. Rotary chair testing was normal in all 12 patients. These findings suggest that central (brainstem) and peripheral vestibular (inner ear) mechanisms do not account for the complaints of dizziness in the pediatric patient with fibromyalgia. The common musculoskeletal abnormalities of fibromyalgia may affect their proprioceptive orientation, therefore giving them a sense of imbalance.

The role of canal-wall-down (CWD) versus intact-canal-wall (ICW) mastoidectomy in the treatment of chronic otitis media with or without cholesteatoma remains a debated issue. Although past conventional wisdom has held that CWD mastoid surgery leads to a "safe" ear and is technically less demanding than the more controversial ICW mastoidectomy, this is often not the case. Although our preference is an ICW technique when possible, 47 of 109 (43%) mastoid procedures for chronic otitis media performed between January 1993 and June 1996 involved a CWD mastoid cavity. More than two thirds of these procedures (32 of 47) represented revision surgery, the most common indication being a poorly contoured, preexisting CWD mastoidectomy with persistent otorrhea. A dry, well-epithelialized ear was obtained in 90% of cases. Our preferred method of ossicular reconstruction (double cartilage block ossiculoplasty) is detailed, and hearing results according to American Academy of Otolaryngology Head and Neck Surgery guidelines are reported.

Objectives/hypothesis: Multiple techniques of ossicular reconstruction have been advocated for hearing rehabilitation in the setting of chronic otitis media No single method can adequately address the clinical spectrum of disease severity. In the situation of a severely diseased ear requiring a canal wall down (CWD) mastoidectomy in the presence of an intact stapes superstructure, the authors have employed a double cartilage block (DCB) ossiculoplasty. The technique and short-term results are reviewed., Study Design: Retrospective chart review in a tertiary referral otologic practice., Methods: Twenty-three patients underwent a CWD tympanomastoidectomy with DCB ossiculoplasty. Ages ranged from 6 to 85 years (mean, 36.1 y). The majority of ears were actively draining at the time of surgery (83%) and most procedures were revisions of prior mastoidectomies (74%). Audiometric data (mean postoperative follow-up, 19.5 mo) were calculated according to 1995 American Academy of Otolaryngology-Head and Neck Surgery guidelines., Results: Audiometric results were available in 20 patients. The mean air-bone gap (ABG) was 23.8 dB after surgery. Closure of the ABG to within 20 dB was achieved in 10 of 20 patients (50%). No cases of DCB extrusion have occurred to date., Conclusions: The DCB represents an excellent alternative to biocompatible prostheses for ossicular reconstruction in the setting of severe chronic ear disease. As with all methods of ossiculoplasty, long-term follow-up will be necessary to determine if this technique remains stable in the hostile environment in which it has been employed.

Release of nitric oxide occurs as a consequence of glutamate stimulation of NMDA receptors and is dependent upon calcium-calmodulin activation of the enzyme nitric oxide synthase. Since nitric oxide may serve as an intracellular messenger for NMDA glutamatergic neurons, it could be hypothesized that blockade of its synthesis may produce pharmacological effects similar to those of NMDA receptor antagonists. The purpose of the present study was to compare the effects of nitric oxide synthase inhibitors to those of the high affinity NMDA open channel blocker phencyclidine in drug discrimination, a pharmacologically selective procedure in which phencyclidine produces distinctive effects. Rats were trained to discriminate 2 mg/kg phencyclidine from saline in a standard two-lever discrimination task with food reward. Whereas phencyclidine dose-dependently substituted for itself, 7-nitroindazole, L-NAME (N(G)-nitro-L-arginine methyl ester), and L-NOARG (N(G)-nitro-L-arginine) failed to substitute for phencyclidine when administered intraperitoneally. L-NAME and 7-nitroindazole were tested up to doses that disrupted responding, providing evidence that a behaviorally-relevant dosage range was evaluated. Although these results conflict with those of a previous study which found that nitric oxide synthase inhibitors substituted for phencyclidine and produced phencyclidine-like catalepsy in pigeons, they are consistent with research showing that these drugs did not produce phencyclidine-like pharmacological effects in behavioral procedures in rats.

Intravenous lidocaine has been reported to alleviate vertigo in Meniere's disease and suggested as a possible antivertigo agent after unilateral labyrinthectomy in a study of cats. To further evaluate the effects of intravenous lidocaine on the acute phase of postural compensation, we subjected 13 pigmented guinea pigs to unilateral labyrinthectomy. Seven received intravenous lidocaine (4 mg/kg) immediately after labyrinthectomy. The other six served as controls and received an equivalent-volume injection of normal saline solution. Total body curvature, trunk curvature, yaw head tilt, and roll head tilt were measured at frequent intervals for up to 30 hours after surgery. Both groups had immediate difficulties with posturing that gradually improved. The lidocaine group tended to exhibit delayed postural compensation, but this was only statistically significant for roll head tilt. These results do not show improvement in postural compensation from unilateral labyrinthectomy after the administration of intravenous lidocaine. A species-specific effect on the vestibular pathways is suggested, and we conclude that further evaluation of lidocaine and the vestibular system is warranted.

Endothelin is a potent vasoactive peptide whose concentration increases in a number of pathophysiological states. In the intact animal, the liver is known to sequester approximately 12% of an injected bolus of [125I]endothelin-1 ([125I]ET-1). Endothelial cells (ECs) isolated from rat liver were maintained in culture in order to examine their role in ET sequestration. LECs were shown to express predominantly ET(B) receptors both by association assays and by Northern blot analysis. In these cells the reaction between [125I]ET-1 and its receptor was essentially irreversible. Ligand binding experiments performed at 4 degrees C showed that LECs in early culture (approximately 3 h) had 4.3 +/- 0.8 fmol of ET receptors per 10(6) cells; this number fell progressively to < or = 1 fmol/10(6) cells during 24 h of culture. The decrease in receptor numbers could be blocked by maintaining the cells at 4 degrees C. Northern blot analysis showed that relative to freshly isolated cells, mRNA for the ET(B) receptor decreased 4-fold in early culture, and recovered somewhat at 24 h. At 37 degrees C [125I]ET-1 bound by the cells was rapidly internalized, with concomitant down-regulation of ET receptors. Recovery of down-regulated ET receptors was sensitive to cycloheximide, making short-term receptor recycling unlikely. Metabolism of [125I]ET-1 was low at short (< 4 h) exposure times, and at 24 h showed a concentration dependence similar to that of ligand association, suggesting that ET-1 metabolism primarily was intracellular. ET stimulation of Kupffer cells and other hepatic cell types is known to activate phosphoinositide signaling, but no such activation was seen in LECs. Moreover, ET did not appear to stimulate protein tyrosine kinase activity in LECs. While hepatic LECs may lack some of the ET-dependent responses seen in other cell types, they likely contribute substantially to the liver's previously reported ability to sequester systemically administered ET.

Controversy exists as to whether a sex bias exists that affects the diagnostic approach to suspected coronary artery disease: previous studies have used coronary angiography, but not other noninvasive testing, as a primary end point. This investigation examined posttest sex differences in diagnostic evaluation after exercise treadmill testing according to a broader end point than just coronary angiography alone. The design was a cohort analytic study with a 90-day follow-up. The study was done at the Cleveland Clinic Foundation, an academic group practice. Patients included consecutive adults (1023 men and 579 women) with chest pain but no documented coronary disease who were referred for symptom-limited exercise treadmill testing without adjunctive imaging; none had undergone prior invasive cardiac procedures. Main outcome measures included (1) performance of any subsequent diagnostic study (invasive or noninvasive) and (2) performance of coronary angiography as the next diagnostic study. During follow-up, 89 (8.7%) men and 48 (8.3%) women underwent a second diagnostic study (odds ratio 0.95; 95% confidence interval 0.66 to 1.37; p > 0.8), whereas 64 (6.3%) men and 21 (3.6%) women went straight to coronary angiography (odds ratio 0.56; 95% confidence interval 0.34 to 0.93; p = 0.02). In multivariable logistic regression analyses, which considered baseline clinical characteristics, the ST-segment response, and other prognostically important exercise responses, women tended to be less likely than men to be referred to any second test (adjusted odds ratio 0.70; 95% confidence interval 0.42 to 1.19; p > 0.1) but were markedly and significantly less likely to be referred straight to coronary angiography (adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.65). After exercise treadmill testing, women were only slightly less likely than men to be referred for subsequent diagnostic testing; they were, however, much less likely to be referred straight to coronary angiography as opposed to another noninvasive study.

Although use of the laser for stapedectomy has become common in recent years, controversy remains regarding whether the CO2 or visible-spectrum lasers (argon and KTP) are best suited for this operation. The main concern has been the potential for thermal injury to the inner ear with the visible-spectrum lasers attributable to their absorption characteristics. To further investigate this issue, the author performed 20 laser stapedectomies on adult chinchillas. Following placement of a 0.127-mm-diameter copper/constantan thermocouple (sampling at 12 Hz) beneath the footplate on the medial wall of the vestibule via a distant fenestration site, thermal changes with a micromanipulator-based CO2 and fiberoptic KTP system were compared. This was the first live animal model comparison of these two lasers. There was no statistical difference in the mean temperature elevation between the two systems (P = 0.395).

Proper healing after surgery of the external auditory canal and open-cavity mastoid depend on epithelialization of exposed surfaces. This may be retarded by the formation of abundant granulation tissue or cicatrix, which can be dealt with by the use of thin, split-thickness skin grafts. This technique, which has received little attention in the literature, is described in detail and nine cases treated for various disorders are illustrated. Patient ages ranged from 5 to 80 years and the mean follow-up was 17.2 years. Results, complications, and caveats for successful grafting are presented.

Objectives: We sought to determine the relative influence of estimated functional capacity and thallium-201 (Tl-201) single-photon emission computed tomographic (SPECT) findings on prediction of short-term all-cause and cardiac-related mortality., Background: Decreased functional capacity and abnormal Tl-201 SPECT findings are predictive of increased cardiovascular risk and mortality. However, the relative importance of these variables as predictors of all-cause mortality is not well established., Methods: Analyses were based on 3,400 consecutive adults undergoing symptom-limited exercise Tl-201 SPECT testing at the Cleveland Clinic Foundation between September 1990 and December 1993; none had previous invasive procedures, heart failure or valve disease. Estimated functional capacity, classified by age and gender, and thallium perfusion defects, expressed as a stress extent thallium score on a 12-segment scale, were analyzed to determine their relative prognostic importance during 2 years of follow-up., Results: Of 3,400 patients, 108 (3.2%) died during follow-up; 32 deaths were identified as cardiac related. On univariable analysis, estimated functional capacity was a strong predictor of death, with 62 (57%) deaths occurring in patients achieving < 6 metabolic equivalents (METs) (log-rank chi-square 86, p < 0.0001). On multivariable analysis, the strongest independent predictors of all-cause mortality were fair or poor functional capacity (adjusted relative risk [RR] 3.96, 95% confidence interval [CI] 2.36 to 6.64, chi-square 27, p < 0.0001) and age (adjusted RR for 10 years 2.25, 95% CI 1.80 to 2.80, chi-square 27, p < 0.0001). The presence of SPECT thallium perfusion defects was a less powerful predictor of death (for each two additional segments with defects, adjusted RR 1.21, 95% CI 1.03 to 1.43, chi-square 5, p = 0.02). Cardiac mortality was predicted by both fair or poor functional capacity (adjusted RR 4.37, 95% CI 1.59 to 12.00, chi-square 8, p = 0.004) and by stress extent thallium score (adjusted RR 1.62, 95% CI 1.25 to 2.11, chi-square 13, p = 0.0003)., Conclusions: In this clinically low risk group, estimated functional capacity was a strong and overwhelmingly important independent predictor of all-cause mortality among patients undergoing exercise Tl-201 SPECT testing. The extent of myocardial perfusion defects was of comparable importance for the prediction of cardiac mortality.

Osteogenesis is a complex process whereby growth factors and mediators from both local and systemic sources modulate the bone-forming activities of osteoblasts. In the present study we utilized primary cultures of fetal rat calvarial cells to characterize osteoblast responsiveness to the vascular mediator endothelin-1 (ET-1) and to investigate whether ET-1 responses are regulated by osteogenic protein-1 (OP-1). We found that a 1- to 2-day exposure to OP-1 diminished ET-1 receptor ligand binding and signal transduction by downregulating ET-1 receptor mRNA expression. ET-1-mediated calcium signaling and ligand binding were completely abolished by the ETA receptor antagonist BQ-123, suggesting that ET-1 effects are mediated by this receptor. Northern analysis of total RNA revealed that ETA mRNA expression was inhibited approximately 50% by OP-1 treatment, whereas ETB receptor mRNA was not detected by this method of analysis. In OP-1-treated cultures, the magnitude and duration of ET-1 calcium signals varied among individual cells. This finding may be related to a heterogeneous OP-1 response, indicated by alkaline phosphatase induction in only a subpopulation of cells. These results suggest that modulation of osteoblast function by ET-1 occurs during distinct periods of phenotypic development and imply that downregulation of ET-1 responsiveness may be necessary for optimal bone formation in vivo.

Objective: The objective of this study was to determine the usefulness of the head impulse test (HIT) and head-shake nystagmus (HSN), two easily performed office maneuvers, in the evaluation of the dizzy patient with reference to caloric irrigation results., Objective and Setting: This was a prospective double-blind trial conducted at an outpatient academic tertiary referral center., Patients: The study population was composed of 105 patients (35 male, 70 female) who presented for evaluation of dizziness and ranged in age from 13 to 87 years (mean 52.1)., Intervention: The intervention was HIT and HSN evaluation followed by bithermal binaural air caloric irrigations., Main Outcome Measures: The main outcome measures were sensitivity, specificity, and predictive values of HIT and HSN evaluation (individually and in combination) in relation to caloric results., Results: Sensitivity of the tests was equally low (35%), whereas specificity was high (HIT 95%, HSN 92%). The positive predictive value for the two tests in combination (80%) was greater than for each individually (HIT 64%, HSN 50%). Negative predictive values remained stable when considering each test individually (HIT 86%, HSN 86%) or in combination (88%)., Conclusions: The low sensitivity renders both tests inadequate as a screening tool for peripheral vestibular disease based on caloric results. However, when HIT and HSN results are both abnormal, there is a high likelihood of a significant caloric deficit.

This study investigated the association between age and referral to coronary angiography among ambulatory adults with an abnormal treadmill thallium scan. The subjects studied were 416 consecutive adults who were > or = 30 years old, under the care of cardiologists, and had an abnormal treadmill thallium scan between 1990 and 1993 at the Cleveland Clinic Foundation. The primary end point was performance of coronary angiography within 90 days of the treadmill test. Coronary angiography was performed in 163 subjects. Coronary angiography was performed in 46% of patients aged 30-49 years, in 53% of those aged 50 to 64 years, in 33% of those aged 65 to 74 years, and in only 18% of those aged > or = 75 years (chi2 test for trend, p < 0.0001). After adjustment for potential confounders, age remained associated with a lower rate of referral to angiography (p < 0.0001). During 2 years of follow-up 34 deaths occurred (14 cardiac), with particularly high mortality rates among those aged >74 years (cumulative rate 31%, 95% confidence interval 16% to 47%). The number of abnormal thallium scan segments was predictive of death (p = 0.02). These data suggest that increasing age is associated with a lower rate of referral to coronary angiography after an abnormal treadmill thallium test.

Considerable controversy exists regarding whether women are less likely than men to be referred to coronary angiography after an abnormal noninvasive test. This prospective cohort study analyzed consecutive subjects (2,351 men and 1,318 women) with no prior history of invasive cardiac procedures who were referred for treadmill thallium testing at the Cleveland Clinic Foundation. The primary end point was performance of coronary angiography within 90 days of treadmill thallium testing. A secondary end point was all-cause mortality during 1.8 years of follow-up. Women were less likely than men to undergo coronary angiography (6% vs 14%, odds ratio [OR] 0.42, 95% confidence interval [Cl] 0.33 to 0.54, p < 0.001), but were also less likely to have an abnormal thallium scan (8% vs 29%, p < 0.001). In logistic regression analyses with adjustment for thallium result and age, women were as likely as men to be referred for coronary angiography (adjusted OR 1.00, 95% Cl 0.75 to 1.34, p > 0.9). Women were less likely to have severe coronary disease on angiography (15% vs 30%, p = 0.006). During 1.8 years of follow-up there were 26 deaths (2%) among women and 84 deaths (4%) among men. After adjusting for age, thallium abnormalities, and clinical characteristics in Cox regression analyses, women had a lower mortality rate than men (relative risk 0.58, 95% Cl 0.36 to 0.94, p = 0.03). Thus, gender-related differences in referral for coronary angiography after treadmill thallium testing can be explained by a higher rate of abnormal tests in men. No evidence of a post-test gender bias was detected, but a pretest bias affecting referral to nuclear testing cannot be excluded. Furthermore, women have a lower prevalence of severe coronary disease and a lower adjusted mortality rate.

A retrospective review is presented of revision stapedectomies performed by the senior authors between 1986 and 1994. A total of 106 stapedectomies was performed during that period, of which 30 were revisions. These revisions were within the first 100 stapedectomies performed by the senior authors. Most failures occurred early in the series. The overall success rate for closure to within 10 dB was 52%, and the average closure was 12.72 dB. Five cases were performed without the laser with no successes and an average closure of 27 dB. After the use of the laser, the success rate was 64%, and the average closure was 9.75 dB. There was a statistically significant difference between the hearing results with and without the laser (p < 0.01). The prognosis was better when surgery was performed primarily for hearing loss and with the laser, with success in 13 (72%) or 18 cases. In two cases, there was a sensorineural decline > 10 dB. The only dead ear occurred preoperatively in a patient with a granuloma. We have found the use of the CO2 laser in revision stapedectomy to be a safe technique that produces reliable results.

Depression following a cerebrovascular accident is common, disabling, and treatable. However, the consequences of a stroke often render the clinical evaluation for depression misleading or difficult to interpret. These factors make a laboratory test for depression especially desirable in this population. We reviewed and evaluated the literature on the dexamethasone suppression test (DST) as a diagnostic tool for depression in stroke patients. Nine studies were identified. Our findings included (1) substantial variation in both methods and results, (2) a median specificity of 87%, and (3) a median sensitivity of 47%. We show that if these estimates of sensitivity and specificity are supported by future studies with improved methodology, then the DST may be clinically useful for the minority of stroke patients in whom a careful evaluation for depression remains inconclusive.

Inappropriate chronotropic response to exercise has been observed to correlate with poor prognosis in patients with coronary disease, but the mechanism for this association is not well defined. We attempted to examine the association between chronotropic response to exercise and angiographic severity of coronary disease in patients with suspected or stable coronary artery disease. The chronotropic response, expressed as peak heart rate, chronotropic index (ratio of heart rate reserve and metabolic reserve utilized), or percent maximal heart rate achieved, was correlated with angiographic findings obtained within 180 days of the test. Significant coronary disease was defined as > or = 1 stenosis of > or = 50% in a major epicardial artery or its main branches; severe coronary disease was defined as > or = 50% stenosis in all 3 epicardial arteries, or in the left main coronary trunk, or 2-vessel disease with > or = 70% proximal left anterior descending artery stenosis. We observed that peak heart rate and percent maximal heart rate achieved were independent negative predictors of both significant and severe coronary disease by logistic regression. The chronotropic index predicted severe coronary disease only. All 3 parameters of chronotropic response exhibited a significant gradient of abnormality across the spectrum of coronary disease (p < 0.01 for all), expressed by the number of vessels involved and correlated with left anterior descending artery involvement (p < 0.05 for all). We conclude that chronotropic response to exercise predicts the presence and angiographic severity of coronary disease. This association is likely related to the proportion of left ventricular myocardium rendered ischemic during stress.

Objectives: This study was designed to assess the angiographic and prognostic implications of an exaggerated systolic blood pressure response to exercise ("exercise hypertension") in adults undergoing evaluation for suspected coronary artery disease., Background: The clinical implications of exercise hypertension are unclear., Methods: Subjects for this prospective cohort study were derived from a consecutive sample of 9,608 adults who were referred for treadmill testing and who augmented their systolic blood pressure by at least 10 mm Hg. There were 594 subjects who underwent coronary angiography within 90 days of treadmill testing. Exercise hypertension was defined as a peak exercise systolic blood pressure > or = 210 mm Hg in men and > or = 190 mm Hg in women. Severe angiographic coronary disease was defined as left main coronary artery disease (> or = 50% diameter stenosis), three-vessel disease (> or = 70% diameter stenosis) or two-vessel disease with > or = 70% diameter stenosis of the proximal left anterior descending coronary artery. All-cause mortality was assessed during a follow-up period of approximately 2 years., Results: Exercise hypertension was present in 196 subjects (33%). Severe coronary disease was less common in subjects with exercise hypertension (14% vs. 25%, odds ratio 0.51, 95% confidence interval [CI] 0.32 to 0.81, p = 0.004). Exercise hypertension remained associated with a lower rate of severe coronary disease even after adjusting for rest hypertension, age, gender, exercise capacity and other possible confounders. During the follow-up period, there were 23 deaths; only 2 occurred in the group with exercise hypertension. After adjusting for severity of coronary disease, exercise hypertension remained associated with a lower mortality rate (adjusted relative risk 0.20, 95% CI 0.05 to 0.84, p = 0.03)., Conclusions: In adults evaluated for coronary artery disease, exercise hypertension is associated with a lower likelihood of angiographically severe disease and a lower adjusted mortality rate.

Circulating endothelin (ET) levels are elevated in conditions such as endotoxemia, hepatic ischemia-reperfusion injury, or orthotopic liver transplantation, and this potent peptide may contribute to hepatic pathophysiology. We measured the surface binding of [125I]ET-1 to rat Kupffer cells in primary culture at 4 degrees C; the dissociation constant (Kd) was 270 pmol/L, and the apparent Bmax was 3,000 receptors/cell. At 37 degrees C, total association (surface binding plus internalization) was much greater than at 4 degrees C, indicating that internalization of the receptor-ligand complex is rapid; the apparent Kd was 30 pmol/L, comparable with other reports for hepatic-derived cells. Studies using [125I]ET-1, [125I]ET-3, and specific ET (ant)agonists showed that Kupffer cells possess predominantly ET(B) type receptors. Prior treatment with 500 pmol/L unlabeled endothelin rapidly ( < 15 minutes) occluded 60% of subsequent [125I]ET association; using 5 nmol/L unlabeled ET, this occlusion occurred within 1 minute. [125I]ET association with Kupffer cells was unaffected by short-term (approximately 1 hour) treatment with cyclic adenosine monophosphate (cAMP), but long-term (20 hour) treatment resulted in a twofold increase in [125I]ET association with no change in the apparent Kd. Stimulation of protein kinase C in Kupffer cells by phorbol 12-myristate acetate had a dual regulatory effect on [125I]ET association. Short-term ( < 1 hour) treatment with phorbol 12-myristate acetate decreased [125I]ET-3 association by 50%, whereas prolonged treatment (20 hour) increased association twofold. In both cases, the apparent Kd for [125I]-endothelin was unaltered.

Endothelins are potent peptide mediators that elicit glycogenolytic and vasoconstrictor actions in the liver. Endothelins were found to stimulate the synthesis and release of the lipid mediator platelet-activating factor in cultured rat Kupffer cells. Endothelin-mediated synthesis of platelet-activating factor required extracellular calcium in that the calcium chelator, EGTA and nifedipine, a calcium ion channel blocker, inhibited platelet-activating factor synthesis. The phospholipase A2 inhibitor, 4-bromophenacyl bromide, strongly inhibited endothelin-induced platelet activating factor synthesis. Endothelin-stimulated platelet activating factor synthesis was inhibited after treatment of Kupffer cells with cholera toxin, whereas pertussis toxin inhibited only this response to endothelin-1. Agents that elevate intracellular cyclic AMP levels were found to inhibit endothelin-induced platelet-activating factor synthesis in Kupffer cells. Staurosporine, a protein kinase C inhibitor minimized endothelin-induced platelet-activating factor synthesis but phorbol myristate acetate, an activator of protein kinase C, did not affect endothelin-induced platelet activating factor synthesis. Thus, the current study demonstrates that activation of an endothelin receptor in cultured rat Kupffer cells results in the synthesis and release of platelet-activating factor. The importance of endothelin-mediated platelet-activating factor synthesis relates to the mechanism of intercellular signaling occurring between endothelial cells (i.e., the site of endothelin synthesis) and Kupffer cells (i.e., the site of formation of secondary mediators such as platelet-activating factor and eicosanoids) within the rat liver exposed to various types of pathophysiological episodes.

A modification of the liberatory maneuver was used to treat 25 patients with benign paroxysmal positional vertigo (BPPV). The modified liberatory maneuver relieved symptoms without recurrence in 11 (44%) patients. A partial response was noted in 6 (24%) patients, and there was no improvement in 8 (32%) patients. Follow-up ranged from 1 to 20 months (median 4.0 months). Patient age was not predictive of response to treatment. Duration of symptoms before treatment, however, was greater in nonresponders (median 15.5 months) than in complete (median 5.0 months) or partial (median 3.5 months) responders. The modified liberatory maneuver takes approximately 5 minutes to perform and provides effective treatment in two thirds of patients who suffer from BPPV.

Platelet-derived growth factor (PDGF) stimulates mitogenesis and exerts other biologic activities in glomerular mesangial cells. The precise mechanism of PDGF-induced mitogenesis in these cells is not clear. The activation of a signal transducing enzyme, phosphatidylinositol 3 kinase (PI 3 kinase) is associated with mitogenesis. Activation of PI 3 kinase results from stimulation of tyrosine kinase and G-protein-coupled classes of receptors. The synthesis of D3 phosphorylated inositides, the products of this enzymatic reaction, in non-nucleated cells such as blood platelets is dependent upon protein kinase C activation and G-proteins. We studied the activation of PI 3 kinase in response to PDGF in human glomerular mesangial cells. Using a PI 3 kinase 85 kD subunit specific antibody, we detected mesangial cell PI 3 kinase protein as 110 and 85 kD heterodimer. PDGF stimulated PI 3 kinase activity in antiphosphotyrosine immunoprecipitates in a dose-dependent manner showing maximum activation at 12 ng/ml. The antiphosphotyrosine associated PI 3 kinase activity showed biphasic kinetics with a fast peak within two minutes followed by a second peak at 10 minutes. Antiphosphotyrosine and PI 3 kinase immunoprecipitation studies indicated the association of the 85 kD PI 3 kinase subunit with PDGFR. Direct immunoprecipitation with PDGFR beta antibody showed the association of PI 3 kinase activity with the PDGF-receptor. The isoquinoline sulfonyl piperazine compound H7 at concentrations that inhibit PDGF-stimulated PKC activity had no effect on PDGF-stimulated PI 3 kinase activity in antiphospotyrosine immunoprecipitates. These data indicate that PI3 kinase activation is insensitive to PKC. Treatment of mesangial cells with pertussis toxin at concentrations that partially inhibited PDGF-induced DNA synthesis in human mesangial cells did not inhibit PDGF-induced PI 3 kinase activation. These data indicate that PDGF activates PI 3 kinase in mesangial cells and that pertussis toxin-sensitive G-proteins are not involved in PI 3 kinase activation. The data further dissociate activation of PI 3 kinase from mitogenesis in human mesangial cells.

Chondrosarcoma, although uncommon, must be included in the differential diagnosis of skull base tumors. The potential for morbidity and mortality, similar to other lesions located at this anatomic site, is related to compromise of adjacent vital neurovascular structures. Optimal surgical management is controversial and reliant on adequate tumor exposure. A case of myxoid chondrosarcoma of the jugular foramen is presented with a review of the common presenting signs and symptoms along with the radiographic and histologic features of these lesions. The surgical approach to chondrosarcoma and other lesions at this location has undergone an evolution in technique in recent years. This report details the approach used by the authors, which allows for reconstruction of the skull base with subsequent normal anatomic contour and functional hearing. The technique employs hydroxylapatite for reconstruction, which has not been previously described in skull base applications.

The diagnosis of perilymphatic fistula can be confusing and prone to error. The signs and symptoms can be extremely varied, and currently there is no clinical or laboratory test that accurately predicts the presence of this entity. The only reliable method of diagnosis, namely surgical exploration, is often frustrating as, commonly, no evidence of an active fistula is found. Four children initially believed to have a perilymphatic fistula were found on exploration instead to have an absent round window reflex with normal mobility of the ossicular chain. These children presented with a history of abrupt, step-wise decreases in their hearing thresholds that frequently progressed from a mixed to a purely sensorineural loss. No anatomic abnormalities were found on high-resolution computed tomography. The authors theorize that this finding may represent altered fluid dynamics within the inner ear. Whether it signifies a prior fistula that has spontaneously healed remains to be confirmed. A review of the literature along with possible pathophysiologic mechanisms is presented.

Endothelin, a potent vasoactive peptide originally isolated from cultured porcine endothelial cells, (1) elicits hemodynamic and glycogenolytic actions in perfused rat liver; (2) evokes phosphoinositide signaling in hepatic cells; and (3) stimulates synthesis of mediators in Kupffer cells and glucose production in hepatocytes. Recently, we characterized receptor(s) for endothelin on hepatocytes (C. R. Gandhi, R. H. Behal, S. A. K. Harvey, T. Nouchi, and M. S. Olson, Biochem. J. 287, 897-904, 1992). Both hepatocytes and Kupffer cells rapidly internalize [125I]endothelin-1 ([125I]ET-1). In the present study we exposed primary cultures of hepatocytes or Kupffer cells to [125I]ET-1 and analyzed the radiolabeled metabolites which appeared in the cell medium. Six metabolites were separated by high-performance liquid chromatography (HPLC) from hepatocyte medium; these peaks had approximate elution times of 5 (free iodide), 22, 35, 37, 38, and 41 min, respectively, whereas the elution time for [125I]ET-1 was 43 min. The kinetics of formation of the metabolites, and experiments using excess unlabeled ET-1, both showed that internalization of the native peptide by hepatocytes is required for the metabolism of [125I]ET-1 into metabolite, and for the subsequent deiodination of metabolite. The formation of metabolites does not require internalization of the native peptide. In Kupffer cells, the cell medium contained only metabolite and metabolite. Internalization of the native peptide was required for the formation of metabolite but not for metabolite. Three classes of [125I]ET-1 metabolites from hepatic cells also were separated by sequential precipitation with trichloroacetic acid (TCA) and with silver nitrate. This procedure facilitated multiple rapid assays of [125I]ET-1 metabolism. Phosphoramidon, an inhibitor of neutral metalloendopeptidases, did not affect significantly the binding or the metabolism of [125I]ET-1 by hepatocytes or Kupffer cells. The aminopeptidase inhibitor bacitracin strongly attenuated [125I]ET-1 metabolism by hepatocytes, with a concomitant increase in the intracellular content of [125I]ET-1. These data suggest that enzymes capable of endothelin degradation are present both on the surface and in the intracellular compartment of hepatic cells, and that endothelin is not metabolized by neutral endopeptidase 24.11 in the liver.

Although successful stapedectomy is very gratifying for both the patient and surgeon, complications can arise, often with disastrous results. Certain clues may alert the surgeon to risk prevention or possible complications, allowing early definitive management. This assumes critical importance today as fewer younger surgeons acquire extensive experience in stapedectomy. A thorough knowledge of possible problems and their management is mandatory for the otologist who undertakes this most challenging of operations.

An innovative hydroxylapatite canal wall implant underlies a new technique for reconstructing canal wall defects in well-pneumatized "disease-free" mastoid cavities. Previous primary reconstruction involving soft-tissue techniques were not always optimal, depending on the size of the defect. The new hard implant provides lasting canal wall contour, and the implantation technique can be duplicated by other otolaryngologists. Our experience with the implant is described in 11 patients (implant duration 2 to 37 months) using a modification of the technique described by Grote (1986). The implant is biocompatible, being incorporated into surrounding tissues. Indications, contraindications (relative and absolute), and the intraoperative sculpturing method are presented. Long-term and short-term complications are reviewed with suggestions to minimize complications.

Numerous studies have demonstrated a lateralized impairment of attention in schizophrenia. In this study, attention in schizophrenia is investigated with a task that involves centering a rod while blindfolded. Symptoms were rated on the Brief Psychiatric Rating Scale (BPRS) for each of the 20 schizophrenic subjects. The more symptomatic patients demonstrated a right-sided hemineglect compared to the less symptomatic patients (p = 0.013). Furthermore, the difference between more and less symptomatic patients was even more distinct when they were categorized by the BPRS schizophrenia subscale alone (p = 0.0025). These findings support the hypothesis that the pathophysiology of schizophrenia involves a lateralized defect in the control of attention, and that this defect is associated with the severity of symptoms. This raises the possibility that effects of neuroleptic medication may be asymmetric, which could account for some of the inconsistencies in studies of hemispheric dysfunction in schizophrenia.

Remarkable advances have been made in the field of neuro-otologic and skull base surgery within the past decade. Each component of the "disease model"--prevention, diagnosis, therapy, and rehabilitation--is undergoing rapid progress. The purpose of this paper is to highlight only a few of these achievements. Each topic chosen has witnessed recent advancement in one aspect of the disease model. Neurofibromatosis (prevention) has been subjected to chromosomal mapping, allowing for genetic counseling. Intraoperative facial nerve monitoring (diagnosis) has allowed improved anatomic and functional preservation of this nerve during surgery. Embolization of glomus tumors (therapy) has rendered these difficult lesions more surgically manageable, and cochlear implantation (rehabilitation) has allowed the profoundly deaf to play a more active role in society. Each of these topics is briefly discussed as it relates to the temporal bone surgeon.

Endothelin, a potent vasoactive peptide originally isolated from the vascular endothelial cells, exerts glycogenolytic and vasoconstrictive actions in the perfused rat liver. In this paper we demonstrate high-affinity binding sites for endothelin-1 (ET-1) on rat hepatocytes. Upon incubation at 37 degrees C, association of ET-1 with hepatocytes occurred in a time-dependent manner, was maximal between 3 and 6 h, and subsequently declined; at this temperature ET-1 was rapidly internalized with the internalized ligand exceeding the surface-bound ligand at all time points. The rate of association of 125I-ET-1 with hepatocytes was much slower when the binding assay was performed at 4 degrees C; sequestration of ET-1 in hepatocytes was also substantially reduced at this temperature. ET-1 was extremely potent in stimulating phosphoinositide metabolism in hepatocytes, with significant activation of this signal transduction process occurring at ET-1 concentrations as low as 0.1 pM, with an EC50 of 1 pM. The effect of ET-1 was coupled via a pertussis toxin-sensitive G-protein. Cholera toxin did not affect ET-1-mediated phosphoinositide metabolism and neither toxin influenced the association of 125I-ET-1 with hepatocytes. PAGE of hepatocyte membranes following exposure of the cells to 125I-ET-1 and cross-linking revealed labelling of three major proteins with apparent molecular masses of 32, 49 and 72 kDa. 125I-ET-1 labelling of each of these proteins was inhibited by unlabelled ET-1, whereas unlabelled ET-3 inhibited the labelling of only the 32 and 49 kDa proteins. 125I-ET-3 labelled the 49 kDa protein and this labelling was inhibited by both unlabelled ET-1 and ET-3. Each of these receptors appears to be functional, since both ET-1 and ET-3 stimulated phosphoinositide metabolism in hepatocytes. Down-regulation of ET-1 association and desensitization of ET-1-induced phosphoinositide metabolism occurred upon incubation of hepatocytes with the homologous ligand. Following down-regulation, the ET-1 receptor was restored to the surface of the hepatocyte by prolonged incubation, although the ET-1-stimulated phosphoinositide response remained inhibited even after complete recovery of the ET-1 association capability. These results demonstrate the presence of multiple high-affinity receptors for ET-1 on hepatocytes and the direct action of this peptide on hepatic parenchymal cells via the phosphoinositide signal transduction pathway.

Colony-stimulating factor-1 (CSF1) is a cell lineage-specific hemopoietin required for the growth, differentiation, and survival of macrophages and their precursors. The human CSF1 receptor (CSF1R) is a 150-kDa transmembrane glycoprotein whose cytoplasmic tyrosine kinase domain is split by a kinase insert (KI) region of approximately 70 amino acids. We tested the ability of CSF1R KI domain deletion mutants to stimulate phosphatidylinositol-3-kinase (PtdIns-3-kinase), an enzyme whose activity is augmented by tyrosine kinase oncogenes and receptor tyrosine kinases, and to support mitogenesis in transfected cells. Receptor immunoprecipitates from CSF1-stimulated cells contained greater than 5-fold more PtdIns-3-kinase activity compared to nonstimulated cells. High performance liquid chromatography analysis of the PtdIns-3-kinase product scraped from thin layer chromatography plates indicated that PtdIns-3-P was produced. CSF1R KI domain deletion mutants retained tyrosine kinase activity in vitro. Receptor immunoprecipitates of two partially overlapping 28 and 30 amino acid KI deletion mutants of CSF1R retained some PtdIns-3-kinase activity, in contrast to immunoprecipitates of CSF1R lacking 67 amino acids of the KI domain. Each deletion mutant stimulated CSF1-dependent DNA synthesis in transfected cells at much reduced levels compared to wild-type receptor expressing cells. These data suggest a role for the CSF1R KI domain in PtdIns-3-kinase association and for CSF1-induced thymidine incorporation into DNA.

Previously, we have used the isolated perfused rat brain (IPRB) to demonstrate authentic cerebral synthesis of the lipid mediator platelet-activating-factor (Kumar, R., Harvey, S.A.K., Kester, M., Hanahan, D.J. and Olson, M.S. (1988) Biochim. Biophys. Acta 963, 375-383). The present study demonstrates that this fluorocarbon perfusion technique maintains the integrity of the blood-brain barrier (BBB), as evidenced by the small volume (1.77-3.33%) accessible to [carboxyl-14C]inulin. 51-66% of the brain was accessible to 3H2O, except for the spinal cord which is poorly perfused (16% accessible to 3H2O). There is no effective perfusion of muscle tissue associated with the preparation (less than 6% accessible to 3H2O). Fast Fourier Transform analysis of digitized EEG data showed that in low frequency bands (less than 7.5 Hz) the IPRB had reduced electrical activity relative to the whole conscious animal. The GABA antagonist bicuculline, which has convulsant effects in vivo, causes a 3-4-fold increase in overall (root-mean-square) electrical activity, but decreases further the relative amplitude of low frequencies. With appropriate corrections, measurement of the oxygen consumption of the IPRB can be made without the necessity for venous cannulation. Oxygen consumption of the IPRB is flow-dependent. At a perfusion rate of 1.54 ml/min per g, unstimulated oxygen consumption of the IPRB is 2.07-2.23 mumol/min per g, or 67-72% of the consumption of the brain in vivo. Administration of bicuculline to the IPRB causes a 31% increase in lactate efflux, but only a 15% increase in oxygen uptake, suggesting that the preparation becomes functionally ischemic. Measurement of ATP/ADP levels in control and bicuculline-treated IPRBs confirms this. Other workers have used the IPRB as a model for the cerebral effects of pharmacological agents and of metabolic insult. The present study shows that under various experimental conditions oxygen uptake, analytical EEG measurements, and the integrity of the blood-brain barrier all can be monitored.

Gadolinium-enhanced magnetic resonance imaging has been used to evaluate 20 patients with surgically confirmed facial nerve lesions. When the nerve could be seen, gadolinium-enhanced magnetic resonance imaging accurately revealed the lesion site as well as the known extent, which in some cases was not predicted by topognostic testing. This technique appears to provide accurate lesion-site testing and may have importance in surgical planning. Currently used topognostic tests of facial nerve function are frequently inaccurate and can only determine the most proximal lesion site when there are multiple or extensive lesions. The focal nerve enhancement seen in nerve injury, globally increased signal intensity within the temporal bone after trauma, and increased signal intensity within the dura after surgery can occasionally mask nerve lesions and may be confused with tumors.

Synaptosomes from normoxic and hypoxic rats were incubated aerobically in the presence and absence of veratridine. In the absence of veratridine, no significant difference was observed between the two types of preparation regarding either ATP/ADP ratio or 14CO2 or [14C]acetylcholine synthesis from D-[U-14C]glucose. However, in the presence of veratridine, significant reductions in the output of 14CO2 and [14C]acetylcholine by synaptosomes from hypoxic rats were apparent. It was concluded that irreversible metabolic lesions occur at the synapse as a result of hypoxia, which are apparent only when the metabolism of the preparation is accelerated to a level comparable with the maximal rate occurring in vivo. The presence of such lesions is further evidenced by the significant reductions in ATP/ADP ratio, 14CO2 output, and [14C]acetylcholine synthesis that occur in synaptosomes from hypoxic rats made anoxic in vitro and permitted to recover. Such decreases are not seen when synaptosomes from normoxic rats are similarly treated.

The energy status (as measured by the ATP/ADP ratio), oxidative metabolism (14CO2 output) and neurotransmitter synthesis ( [14C]acetylcholine production) by rat brain synaptosomes utilizing [U-14C]glucose has been studied. The ability of anoxia in vitro to permanently alter these parameters was investigated with reference to external [Ca2+] and [H+]. It has previously been shown that anoxic damage to synaptosomal preparations is only apparent when their metabolism is stimulated by veratridine [Harvey, Booth & Clark (1982) Biochem. J. 206, 433-439]. It is concluded that low [Ca2+] ameliorates, and high [H+] exacerbates, the damage sustained by veratridine-stimulated anoxic synaptosomes. The combined effects of low pH, anoxia and veratridine stimulation on synaptosomal metabolism most closely approximated to the irreversible damage to brain metabolism observed during acute hypoxia in vivo [Booth, Harvey & Clark (1983) J. Neurochem. 40, 106-110]. Suitably treated synaptosomal preparations may therefore be usefully employed as models to study impaired neurotransmitter synthesis in vivo.

The synthesis of platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) in rat brain was evaluated. Extracted PAF was characterized using standard HPLC and TLC techniques, and by correlation of its bioactivity with the acetylation state of the 2-position of the molecule. PAF was quantified by bioassay, its ability to cause [3H]serotonin release from washed rabbit platelets. The low basal level of PAF (0.25 +/- 0.15 pmol/g wet wt., mean +/- S.E.) in the brain of the intact rat was greatly increased by intraperitoneal injection of the chemoconvulsant drugs picrotoxin or bicuculline, to levels of 10.68 +/- 2.18 and 4.97 +/- 0.75 pmol/g wet wt., respectively. Electroconvulsion also increased brain PAF, to 1.76 +/- 0.30 pmol/g wet wt. Equivalent experiments using bicuculline in the isolated perfused rat brain yielded qualitatively similar results, indicating that the production of PAF in the brain is independent of systemic metabolism. When a 32P-labeled nerve-ending (synaptosome) preparation from rat brain was challenged with synthetic PAF (denoted AGEPC) at 0.1 nM concentration, responses were observed consistent with accelerated turnover of polyphosphoinositides. AGEPC also caused an increase in the Na+-Ca2+ exchange of synaptic membrane vesicles. Furthermore, AGEPC infused into the vasculature of the isolated perfused rat brain caused changes consistent with an increase in blood-brain barrier permeability, although AGEPC did not itself significantly penetrate the blood-brain barrier. It is concluded from these studies that PAF is synthesized within the rat brain in response to convulsant stimuli and that one of its effects is to accelerate synaptic polyphosphoinositide turnover. In addition, circulating PAF can influence blood-brain barrier permeability without itself penetrating the blood-brain barrier.

The possibility that 2-oxoglutarate may supply acetyl units for the cytosolic synthesis of acetylcholine in rat brain synaptosomes was investigated. The contribution of [14C]2-oxoglutarate to the synaptosomal synthesis of [14C]acetylcholine was found to be negligible despite evidence for its uptake and oxidation. The activity of the enzymes NADP-isocitrate dehydrogenase (EC 1.1.1.42), aconitate hydratase (EC 4.2.1.3), and ATP citrate-lyase (EC 4.1.3.8) were measured in the synaptosol. NADP-isocitrate dehydrogenase and aconitate hydratase are present at three- to 1.5-fold higher activities than ATP citrate-lyase. It seems likely that these enzymes contribute to the metabolism of citrate and prevent detectable formation of cytosolic acetyl-CoA from exogenously added 2-oxoglutarate (or citrate). The data further suggest that ATP citrate-lyase may in part be associated with the mitochondrial fraction.

The activity of choline acetyltransferase was used as an index of cholinergic structures in regions of rat brain. The activities of ATP citrate lyase and choline kinase correlated poorly with cholinergic activity in whole tissue fractions, contrasting with the good correlation between acetylcholinesterase and choline acetyltransferase. Choline acetyltransferase was preferentially localised in synaptosomes prepared from regions of high (striatum) or intermediate (cortex, medulla oblongata/pons) cholinergic activity. In general, this was not true for either choline kinase or ATP citrate lyase.

Acetylcholine and choline release was measured by using an automated and modified version of the chemiluminescence technique of Israel & Lesbats [(1981) Neurochem. Int. 3, 81-90]. A comparison of acetylcholine and choline release from synaptosomes demonstrated that acetylcholine release was K+-stimulated and inhibited by the Ca2+ ionophore A23187 and cyanide. Choline release, however, did not vary markedly under different conditions, suggesting that it is not associated with acetylcholine release at the nerve ending. Total acetylcholine synthesis in synaptosomal preparations was measured concurrently with the incorporation of [14C]acetyl and [3H]choline moieties by using the chemiluminescence method. Under sub-optimal glucose concentrations or in the absence of treatment of the synaptosomes with the acetylcholinesterase inhibitor phospholine, the incorporation of radioactivity exceeded total synthesis, indicating that cycling between acetylcholine and its precursors may occur. After treatment with phospholine, acetyl-group incorporation from D-[U-14C]glucose occurred without dilution of the precursor at optimal (1.0 mM) and low (0.1 mM) glucose concentrations; however, at very low (0.01 mM) glucose concentrations, dilution by a small endogenous pool occurred. [14C]Acetyl incorporation into acetylcholine was compared with various metabolic parameters. A closer correlation was observed between [14C]acetyl-group incorporation into acetylcholine and the calculated acetyl-carrier efflux from the mitochondria than with the calculated pyruvate-dehydrogenase-complex flux. The results are discussed with respect to the regulation of acetylcholine concentrations at the synapse and the mechanism whereby turnover occurs.

Synaptosomes from several regions of the rat brain were found to exhibit half-maximal rates of 14CO2 output and [14C]acetylcholine synthesis from D-[U-14C]glucose at glucose concentrations approx. 50-fold lower than those required by the brain in situ. However, synaptosomal acetylcholine synthesis was found not to be directly proportional to substrate oxidation as measured by 14CO2 output. When synaptosomes had been exposed to anoxia in vitro, their metabolic indices (14CO2 and [14C]acetylcholine synthesis, and adenine nucleotide levels) were found not to be significantly different from control aerobic values, unless they had been subjected to veratridine depolarization. This is in accord with previous findings that neither the absolute metabolic rates nor the vulnerability to hypoxic damage exhibited by brain in situ is reflected by brain slices in vitro, unless these are stimulated by depolarization. The use of synaptosomes as a model for synaptic damage in vivo is discussed.

The in vitro incorporation of 14C-leucine by nonsynaptic and synaptic rat brain mitochondria purified by means of discontinuous Ficoll gradients has been characterised. The incorporation was linear for the first 45 min for both populations. Synaptic mitochondria showed a higher rate of incorporation than the nonsynaptic mitochondria at high concentrations of leucine. The incorporation was more effective in the presence of Mg2+ and inhibited by dinitrophenol. The incorporation was sensitive to chloramphenicol and insensitive to cycloheximide. Bacterial contamination was in any case lower than 1,000 colonies per ml after the incubation period. The incorporation was carried out in the presence of either an external ATP-generating system consisting of ATP, phosphoenolpyruvate and pyruvate kinase or with mitochondria respiring with oxidisable substrates plus ADP (state III). The rates obtained for incorporation in this state III were higher for all the substrates assayed (succinate, pyruvate and glutamate) than in the presence of exogenous ATP. The highest rate obtained was found when glutamate was the respiratory substrate. No significant metabolic oxidation of leucine occurs in either synaptic or nonsynaptic mitochondria in the presence of exogenous ATP. Glutamate did not increase leucine uptake in any mitochondrial populations.

Acetylcholine and choline release from rat brain synaptosomes have been measured using a chemiluminescent technique under a variety of conditions set up to mimic anoxic insult, including conditions of low pH (6.2) and the presence of lactate plus pyruvate as substrate. Lactate plus pyruvate as substrate consistently gave higher respiration rates than glucose alone, but with either substrate (glucose or lactate plus pyruvate) the omission of Ca2+ caused an increase in respiration whereas a low pH caused a decreased respiration. Acetylcholine release under control conditions (glucose, pH 7.4) was Ca2+-dependent, stimulated by high K+ concentrations, and decreased significantly during anoxia but recovered fully after a period of postanoxic oxygenation. Low pH (6.2) suppressed K+ stimulation of acetylcholine release, and after a period of anoxia at low pH the recovery of acetylcholine release was only partial. With lactate plus pyruvate as substrate, the effects of anoxia and/or low pH on acetylcholine release and its subsequent recovery were exacerbated. Choline release from synaptosomes, however, was not affected by anoxic/ionic conditions in the same way as acetylcholine release. At low pH (6.2) there was a marked reduction in choline release both under aerobic and anoxic conditions. These results suggest that acetylcholine release per se from the nerve is very sensitive to anoxic insult and that the low pH occurring during anoxia may be an important contributory factor.