Lung nodule volumetry: segmentation algorithms within the same software package cannot be used interchangeably.

OBJECTIVE: We examined the reproducibility of lung nodule volumetry software that offers three different volumetry algorithms. METHODS: In a lung cancer screening trial, 188 baseline nodules >5 mm were identified. Including follow-ups, these nodules formed a study-set of 545 nodules. Nodules were independently double read by two readers using commercially available volumetry software. The software offers readers three different analysing algorithms. We compared the inter-observer variability of nodule volumetry when the readers used the same and different algorithms. RESULTS: Both readers were able to correctly segment and measure 72% of nodules. In 80% of these cases, the readers chose the same algorithm. When readers used the same algorithm, exactly the same volume was measured in 50% of readings and a difference of >25% was observed in 4%. When the readers used different algorithms, 83% of measurements showed a difference of >25%. CONCLUSION: Modern volumetric software failed to correctly segment a high number of screen detected nodules. While choosing a different algorithm can yield better segmentation of a lung nodule, reproducibility of volumetric measurements deteriorates substantially when different algorithms were used. It is crucial even in the same software package to choose identical parameters for follow-up.

A comparison of 82Rb+ and 13NH3 for myocardial positron scintigraphy.

Rubidium-82 (75-sec half-life) is eluted from a 82Sr (25-day half-life) generator and infused into phantom and dog to show that it gives images of myocardial accumulation comparable to 13N-ammonia with the positron camera.

Three-dimensional reconstruction of lung perfusion image with positron detection.

Transverse section images of the distribution of pulmonary perfusion in a canine have been obtained using microspheres labeled with the positron-emitting isotope 68Ga and a three-dimensional reconstruction technique. The reconstruction method is more accurate than conventional tomographic procedures and is facilitated by the use of positron detection. The transverse sections presented demonstrate the capacity of the technique to delineate reduction in regional perfusion resulting from occlusion of the artery to the left lower lobe.

A model for regional cerebral oxygen distribution during continuous inhalation of 15O2, C15O, and C15O2.

Equilibrium positron brain scans were obtained during continuous inhalation of C15O, C15O2, and 15O2. Inhalation of C15O labels hemoglobin, whereas C15O2 instantaneously labels stable water to H215O. During the continuous inhalation of 15O2, body tissues extract it from the blood in proportion to local metabolism and ultimately convert it to water of metabolism. After 6-8 min of inhalation, a steady-state equilibrium is established in which the inflow of tracer is balanced by its disappearance due to radioactive decay (T1/2 = 2 min) and biologic removal. Mathematical models of the steady-state distributions of C15O, C15O2/H215O, and 15O/H215O are derived. The major results are: a) The steady-state distribution of C15O is insensitive to variations in blood flow and essentially measures blood volume. b) The distribution of H215O during inhalation of C15O2 is dependent, though nonlinearly, on blood flow. c) The distribution of H215O during inhalation of 15O2 depends linearly on the oxygen extraction fraction and nonlinearly on blood flow. d) The dependence on blood flow in the 15O2 steady-state image can be removed by the division, point by point, of the 15O2 image by the C15O2 image.

F-18-labeled 3-deoxy-3-fluoro-D-glucose for the study of regional metabolism in the brain and heart.

Glucose is the major physiological substrate of the brain and an important physiological substrate for the myocardium. [19F]fluoro-3-deoxy-glucose [3-FDG(F-18)] was studied to determine whether it is a suitable tracer for evaluating the metabolic function of the brain and myocardium. 3-FDG(F-18) was rapidly accumulated in the mouse myocardium (10-12% injected dose/g) and remained constant up to 120 min. Blood, liver, and lung activities exhibited a rapid accumulation of activity (4% injected dose/g) at 1 min, followed by elimination of activity up to 30 min (2% injected dose/g), and then remaining unchanged for a period of 120 min. The arterial blood curve in the dog was fit best by three exponential components (T 1/2 = 0.52 min, 2.75 min, and 142.8 min). Transverse-section images were obtained of the dog's brain and myocardium. From sequential two-dimensional images, a clearance half-time of 26.88 min was determined for the canine brain. Radiation doses for man were calculated from tissue distribution data for mice.

Rubidium-82 generators for imaging studies.

Strontium-82, produced by spallation reaction with medium-energy proton beams, was used to evaluate Bio-Rex 70 and Chelex-100 ion-exchange resins for use in a compact Rb-82 generator. Adsorption of Sr-82 to the resin column, Rb-82 elution yields, Sr breakthrough, and 82Rb-Sr separation factors were determined for newly prepared columns and for longterm elution conditions. Separation factors of 10(7) to 10(8) were obtained with 2% NaCl elutions from Bio-Rex 70 resin columns while the separation factors was about 5 X 10(4) with the Chelex-100 resin column.

Techniques for positron scintigraphy of the brain.

Positron scintigrams were obtained in normal subjects and in patients with intracranial tumors and cerebral vascular disease, using a multicrystal positron camera. The radiopharmaceuticals were 68Ga complexed with adenosine triphosphate (68Ga-ATP), 13N-ammonia (13NH3), and 15O2. Six clinical cases are described to illustrate the different cerebral distributions of intravenously administered 68Ga-ATP, 13NH3, and inhaled 15O2. The possible value of these agents in the study of cerebral metabolism and in differential diagnosis of intracranial disease is discussed.

Glutamic acid and gamma-aminobutyric acid neurotransmitters in central control of breathing.

We review recent cross-disciplinary experimental and theoretical investigations on metabolism of the amino acid neurotransmitters glutamic acid and gamma-aminobutyric acid (GABA) in the brain during hypoxia and hypercapnia and their possible role in central control of breathing. The roles of classical modifiers of central chemical drive to breathing (H+ and cholinergic mechanisms) are summarized. A brief perspective on the current widespread interest in GABA and glutamate in central control is given. The basic biochemistry of these amino acids and their roles in ammonia and bicarbonate metabolism are discussed. This review further addresses recent work on central respiratory effects of inhibitory GABA and excitatory glutamate. Current understanding of the sites and mechanisms of action of these amino acids on or near the ventral surface of the medulla is reviewed. We focus particularly on tracer kinetic investigations of glutamatergic and GABAergic mechanisms in hypoxia and hypercapnia and their possible role in the ventilatory response to hypoxia. We conclude with some speculative remarks on the critical importance of these investigations and suggest specific directions of research in central mechanisms of respiratory control.

Brain glutamate metabolism during metabolic alkalosis and acidosis.

Glutamate modifies ventilation by altering neural excitability centrally. Metabolic acid-base perturbations may also alter cerebral glutamate metabolism locally and thus affect ventilation. Therefore, the effect of metabolic acid-base perturbations on central nervous system glutamate metabolism was studied in pentobarbital-anesthetized dogs under normal acid-base conditions and during isocapnic metabolic alkalosis and acidosis. Cerebrospinal fluid transfer rates of radiotracer [13N]ammonia and of [13N]glutamine synthesized de novo via the reaction glutamate+NH3-->glutamine in brain glia were measured during normal acid-base conditions and after 90 min of acute isocapnic metabolic alkalosis and acidosis. Cerebrospinal fluid [13N]ammonia and [13N]glutamine transfer rates decreased in metabolic acidosis. Maximal glial glutamine efflux rate jm equals 85.6 +/- 9.5 (SE) mumol.l-1 x min-1 in all animals. No difference in jm was observed in metabolic alkalosis or acidosis. Mean cerebral cortical glutamate concentration was significantly lower in acidosis [7.01 +/- 0.45 (SE) mumol/g brain tissue] and tended to be larger in alkalosis, compared with 7.97 +/- 0.89 mumol/g in normal acid-base conditions. There was a similar change in cerebral cortical gamma-aminobutyric acid concentration. Within the limits of the present method and measurements, the results suggest that acute metabolic acidosis but not alkalosis reduces glial glutamine efflux, corresponding to changes in cerebral cortical glutamate metabolism. These results suggest that glutamatergic mechanisms may contribute to central respiratory control in metabolic acidosis.

Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response.

Recent data suggest that the increase in ventilation during hypoxia may be related to the release of the excitatory amino acid neurotransmitter glutamate centrally. To further investigate this, we studied the effects of MK-801, a selective noncompetitive N-methyl-D-aspartate receptor antagonist, on the hypoxic ventilatory response in lightly anesthetized spontaneously breathing intact dogs. The cardiopulmonary effects of sequential ventriculocisternal perfusion (VCP) at the rate of 1 ml/min with mock cerebrospinal fluid (CSF, control) and MK-801 (2 mM) were compared during normoxia and 8 min of hypoxic challenge with 12% O2. Minute ventilation (VE), tidal volume (VT), and respiratory frequency (f) were recorded continuously, and hemodynamic parameters [heart rate (HR), blood pressure (MAP), cardiac output (CO), pulmonary arterial pressure, and pulmonary capillary wedge pressure] were measured periodically. Each dog served as its own baseline control before and after each period of sequential VCP under the two different O2 conditions. During 15 min of normoxia, there were no significant changes in the cardiopulmonary parameters with mock CSF VCP, whereas with MK-801 VCP for 15 min, VE decreased by approximately 27%, both by reductions in VT and f (17 and 9.5%, respectively). HR, MAP, and CO were unchanged. During 8 min of hypoxia with mock CSF VCP, VE increased by 171% associated with increased VT and f (25 and 125%, respectively). HR, MAP, and CO were likewise augmented. In contrast, the hypoxic response during MK-801 VCP was characterized by an increased VE of 84%, mainly by a rise in f by 83%, whereas the VT response was abolished. The cardiovascular excitation was also inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Central respiratory effects of glutamine synthesis inhibition in dogs.

Glutamic acid is an excitatory neurotransmitter that may have a significant role in the central chemical drive of ventilation. Therefore cardiorespiratory function was measured in pentobarbital sodium-anesthetized dogs before and after central inhibition of glutamate metabolism by means of methionine sulfoximine (MSO), a specific inhibitor of glutamine synthase (GS) catalyzing amidation of glutamate to glutamine. GS was inhibited centrally by perfusing the ventriculocisternal space with artificial cerebrospinal fluid (CSF) containing 92.5 mmol MSO per liter at a fixed pH, perfusion rate, and pressure. After GS inhibition, CSF transfer rate of [13N]glutamine synthesized from 13NH4+ amidation of glutamate was reduced five-fold, and minute ventilation increased from 2.90 +/- 0.41 (SE) l/min (0.164 +/- 0.020 l.min-1.kg body wt-1) to 4.46 +/- 0.52 l/min (0.254 +/- 0.029 l.min-1.kg body wt-1). This increase in ventilation with endogenous glutamate and the increase in ventilation previously observed during ventriculocisternal perfusion of exogenous glutamate are compared quantitatively via a model of central neurotransmitter glutamate chemoreception. The results support the hypothesis that the endogenous brain glutamate is important in the central chemical drive of ventilation.

Brain glutamate metabolism during hypoxia and peripheral chemodenervation.

Glutamate stimulates resting ventilation by altering neural excitability centrally. Hypoxia increases central ventilatory drive through peripheral chemoreceptor stimulation and may also alter cerebral perfusion and glutamate metabolism locally. Therefore the effect of hypoxia and peripheral chemodenervation on cerebrospinal fluid (CSF) transfer rate of in vivo tracer amidated central nervous system glutamate was studied in intact and chemodenervated pentobarbital-anesthetized dogs during normoxia and after 1 h of hypoxia induced with 10 or 12% O2 in N2 breathing at constant expired ventilation and arterial CO2 tension. Chemodenervation was performed by bilateral sectioning of the carotid body nerves and cervical vagi. CSF transfer rates of radiotracer 13NH4+ and [13N]glutamine synthesized via the reaction, glutamate + NH4(+)----glutamine, in brain glia were measured during normoxia and after 1 h of hypoxia. At normoxia, maximal glial glutamine efflux rate jm = 103.3 +/- 11.2 (SE) mumol.l-1.min-1 in all animals. After 1 h of hypoxia in intact animals, jm = 78.4 +/- 10.0 mumol.l-1.min-1. In denervated animals, jm was decreased to 46.3 +/- 4.3 mumol.l-1.min-1. During hypoxia, mean cerebral cortical glutamate concentration was higher in denervated animals (9.98 +/- 1.43 mumol/g brain tissue) than in intact animals (7.63 +/- 1.82 mumol/g brain tissue) and corresponding medullary glutamate concentration tended to be higher in denervated animals. There were no differences between mean glutamine and gamma-aminobutyric acid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Chloride flux from blood to CSF: inhibition by furosemide and bumetanide.

Movement of chloride from blood to cerebrospinal fluid (CSF) is one of the factors that may be involved in regulation of CSF [Cl-], which is important to CSF acid-base balance. We made quantitative measurements of the unidirectional flux of radiolabeled chloride between blood and CSF in anesthetized dogs, using 38Cl, a short-lived isotope (half-life 37.3 min). This allowed multiple studies to be performed in a given animal. A three-compartment model for the blood, CSF, brain extracellular fluid, and ventriculocisternal perfusion system was used to determine the flux rate. With normocapnia, the flux was 0.01.1 min-1. The influx could be reproducibly measured for three separate determinations in the same animal over a period of 6 h, being 98 +/- 6% of the control first run on the second run and 113 +/- 6% on the third. Furosemide and bumetanide, inhibitors of sodium-coupled chloride movement, lowered the flux to 43 +/- 3% and 55 +/- 6% of control, respectively. The combination of hypercapnia and furosemide lowered the influx to 63 +/- 9% of control. These results indicate that a major mechanism of chloride entry into CSF is sodium-coupled chloride transport.

Effect of centrally administered gamma-aminobutyric acid on metabolic function.

gamma-Aminobutyric acid (GABA) content of the brain increases during hypoxia and hypercapnia and GABA by itself is a central ventilatory depressant and may depress metabolism as well. Therefore the effect of centrally administered GABA by ventriculocisternal perfusion on O2 consumption (VO2) and CO2 production (VCO2) was studied in pentobarbital-anesthetized dogs. GABA (30 mM) in mock cerebrospinal fluid (CSF) was perfused for 15 min at the rate of 1.0 ml/min followed by perfusion with mock CSF alone. Body temperature, perfusion pressure, and CSF pH were kept constant. Minute ventilation (VE) was kept constant mechanically. Under these conditions, VO2, VCO2, alveolar ventilation (VA), and relative pulmonary dead space volume (VD/VT) were measured. During perfusion with 30 mM GABA, mean VO2 (+/- SE) decreased from 96.5 +/- 3.3 to 81.9 +/- 5.1 ml/min, VCO2 from 72.1 +/- 3.8 to 60.7 +/- 3.0 ml/min, and VA from 1.7 +/- 0.1 to 1.3 +/- 0.1 l/min. VD/VT increased from 0.55 +/- 0.02 to 0.65 +/- 0.01. Perfusion with mock CSF alone restored these parameters to initial levels within 15 min. We conclude that centrally administered GABA depresses VO2 and VCO2. This reduction in metabolic function is independent of the central modulatory effects of GABA on respiration.

Central cardiorespiratory effects of glutamate in dogs.

Metabolism of certain amino acid neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA) are closely linked in the brain to CO2 fixation and H+ metabolism. Additionally they may also affect central modulation of cardiorespiratory function. Therefore central cardiorespiratory effects of L-glutamate were determined in lightly anesthetized dogs using ventriculocisternal perfusion with artificial cerebrospinal fluid (CSF) (pH 7.25-7.28) containing 30 or 60 mM glutamate at a flow rate of 1.0 ml/min for 20 min followed by perfusion with artificial CSF alone. Tidal volume and minute ventilation increased with 60 mM glutamate, as did respiratory drive. These changes returned to normal with mock CSF perfusion. Glutamate (30 mM) had no significant effect on ventilation. At both concentrations, glutamate significantly increased mean femoral arterial pressure and mean pulmonary arterial pressure, which was accompanied by bradycardia. All these increases rapidly returned to normal with mock CSF perfusion. Cardiac output and pulmonary capillary wedge pressure did not change with glutamate perfusion. The results suggest that glutamate may have a significant central excitatory role in modulation of ventilatory drive as well as of hemodynamic functions.

Quantitative high-resolution measurement of cerebrovascular physiology with slip-ring CT.

PURPOSE: To implement and validate spiral slip-ring CT for use in cerebrovascular studies. METHODS: Continuous data were acquired from an experimental, first-pass, iodine contrast, bolus study by unidirectional X-ray tube rotation, and images were reconstructed at 100-millisecond intervals. Functional maps of cerebral blood volume (CBV) and cerebral blood flow (CBF) were constructed with voxel-by-voxel gamma variate fitting. Reproducibility studies, different injection volumes and sites, and CO2 challenge were applied to verify the technique. RESULTS: Average absolute cortical gray and white matter and basal ganglia results were reproducible within +/- 0.8 ml/100 g for CBV and +/- 20 ml/100 g per minute for CBF, CBV response to changing arterial CO2 tension was significant only in cortical gray matter and basal ganglia; CBF response was significant in gray and white matter, as well as in the basal ganglia. CONCLUSION: Functional CT and constructed functional maps provide an optimal, high-resolution tool with which to visualize cerebrovascular parameters and their changes.

Operability of nuclear instruments for medical use in developing countries. A decision-analytic approach.

Nuclear technology in diagnostic medicine has become a world-wide phenomenon. One of the problems encountered in implementing this technology in developing countries is predicting the operability of nuclear instruments under local conditions of maintenance and use. Our approach to this problem employs an analytic method often applied in medical decision making, and which can be incorporated into schemes for evaluating the total diagnostic process which utilizes nuclear technology. A recent survey of nine types of nuclear instruments in medical use in eight countries in Southeast Asia provided comprehensive information on the application and maintenance of these instruments, as well as a detailed record of actual operability and use of these instruments over a six-month period. A multivariate statistical analysis for predicting the operability of these instruments was carried out with some of the survey data. Responses to a set of 14 potentially important attributes of instrument use and maintenance obtained from the survey data were used to estimate the posterior probabilities of an instrument being inoperable for more than a given total number of hours in the six-month period during which operability was required. The posterior probabilities were determined by means of both Bayesian and discriminant analysis and summarized in the form of receiver operating characteristic (ROC) curves. Among a number of possible interpretations of the results, the analysis suggests that attributes generally involving installation, documentation, environment, and personnel training appear to be particularly important in predicting the operability of the instruments surveyed.

A cost-effectiveness analysis of screening for hepatitis B surface antigen in India.

We have developed a quantitative model to study the impact of screening for the hepatitis B surface antigen using either second-generation (counterimmunoelectrophoresis) or third-generation (radioimmunoassay) tests. This model was fashioned for general use but was applied to data on hepatitis for India, in an attempt to determine what factors would most influence the decision to institute a screening program for the surface antigen in that country. Screening for the surface antigen should reduce post-transfusion hepatitis B significantly--second-generation testing by 81% and third-generation testing by 99.4%. The marginal cost of substituting counter-immunoelectrophoresis testing for no testing is 557 rupees per case averted, and that of substituting radioimmunoassay for counterimmunoelectrophoresis testing is 1,120 rupees per case averted. Sensitivity analyses suggest that the major impact on costs will result not from changes in the sensitivity or specificity of new screening tests, but rather in their costs.

[A model of the central control of respiration]. / Modell der zentralen Atemregulation.

Central respiratory drive is very much dependent upon the CO2-tension, the H+-content and the ionic composition of the blood and the extracellular fluid of the brain. Ventilation is linearly related in the steady state to the H+-content in the cerebrospinal fluid (CSF). Semiaquatic turtles are an excellent model to study central chemical control of ventilation, and in particular their tolerance to asphyxia. Their ability to maintain prolonged dives is seemingly incongruous with highly-developed mechanisms of central chemical control of ventilation. Experiments were performed on four groups of turtles subjected to two hours of either apneic dives, hypercapnia, anoxia or anoxia plus hypercapnia. One additional group was breathing room air and served as control. At the end of the two-hour period the animals were immediately decapitated and the heads instantly frozen in liquid nitrogen. Brain tissue was removed from the skull and free aminoacids were measured chromatographically. Gamma-aminobutyric acid (GABA) increased significantly in those animals subjected to anoxia (p less than 0.01). These results suggest that the central ventilatory drive during diving and related experimental conditions may be related to alterations in brain concentrations of aminoacid neurotransmitters. GABA is a potent inhibitor of respiratory responses which may function under physiologic and pathophysiologic circumstances to modify ventilatory drive. The role of taurine is not yet clear and has to be further investigated.

Semi-automatic construction of reference standards for evaluation of image registration.

Quantitative evaluation of image registration algorithms is a difficult and under-addressed issue due to the lack of a reference standard in most registration problems. In this work a method is presented whereby detailed reference standard data may be constructed in an efficient semi-automatic fashion. A well-distributed set of n landmarks is detected fully automatically in one scan of a pair to be registered. Using a custom-designed interface, observers define corresponding anatomic locations in the second scan for a specified subset of s of these landmarks. The remaining n-s landmarks are matched fully automatically by a thin-plate-spline based system using the s manual landmark correspondences to model the relationship between the scans. The method is applied to 47 pairs of temporal thoracic CT scans, three pairs of brain MR scans and five thoracic CT datasets with synthetic deformations. Interobserver differences are used to demonstrate the accuracy of the matched points. The utility of the reference standard data as a tool in evaluating registration is shown by the comparison of six sets of registration results on the 47 pairs of thoracic CT data.