Relation between work and phosphate metabolite in the in vivo paced mammalian heart.

Nuclear magnetic resonance (NMR) spectroscopy was used to monitor, on a beat-to-beat basis, the concentration of creatine phosphate and adenosine triphosphate during alterations in the work output of canine hearts in vivo. Over a wide range of rate-pressure products (5,000 to 25,000 mmHg/min), the relative amounts of creatine phosphate and adenosine triphosphate within the heart remained constant. The relative concentration of free adenosine diphosphate was calculated under the reasonable assumption that the creatine kinase-catalyzed reaction is near equilibrium in this tissue. The free concentration of adenosine diphosphate also did not change over this range of rate-pressure products. The data demonstrate that the concentration of these compounds is highly regulated in vivo and suggest that factors other than their concentration may be involved in the modulation of steady-state myocardial work output with oxygen consumption.

Acute effects of cocaine on human brain activity and emotion.

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.

A calorimetric examination of stable and fusing lipid bilayer vesicles.

Mixed lipid samples containing dimyristoylglycerophosphocholine and small amounts of myristic acid were examined calorimetrically. Examination of multilamellar and small vesicle samples indicated that upon heating small vesicles combine to form more extended structures. An exothermic peak (at 19 . 5 degrees C) can be associated with the structural transformation. The enthalpy for this process, which may be interpreted as vesicle-vesicle fusion, is found to be approx.--2 kcal/mol.

Kinetics of creatine phosphokinase and adenylate kinase. A two-dimensional NMR analysis.

The kinetics of creatine phosphokinase and adenylate kinase catalyzed reactions were studied at equilibrium by two-dimensional Fourier transform phosphorus-31 nuclear magnetic resonance. For the creatine phosphokinase reaction, a pseudo-first-order rate constant of 0.29 s-1 was determined for the transfer of a phosphate group from adenosine triphosphate to creatine phosphate. For the adenylate kinase reaction two slow rate processes were required to describe the experimental results. The conversion of adenosine diphosphate to adenosine monophosphate was found to have a pseudo-first-order rate constant of 1.2 s-1, whereas that for the release of adenosine triphosphate from its enzyme complex occurred at a rate of 14 s-1.

Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects.

The authors used functional magnetic resonance imaging (fMRI) to determine whether acute intravenous (i.v.) cocaine use would change global cerebral blood flow (CBF) or visual stimulation-induced functional activation. They used flow-sensitive alternating inversion recovery (FAIR) scan sequences to measure CBF and blood oxygen level-dependent (BOLD) sensitive T2* scan sequences during visual stimulation to measure neuronal activation before and after cocaine and saline infusions. Cocaine (0.6 mg/kg i.v. over 30 seconds) increased heart rate and mean blood pressure and decreased end tidal carbon dioxide (CO2). All measures returned to baseline by 2 hours, the interinfusion interval, and were unchanged by saline. Flow-sensitive alternating inversion recovery imaging demonstrated that cortical gray matter CBF was unchanged after saline infusion (-2.4 +/- 6.5%) but decreased (-14.1 +/- 8.5%) after cocaine infusion (n = 8, P < 0.01). No decreases were detected in white matter, nor were changes found comparing BOLD signal intensity in cortical gray matter immediately before cocaine infusion with that measured 10 minutes after infusion. Visual stimulation resulted in comparable BOLD signal increases in visual cortex in all conditions (before and after cocaine and saline infusion). Despite a small (14%) but significant decrease in global cortical gray matter CBF after acute cocaine infusion, specific regional increases in BOLD imaging, mediated by neurons, can be measured reliably.

Nosocomial transmission of tuberculosis from unsuspected disease.

Tuberculosis remains an occupational hazard for hospital employees. A case of acute generalized tuberculosis occurring in a patient with a malignancy who had received corticosteroids was undetected during life and during a gross autopsy examination. Histologic examination of tissue performed one month later was necessary to establish the diagnosis. Of susceptible hospital staff members who were exposed to the index case, infection developed in nine of 56 (16 percent) compared with three of 333 (0.9 percent) unexposed personnel with similar risk but no known exposure (p less than 0.001). This was a 17.8-fold increase in the infection rate for the exposed group. Three employees infected had evidence of active disease: two had pleural effusions and one had cavitary pulmonary infiltrates; six were asymptomatic. The high rate of infection was associated with inadequate air ventilation and exposure to uncontained infectious aerosol. Preventive therapy with isoniazid, high-change-ventilating systems, ultraviolet radiation, and primary barrier systems are recommended methods to reduce the infection risk.

Ischemic intervals during warm blood cardioplegia in the canine heart evaluated by phosphorus 31-magnetic resonance spectroscopy.

OBJECTIVE: Warm blood cardioplegia requires interruption by ischemic intervals to aid visualization. We evaluated the safety of repeated interruption of warm blood cardioplegia by normothermic ischemic periods of varying durations. METHODS: In three groups of isolated cross-perfused canine hearts, left ventricular function was measured before and for 2 hours of recovery after arrest, which comprised four 15-minute periods of cardioplegia alternating with three ischemic intervals of 15, 20, or 30 minutes (I15, I20, and I30). Metabolism was continuously measured by phosphorus 31-magnetic resonance spectroscopy. RESULTS: Adenosine triphosphate level fell progressively as ischemia was prolonged; after recovery, adenosine triphosphate was 99% +/- 6%, 90% +/- 1% (p = 0.0004 vs control), and 68% +/- 3% (p = 0.0002) of control levels in I15, I20, and I30, respectively. Intracellular acidosis with ischemia was most marked in I30. After recovery, left ventricular maximal systolic elastance at constant heart rate and coronary perfusion pressure was maintained in I15 but fell to 85% +/- 3% in I20, (p = 0.003) and to 65% +/- 6% (p = 0.003) of control values in I30, while relaxation (tau) was prolonged only in I30 (p = 0.007). CONCLUSIONS: Hearts recover fully after three 15-minutes periods of ischemia during warm blood cardioplegia, but deterioration, significant with 20-minute periods, is profound when the ischemic periods are lengthened to 30 minutes. This suggests that in the clinical setting warm cardioplegia can be safely interrupted for short intervals, but longer interruptions require caution.

Local relation between oxidative metabolism and perfusion in leg muscles of patients with heart failure studied by magnetic resonance imaging and spectroscopy.

BACKGROUND: We studied the local relation of muscle perfusion and metabolism in patients with severe chronic heart failure. Alterations of skeletal muscle blood flow and oxidative capacity contribute to exercise intolerance in these patients. The interdependence of both parameters has often been questioned. METHODS AND RESULTS: With the use of nuclear magnetic resonance, we quantified leg and muscle perfusion during reactive hyperemia in 7 patients with heart failure (New York Heart Association class III and IV) and 7 age-matched control subjects from the difference in longitudinal relaxation rate (1/T1). By using 31P nuclear magnetic resonance spectroscopy, we assessed oxidative metabolism from the creatine rephosphorylation time constant after a short ischemic exercise. Phosphocreatine recovery is slowed (74.6 +/- 11.3 vs 49.9 +/- 13.9 seconds, p = .002) and reactive hyperemic flow is reduced (48.5 +/- 24.9 vs 113 +/- 30.4 mL/100 mL per minute, p = .0005). CONCLUSIONS: By using a totally noninvasive protocol, we demonstrated that reactive hyperemic flow correlates with oxidative capacity in calf muscles from patients with heart failure, showing that exercise performance and local circulatory dysfunction are decreased in parallel in severe heart failure.

Comparative psychologic effects of estrogen administration on institutional and noninstitutional elderly women.

Previous research on elderly women living in institutions has showm a postiive relationship between the administration of estrogen and improved psychologic status. In the current 12-month study, the effects of estrogen therapy were compared in 18 institutional women versus 21 noninstitutional women who volunteered to participate. Both groups received conjugated estrogens (Premarin, 0.3 mg daily) in interrupted courses. Throughout the year, the women were evaluated by means of the Eysenck Personality Inventory, the Profile of Mood States, the Lawson Morale Scale, and various self-perception items. Statistically, significant changes occurred in the areas of neuroticism, tension, morale, and subjective mood states, but the improvement was greater in the institutional subjects. The main conclusion was that estrogen therapy has a positive effect upon psychologic status, particularly for women who reside in an institution.

Fornix lesions, plasma ACTH levels, and shuttle box avoidance in rats.

Male hooded rats served as subjects for the two experiments conducted in this study. In Experiment 1, the consequences of fornix lesions for partial acquisition, and performance at three postacquisition time intervals, of shuttle box avoidance were tested. Fornix-damaged rats achieved criterion performance more rapidly than controls. The performance of control rats was depressed when they were tested 1 hr after acquisition ("Kamin effect"), but the performance of fornix-damaged rats was not impaired. The possibility that fornix lesions altered plasma ACTH concentrations at the intervals after avoidance training used in Experiment 1 was examined in Experiment 2. Plasma ACTH concentrations were elevated in rats with fornix lesions, compared with those in unoperated and sham-operated controls, both immediately after and 1 hr after avoidance training. Plasma ACTH levels were not elevated in fornix-damaged rats following either stress alone or 24 hr after avoidance training. These results are interpreted to indicate that fornix lesions cause elevated ACTH levels in rats after avoidance training and that the elevated plasma ACTH concentrations in these rats are responsible for elimination of the Kamin effect. In addition, these data support the contention that enhanced acquisition of two-way active avoidance by rats with fornix or hippocampal damage might be attributable to increased plasma ACTH levels.

Interrelationship of oxidative metabolism and local perfusion demonstrated by NMR in human skeletal muscle.

Using nuclear magnetic resonance (NMR), we have examined the relationship of high-energy phosphate metabolism and perfusion in human soleus and gastrocnemius muscles. With 31P-NMR spectroscopy, we monitored phosphocreatine (PCr) decay and recovery in eight normal volunteers and four heart failure patients performing ischemic plantar flexion. By using echo-planar imaging, perfusion was independently measured by a local [inversion-recovery (T1-flow)] and a regional technique (NMR-plethysmography). After correction for its pH dependence, PCr recovery time constant is 27.5 +/- 8.0 s in normal volunteers, with mean flow 118 +/- 75 (soleus and gastrocnemius T1-flow) and 30.2 +/- 9.7 ml.100 ml-1.min-1 (NMR-plethysmography-flow). We demonstrate a positive correlation between PCr time constant and local perfusion given by y = 50 - 0.15x (r2 = 0.68, P = 0.01) for the 8 normal subjects, and y = 64 - 0.24x (r2 = 0.83, P = 0.0001) for the 12 subjects recruited in the study. Regional perfusion techniques also show a significant but weaker correlation. Using this totally noninvasive method, we conclude that aerobic ATP resynthesis is related to the magnitude of perfusion, i.e., O2 availability, and demonstrate that magnetic resonance imaging and magnetic resonance spectroscopy together can accurately assess muscle functional status.

Cardioplegia and ischemia in the canine heart evaluated by 31P magnetic resonance spectroscopy.

BACKGROUND: Warm continuous blood cardioplegia provides excellent protection, but must be interrupted by ischemic intervals to aid visualization. We hypothesized that (1) as ischemia is prolonged, the reduced metabolic rate offered by cooling gives the advantage to hypothermic cardioplegia; and (2) prior cardioplegia mitigates the deleterious effects of normothermic ischemia. METHODS: Isolated cross-perfused canine hearts underwent cardioplegic arrest followed by 45 minutes of global ischemia at 10 degrees C or 37 degrees C, or 45 minutes of normothermic ischemia without prior cardioplegia. Left ventricular function was measured at baseline and during 2 hours of recovery. Metabolism was continuously evaluated by phosphorus-31 magnetic resonance spectroscopy. RESULTS: Adenosine triphosphate was 71% +/- 4%, 71% +/- 7%, and 38% +/- 5% of baseline at 30 minutes, and 71% +/- 4%, 48% +/- 5%, and 39% +/- 6% at 42 minutes of ischemia in the cold ischemia, warm ischemia, and normothermic ischemia without prior cardioplegia groups, respectively. Left ventricular systolic function, left ventricular relaxation, and high-energy phosphate levels recovered fully after cold cardioplegia and ischemia. Prior cardioplegia delayed the decline in intracellular pH during normothermic ischemia initially by 9 minutes, and better preserved left ventricular relaxation during recovery, but did not ameliorate the severe postischemic impairment of left ventricular systolic function, marked adenosine triphosphate depletion, and creatine phosphate increase. Left ventricular distensibility decreased in all groups. CONCLUSIONS: When cardioplegia is followed by prolonged ischemia, better protection is provided by hypothermia than by normothermia. Prior cardioplegia confers little advantage on recovery after prolonged normothermic ischemia but delays initial ischemic metabolic deterioration, which would contribute to the safety of brief interruptions of warm cardioplegia.

Survey of multiply resistant Providencia stuartii in a chronic care unit.

Providencia stuartii was cultured over a 4-year period from the urinary tract, throat, perineum, axilla and stools of patients in a long-term chronic care unit, the most common site of colonization being the urinary tract. A total of 17 patients had Prov. stuartii bacteraemia and manipulation of the urinary tract preceded bacteraemia in 10 cases. Eighty-two per cent of the patients had long-term urinary tract colonization from 1 month to 4 years. Although most isolates were resistant to all aminoglycosides except amikacin, the organisms were all susceptible to thienamycin, ceftazidime, cefotaxime, ceftizoxime and moxalactam.

Depressive symptomatology and cocaine-induced pituitary-adrenal axis activation in individuals with cocaine dependence.

The hypothalamic-pituitary-adrenal (HPA) axis plays a role in cocaine dependence and major depressive disorder. The authors examined the correlation between baseline depressive symptomatology and pituitary-adrenal axis activation induced by acute cocaine challenge. Twelve patients with cocaine dependence were administered an iv bolus of cocaine (0.6 mg/kg) and their plasma was assayed for levels of adrenocorticotropic hormone (ACTH) and cortisol. Depressive symptomatology was assessed with total Hamilton rating scale for depression (HRSD) scores and its vegetative and cognitive superfactors. Cocaine produced a mean increase from baseline of 261% for ACTH and 73% for cortisol plasma levels. Changes in ACTH (r=0.69) and cortisol (r=0.59) were positively and significantly correlated with total HRSD scores and its vegetative, but not cognitive, factor symptom cluster. These results suggest that the HPA axis may be involved in affective disturbances associated with the use of cocaine. Implications of these data for the pathophysiology of cocaine dependence are discussed.

Cardiac problems in patients with neurologic disease.

The cardiologist and internist can make a major contribution to the care of patients with neurologic disease, both in terms of treating patients with symptomatic cardiac involvement and reducing mortality. This article highlights the need to recognize ECG abnormalities that may represent purely neurologic disease as well as indicate cardiac pathology that may be part of the neurophysiologic disease process. The role of cardiac emboli in stroke and the essential role of anticoagulation in stroke prevention have been discussed. Additionally, the importance of emboli in relation to endocarditis and the essential role of anticoagulation for stroke prevention in patients with prosthetic valves have been emphasized. Finally, the cardiac manifestations of several neuromyopathic diseases have been indicated, and the importance of cardiac issues in patient management decisions has been shown. The interplay of cardiac and neurologic concerns demonstrates how a collaboration of neurologists and cardiologists can yield rewarding results in resolving some of the more difficult problems in clinical medicine.

Magnetic resonance imaging with superparamagnetic iron oxide particles for the detection of myocardial reperfusion.

The effect of superparamagnetic iron oxide particles on magnetic resonance myocardial signal intensity was examined in order to define the ability of this agent to identify normal, ischemic, and reperfused myocardium. Data were obtained from 6 normal rats (group 1) and from 6 heterotopic isogenic rat heart transplants (group 2) at 4.7 T with a multislice spin-echo sequence. Images were acquired in (a) normal rats before and after the infusion of 36 mumol Fe/kg of AMI-25 (group 1) and (b) rat heart transplants during control, global myocardial ischemia (before and after the injection of 72 mumol Fe/kg of AMI-25), and following reperfusion (group 2). Myocardial signal intensity decreased by 36 +/- 4%, p less than 0.001, following contrast infusion in normal hearts (group 1). The intensity remained constant in the rat heart transplants (group 2) during coronary occlusion, both before and after the infusion of AMI-25 and decreased by 61 +/- 7%, p less than 0.001, upon reperfusion. The larger effect of AMI-25 in reperfused as compared to normal myocardium suggests the presence of ischemia-induced hyperemia. There was no significant difference (analysis of variance) among intensities from different myocardial regions in either group at any stage of the experiment. We conclude that the use of AMI-25 permits identification of normal, ischemic, and reperfused myocardium and may therefore be helpful for the early detection of reperfusion following thrombolytic therapy for acute myocardial infarction.

Behavior of atherosclerotic plaque components after in vitro angioplasty and atherectomy studied by high field MR imaging.

AIMS: Using magnetic resonance imaging (MRI), we developed in vitro models to image the response of fatty, fibrous, and calcified plaques to in vitro models of angioplasty and atherectomy, and tested the resistance of collagenous cap and lipid core to radial compression. METHODS AND RESULTS: We studied the effects of balloon compression on 10 fibrous plaques with a complete collagenous cap (group A), 6 fatty plaques without cap (group B), and 5 calcified plaques (group C). Atherectomy was performed on nine other fibrous lesions (group D). In group A, fibrous cap, lipid core, and plaque did not change after radial compression despite a decrease in luminal obstruction due to medial stretching. In group B, a reduction of plaque (-30%) and lipid core (-35%) were observed. Compression dissected calcified plaques at the shoulder level. In group D, atherectomy reduced collagenous cap by 54%, and plaque by 35%. CONCLUSIONS: In these models, MRI shows 1) the high resistance of collagenous caps to radial compression, 2) a stretching effect of compression on disease-free walls, enlarging lumen in case of fibrous plaque, but a reduction and redistribution of lipid cores in case of fatty plaques, 3) the rupture of calcified arteries at the plaque shoulder, and 4) the reduction of fibrous components by atherectomy but not by angioplasty. By characterizing plaque composition, MRI may allow a predictable response of atherosclerotic arteries to interventional procedures.

Effect of hyperosmotic mannitol on magnetic resonance relaxation parameters in reperfused canine myocardial infarction.

To determine how administration of a hyperosmotic agent alters regional nuclear magnetic resonance (NMR) relaxation parameters and imaging characteristics in ischemic-reperfused myocardium, 7 dogs were infused with mannitol for 15 minutes before and after the release of a 3 hour left anterior descending coronary artery (LAD) occlusion. Nine control animals received normal saline during the 3 hour occlusion and 1 hour reperfusion periods. Normal posterior left ventricular (LV) wall and the ischemic anterior LV wall (risk area) myocardium was sampled for calculation of segmental microsphere myocardial blood flow, % tissue water content, NMR relaxation times (T1, T2) and myocyte ultrastructure using electron microscopy. Mean infarct T1 values were 14% greater than normal segments in saline-treated controls, but only 5% greater after mannitol. The difference in tissue water content between infarcted and normal segments was 4% in saline-treated (83 vs. 79%) compared to 2% in mannitol-treated dogs (79 vs. 77%). T1, T2 and % water content of control infarct segments were greater than treated infarcts (p less than 0.01). T1 and T2 rose as occlusion flow fell below 0.5 ml/min/g in control hearts but did not rise until flows were reduced to 0.1 ml/min/g in mannitol-treated hearts. Areas of increased signal in T1 and T2 NMR images correlated well with histochemical infarct volume (r = 0.98, SEE = 1.1 cc) in mannitol-treated dogs, but infarct borders were qualitatively less well-defined than in controls. We concluded that mannitol (1) diminishes tissue edema and reduces NMR relaxation parameters (T1, T2) in infarcted myocardium; and (2) attenuates the rise in T1 and T2 and ultrastructural myocyte injury in ischemic-reperfused myocardium.

Contrast induced myocardial signal reduction: effect of lanthanide chelates on ultra high speed MR images.

The myocardial MR signal reduction associated with an intravenous bolus of Gd-DTPA and Dy-DTPA was studied in a canine model. Imaging was performed with a high speed echo-planar type imaging system (Instascan, Advanced NMR Systems, Inc.). Gated spin-echo images were obtained with TE of 30 ms, which permits image acquisition in approximately 40 ms. The gated TR was dependent on the heart rate, with an average TR of 2.4 s. After 0.1 mmol/kg of contrast was injected, 70 images were acquired, which showed in an 80-image data set a reduction in myocardial signal with a gradual return to normal. After dipyridamole infusion, the signal loss was significantly more pronounced, and earlier than in the control data set. There was no significant difference between Gd-DTPA and Dy-DTPA in these imaging studies despite the theoretical prediction of better Dy signal reduction, possibly due to physiological variability during the course of a study or between studies. The cause of enhanced contrast effect after dipyridamole infusion is discussed, as is the basis for dipyridamole enhancement, and the possible role of contrast enhanced MR imaging in the detection of cardiac disease.

Imaging perfusion deficits in ischemic heart disease with susceptibility-enhanced T2-weighted MRI: preliminary human studies.

AIM: This feasibility study explores relative myocardial perfusion characterization with an investigational T2/T2 contrast agent. METHODS: Dysprosium-DTPA bis (methylamide) was administered peripherally in six patients with thallium defects. Rest and stress multi-section, gated, T2-weighted images were acquired with a 1.5 T echo-planar imager. Change in transverse relaxation rate was calculated in four segments for each subject. RESULTS: Magnetic resonance (MR) identified five of five instances of ischemia or infarction, at a dose of agent (0.25 mmol/kg) that was comparable to that currently used with clinically approved gadolinium agents. Injection at twice this dose resulted in saturation of the signal change, and the one ischemic segment corresponding to the higher dose was not identified by MR. MR was negative in two segments which, on final diagnosis, were determined to manifest thallium attenuation artifact. CONCLUSION: MR perfusion imaging with high susceptibility agents has the potential to characterize myocardial perfusion deficits.