Effect of ursodeoxycholic acid therapy on hepatic function in children with intrahepatic cholestatic liver disease.

BACKGROUND: Ursodeoxycholic acid (UDCA) has been shown to improve pruritus, alanine aminotransferase (ALT), and cholesterol levels in children with intrahepatic cholestatic liver disease. However, the effect of UDCA on quantitative tests of hepatic function in children is uncertain. METHODS: A 2.5-year, open label, crossover study, was designed to determine the effect of UDCA (15-20 mg/kg per day for 12 months, off for 6 months, and on again for 12 months) on clinical symptoms, biochemical test results, galactose and caffeine elimination half-lives (t1/2), and quantitative hepatic scintigraphy in 13 subjects aged 13.1 +/- 2.1 years (10 of whom completed the entire study), with intrahepatic cholestasis. RESULTS: Pruritus improved with UDCA in the 6 patients with pruritus on entry into the study. At 12 months, there was a significant decline in ALT, gamma-glutamyl transpeptidase, and plasma levels of copper and manganese, with no further decline in these levels at 24 months. There were no changes in bilirubin or cholylglycine levels. After therapy was discontinued at 12 months, UDCA was restarted within 1 month in 9 of 12 patients in response to a doubling of ALT (n = 6) or worsening pruritus (n = 3). Galactose t1/2 increased after 12 months, with no further increases after 24 months of UDCA therapy, whereas caffeine t1/2 did not change. There were no significant changes in hepatic scintigraphy throughout the study. CONCLUSIONS: These data suggest that although UDCA therapy improves pruritus and results in a reduction in ALT and gamma-glutamyl transpeptidase, UDCA therapy did not improve quantitative measures of hepatic function in children with intrahepatic cholestasis.

DTPA aerosol in ventilation/perfusion scintigraphy for diagnosing pulmonary embolism.

UNLABELLED: The use of lung scintigraphy in evaluating suspected pulmonary embolism (PE) is controversial. Several diagnostic methods have been described for lung scans, of which the most widely applied uses 99mTc-MAA for perfusion, 133Xe for ventilation and PIOPED diagnostic criteria. This study evaluates the accuracy of lung scintigraphy using an alternative ventilation agent, 99mTc-diethylenetriamine pentacetic acid (DTPA) aerosol, and specific criteria. METHODS: Diagnostic criteria for DTPA aerosol ventilation were prospectively applied to 5017 patients over a 9-yr period. Lung scan interpretations were analyzed for frequency of occurrence, and results were compared to those of angiography in 455 patients. RESULTS: Scans were interpreted as normal, low or high probability in 79% of patients and as either indeterminate or medium probability in 21% of patients. Three patients had normal scans and negative angiography. In patients with low-probability scans, 111 angiograms were performed: 103 (93%) were negative, and 8 (7%) were positive. In patients with indeterminate scans, 114 angiograms were performed: 85 (75%) were negative, and 29 (25%) were positive. In patients with medium-probability scans, 149 angiograms were performed: 86 (58%) were negative, and 63 (42%) were positive. In patients with high-probability scans, 78 angiograms were performed: 6 (8%) were negative, and 72 (92%) were positive. CONCLUSION: These results indicate that lung scintigraphy using DTPA aerosol and our criteria is accurate in diagnosing and stratifying risk of pulmonary embolic disease. Compared with 133Xe and PIOPED criteria, DTPA ventilation and our criteria reduced the false-negative rate in low-probability scans (7% versus 16%, p < 0.005) and decreased the fraction of intermediate-probability scans (21 % versus 39%, p < 0.01).

Direct reconstruction of single-photon emission computed tomography images using retained matrix elements.

In clinical applications, two methods of single-photon emission computed tomography (SPECT) reconstruction are widely used. These are filtered backprojection and iterative reconstruction. Filtered backprojection is fast and produces acceptable images. Iterative reconstruction is slow, but produces images of greater accuracy than backprojection. The authors sought to develop a method of SPECT reconstruction that would have the advantages of both established methods: close in speed to backprojection and with the accuracy of iterative reconstruction. This was accomplished by computing a direct solution to the set of linear equations governing SPECT reconstruction. We tested this method of SPECT reconstruction using a set of projections from a cold rod and sphere phantom. Direct reconstruction produced images having equivalent resolution to backprojected images, but with double the contrast ratio. The direct method required 10 seconds of computation per slice on a Macintosh Quadra 950 (Apple Computer; Cupertin, CA), significantly faster than most iterative methods.

Redundant array of independent disks: practical on-line archiving of nuclear medicine image data.

While various methods for long-term archiving of nuclear medicine image data exist, none support rapid on-line search and retrieval of information. We assembled a 90-Gbyte redundant array of independent disks (RAID) system using 10-, 9-Gbyte disk drives. The system was connected to a personal computer and software was used to partition the array into 4-Gbyte sections. All studies (50,000) acquired over a 7-year period were archived in the system. Based on patient name/number and study date, information could be located within 20 seconds and retrieved for display and analysis in less than 5 seconds. RAID offers a practical, redundant method for long-term archiving of nuclear medicine studies that supports rapid on-line retrieval.

Functional asplenia in hemoglobin SC disease.

The incidence of functional asplenia in sickle-hemoglobin C (SC) disease has not been defined, and the use of prophylactic penicillin to prevent life-threatening septicemia in this disorder is controversial. The percentage of red blood cells with pits (pit count) is a reliable assay of splenic function in other disorders but has not been validated in hemoglobin SC disease. To address these issues, we conducted a prospective, multicenter study of splenic function in persons with hemoglobin SC disease. Baseline clinical data were recorded, and red blood cell pit counts were performed on 201 subjects, aged 6 months to 90 years, with hemoglobin SC; 43 subjects underwent radionuclide liver-spleen scanning. Pit counts greater than 20% were associated with functional asplenia as assessed by liver-spleen scan, whereas pit counts less than 20% were found in subjects with preserved splenic function. Pit counts greater than 20% were present in 0 of 59 subjects (0%) less than 4 years of age, in 19 of 86 subjects (22%) 4 to 12 years of age, and in 25 of 56 subjects (45%) greater than 12 years of age. Other subjects with hemoglobin SC, who had previously undergone surgical splenectomy, had higher pit counts (59.7% +/- 9.5%) than splenectomized subjects without hemoglobinopathy (38.5% +/- 8.8%) or with sickle cell anemia (20.5% +/- 1.9%; P < .001). Two subjects with hemoglobin SC disease (not splenectomized), ages 14 and 15 years, with pit counts of 40.3% and 41.7% died from pneumococcal septicemia. These data indicate that functional asplenia occurs in many patients with hemoglobin SC disease, but its development is usually delayed until after 4 years of age. The pit count is a reliable measure of splenic function in hemoglobin SC disease, but values indicative of functional asplenia (> 20% in our laboratory) are higher than in other disorders. The routine administration of prophylactic penicillin to infants and young children with hemoglobin SC disease may not be necessary.

A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry.

OBJECTIVE: Our purpose was to evaluate the subclinical occurrence of heparin-induced osteoporosis in pregnancy, by means of bone densitometry. STUDY DESIGN: A prospective, consecutive cohort of 14 pregnant women requiring heparin therapy and 14 pregnant controls matched for age, race, and smoking status was identified by 20 weeks' gestation at a university medical center. Proximal femur bone density measurements were taken at baseline, immediately post partum, and 6 months post partum in the cases and controls. Vertebral measurements were also obtained on both groups immediately post partum and 6 months post partum. Bone density as a function of heparin dosing and duration was examined. Nonparametric statistical tests were used for all comparisons. RESULTS: Five of 14 cases (36%) had a > or = 10% decrease from the baseline proximal femur measurements to immediate postpartum values versus none of the 14 matched controls (p = 0.04). Mean proximal femur bone density measurements also decreased in the cases (p = 0.01); this difference continued to be statistically significant 6 months post partum (p = 0.03). No dose-response relationship could be demonstrated. CONCLUSION: Heparin adversely affected bone density in about one third of exposed patients.

User-definable bull's-eye database analysis.

Several quantitative bull's-eye database programs have been developed and employed successfully, but generally they restrict the user to limited types of quantitative analysis. We developed a type of bull's-eye analysis which facilitates user-defined processing, and then explored the effects of various types of processing on the comparisons of patient information with that of reference databases. Male and female bull's-eye database were generated from 32 normal patients using unweighted 2D prefiltering, ramp backprojection, unweighted 3D postfiltering, and peak value circumferential plotting (base method). The data from each patient were then reprocessed and compared to the databases by means of three different approaches: (1) using the base method, (2) using average as opposed to peak value profiles, and (3) using a resolution recovery prefilter instead of a smoothing prefilter. Significant differences in the number of apparently abnormal regions were found between the three methods. In other words, the type of single-photon emission tomography (SPET) processing affected the accuracy of comparisons between patient and database information. Because even sophisticated analysis can now be performed on personal computers, we conclude that, rather than a preprocessed data file, clinical "normal reference" information should consist of original SPET data (in a standard format, e.g., Interfile) from a series of documented normal patients. Each user could then generate reference bull's-eye database by applying his or her own clinical processing procedures to the data.

Increased single-photon emission computed tomography image processing speed achieved in personal computers with memory-intensive algorithms.

Recent dramatic reductions in the cost of computer random access memory (RAM) and the ability of newer microprocessors and associated personal computer operating systems to address large amounts of memory make novel strategies for high-speed image processing possible. We developed image processing algorithms that use this newly available memory to achieve increases in effective processing speed. These algorithms rely on the use of precomputed lookup tables to avoid repeated use of relatively expensive machine instructions, such as multiplications and divisions. Programs using this strategy to perform single photon emission computer tomography (SPECT) analysis were written in C and assembly language and tested on a Macintosh Quadra 950 (Apple Computer, Cupertino, CA) having 64 megabytes of RAM. The measured processing times are competitive with most dedicated nuclear medicine computers. A general implementation of such programs will allow personal computers to compete with dedicated imaging systems, at a substantial reduction in cost.

Regional variations in bone mineral density as assessed with dual-energy photon absorptiometry and dual x-ray absorptiometry.

Total-body, lumbar spine, and hip bone mineral density (BMD) scans were obtained in postmenopausal women to examine regional variations in mineralization of trabecular bone. One hundred ninety-nine patients were studied with dual-energy photon absorptiometry (DPA) and/or dual x-ray absorptiometry (DXA). Comparison of BMD at the different sites showed statistically significant correlations (P < .001) among all the sites; however, variations between sites were observed in many patients. Total-body measurements were within normal limits as defined by the system software in 90% of patients with substantial bone mineral loss in the spine or hip. Lumbar spine measurements calculated from the total-body scan differed from the direct measurements by an average of 10% (DPA) and 12% (DXA). These results suggest that site-specific measurements are required to assess regional osteopenia. While total-body scans may be precise and offer the advantage of total-body composition determination, BMD values derived from total-body scans cannot currently replace direct measurements.

Effects of variations in the duration of diffusible-tracer infusions on calculated values of global and local cerebral blood flow.

Using dual tracer quantitative digital autoradiography and iodoantipyrine (IAP), we compared local cerebral blood flow (LCBF) measurements using two different infusion times within the same animal. Rats were given concurrent infusions of 14C-IAP and 123I-IAP; one tracer was administered over 20 seconds and the other over 40 seconds. Pairs of autoradiograms, one representing predominantly 123I and the other 14C, were then produced from 20 micron-thick brain sections and images from each section were digitized and processed to produce pairs of digital images of LCBF. The corresponding LCBF images were compared quantitatively on a pixel-by-pixel basis. Global LCBF values were greater (28%) at 20 seconds compared to 40 seconds, consistent with the previously reported "falling flow" phenomenon. Perhaps more importantly, the actual pattern of LCBF differed in certain regions such as the cortex, hippocampus, thalamus, and cerebellum between the two time points. In other words, the quantitative patterns of calculated LCBF values were dependent upon the duration of tracer infusion, even when the infusion times were kept below recommended limits (45 seconds). Thus, errors in LCBF measurements may occur in certain structures even in brief experiments. Because these errors are spatially dependent rather than blood flow dependent, there is presently no model which can be globally applied to the brain to correct them.

Comparison of regional blood-brain transport kinetics between glucose and fluorodeoxyglucose.

The fluorodeoxyglucose (FDG) method for estimating regional cerebral glucose metabolic rate (LCMRglc) requires that a fixed relationship (the "lumped constant") exists between net FDG and glucose (GLC) extraction throughout the brain. In addition to the relative rate of metabolism between FDG and GLC, this assumed constant is affected by the relative rate of blood-to-brain FDG transport compared to that of glucose. However, little data is available regarding the regional stability of the FDG versus GLC transport-rate relationship. We therefore used high resolution, quantitative dual-tracer digital autoradiography to directly compare the blood-to-brain transport rate constants (K1) of radiolabeled GLC and FDG in normal and pharmacologically-stimulated rats. The rats were given 45 sec terminal intravenous infusions of a mixture of 18F-FDG and 14C-GLC. Autoradiograms of the brain representing the FDG and GLC tracer concentrations were produced, digitized, and converted into digital images of K1. We found that the global K1 values of FDG and GLC were not significantly different from each other. However, detailed analysis revealed that some structures in the normal animals, such as the hippocampus and cerebellum, had different quantitative patterns of FDG transport compared to GLC transport. Thus, our results indicate that the relationship between GLC and FDG transport is not uniform throughout the brain as has previously been assumed. This observation suggests that regional variations in the type and distribution of glucose transporters may exist and that the fluorodeoxyglucose "lumped constant" may vary somewhat among different brain regions.

Real-time list-mode processing of gated cardiac blood pool examinations with forward-backward framing.

List-mode processing of gated cardiac blood pool data has be shown to been more accurate than standard frame-mode processing, but it has not gained widespread clinical use because of the difficulties associated with post-processing of the acquired data. We therefore investigated the possibility of performing the list-mode processing concurrently with the acquisition of the data, i.e. real-time list-mode processing. A programme for simultaneous acquisition and processing of gated cardiac images was written in assembly code and implemented on a personal computer. The programme was tested in phantom studies, then used in 200 consecutive patient examinations. Data could be concurrently acquired from the gamma-camera and processed with forward-backward framing at a great enough speed so that no loss of information occurred at up to 40,000 counts per second, a value exceeding typical count rates observed in clinical practice. The ease-of-use and the clinical benefits of real-time list-mode processing suggest that it may become a standard method for gated examinations of the left ventricle in the near future.

Distribution of a breast-directed I-131-radiolabeled monoclonal antibody in blood and bone marrow: implications for radiation immunotherapy.

Bone marrow is most often the dose-limiting organ in radiation immunotherapy. Controversy exists over optimal methods of estimating radiation dose to bone marrow. The authors compared findings in serial blood samples to findings in bone marrow biopsy samples as measures of bone marrow activity from which to calculate bone marrow dose. Peripheral blood samples and bone marrow biopsy samples were obtained from 11 female patients at 48 and 168 hours after infusion of iodine-131-labeled Mc5 antibody. Bone marrow biopsy data demonstrated markedly decreased specific activity compared with that measured in the peripheral blood. Activities at 48 hours after infusion ranged from 3% to 22% of the peripheral blood activity. These results indicate that activity concentration in the bone marrow is not equivalent to activity concentration in the blood for the Mc5 antibody. These results imply that a dose three to four times that indicated from serial blood samples could be tolerated by patients, provided the antibody-radioisotope does not bind to the marrow.

Autoradiographic measurement of cerebral lactate transport rate constants in normal and activated conditions.

We used quantitative autoradiography to measure the regional rate constants of blood-to-brain transport of lactate in normal rats and rats treated with kainic acid. Mean cerebral values of lactate transport rate constants were not significantly different between the normal and treated rats, being 0.13 and 0.14 min-1 (ml/g), respectively. Regional values were also generally similar between the groups, but structures that are known to be activated by kainic acid showed increased values in the treated rats compared with rates in the controls. Our measured values of lactate transport rate constants are approximately 50% as great as those published for glucose, indicating that blood-brain transfer of lactate can be significant. This observation supports the hypothesis that radiolabel derived from glucose can leave the brain as radiolabeled lactate in conditions in which intracerebral lactate concentration rises, a hypothesis that has previously been presented to explain differences between rates of accumulation of radiolabel derived from deoxyglucose and glucose in such conditions.

Splenic function in persons with sickle cell trait at moderately high altitude.

We investigated the possibility that persons with sickle cell trait who reside chronically at moderately high altitude might develop impaired splenic reticuloendothelial function. Seventeen healthy young black men with sickle trait who had lived at greater than or equal to 1,609 m for greater than or equal to 10 years participated in the study along with 25 matched control subjects with normal hemoglobin. Splenic function was assessed by radionuclide liver-spleen scanning and by red cell pit counts. No evidence of impaired splenic function was found in the sickle trait group. The data suggest that long-term residence at moderately high altitude does not place persons with sickle cell trait at risk for splenic dysfunction.

Improved tumor imaging with radiolabeled monoclonal antibodies by plasma clearance of unbound antibody with anti-antibody column.

Imaging of tumors by using radiolabeled monoclonal antibodies (MoAs) is hindered by the presence of background activity. To reduce this problem, the authors investigated the process of removing labeled MoAs from plasma at selected times by means of extracorporeal immunoadsorption. In seven patients with either lung or breast carcinoma, an indium-111-labeled murine antibody was intravenously administered. Six to 24 hours later, immunoadsorption was performed by passing the patients' plasma through a goat anti-mouse antibody column connected to a plasma separator. Whole-body computer images were obtained before and after the treatment. Blood pool activity in the images was reduced by an average of 59%, while tumor activity dropped by only 10%. Tumor-to-blood activity ratios therefore more than doubled, improving by an average of 121% between the pre- and posttreatment image sets. Eight of 12 areas of known disease and three areas of unknown but later documented disease were detected after the immunoadsorption process, while the three areas of unknown disease and three of the areas of known disease were not detected in the preclearance images. Thus, the feasibility of using extracorporeal immunoadsorption to improve MoA imaging of tumors was demonstrated.

Imaging of non-small cell lung cancers with a monoclonal antibody, KC-4G3, which recognizes a human milk fat globule antigen.

To determine the role of lung cancer tumor imaging with monoclonal antibodies directed against high molecular weight human milk fat globule antigens, we administered i.v. 111In-KC-4G3 to 24 patients with advanced non-small cell lung cancer. One mg of 111In-KC-4G3 was mixed with 0, 9, 49, 99, or 499 mg of unlabeled KC-4G3 and infused i.v. over 1 to 5 h. The mean 111In-KC-4G3 radiochemical purity was greater than 97% and the resultant immunoreactivity averaged 62%. Successful imaging of cancer sites was accomplished in 92% of 24 patients, and 57% of 91 total lesions were visualized. Successful localization of tumor sites related to size (P less than 0.001), with 81% of lesions greater than 3.0 cm in diameter, 50% of lesions 1.5 to 3 cm, and 6% of lesions less than 1.5 cm successfully imaging, and to location (P less than 0.05), with 69% of pulmonary lesions, 80% of soft tissue lesions, and only 32% of bone metastases being visualized. Nonspecific reticulo-endothelial uptake of radioactivity was a major problem. Approximately 35% of 111In was chelated to serum transferrin by 24 and 48 h after infusion. The mean t 1/2 beta for plasma radioisotope and immunoreactive KC-4G3 was 29 and 27 h, respectively. There was no correlation between total infused antibody dose and imaging success or between total dose and effect on 111In and KC-4G3 kinetics. Circulating free KC-4 antigen was measurable in all but one patient before study. Tumor biopsy following infusion could demonstrate antibody presence but not saturable antigen binding. We conclude that (a) 111In-KC-4G3 demonstrates successful tumor localization in non-small cell lung cancers bearing generally high expression of its antigen and (b) further investigations to diminish nonspecific radioactivity for imaging and utilization of high dose radiolabeled antibody for therapeutic intent are warranted.

Quantification of patterns of regional cardiac metabolism.

To quantitatively map and compare patterns of regional cardiac metabolism with greater spatial resolution than is possible with positron emission tomography (PET), the authors developed autoradiographic techniques for use with combinations of radiolabeled fluorodeoxyglucose (FDG), glucose (GLU), and acetate (ACE) and applied the techniques to normal rats. Kinetic models were developed to compare GLU-based oxidative glucose metabolism with FDG-based total glucose metabolism (oxidative plus anaerobic) and to compare ACE-based overall oxidative metabolism with FDG-based total glucose metabolism. GLU-based metabolism generally paralleled FDG-based metabolism, but divergence occurred in certain structures such as the papillary muscles, where FDG-based metabolism was much greater. ACE-based metabolism also generally paralleled FDG-based metabolism, but again, the papillary muscles had relatively greater FDG-based metabolism. These discrepancies between FDG-based metabolism and GLU- or ACE-based metabolism suggest the presence of high levels of anaerobic glycolysis. Thus, the study indicates that anaerobic glycolysis, in addition to occurring in ischemic or "stunned" myocardium (as has been shown in recent PET studies), occurs normally in specific cardiac regions, despite the presence of abundant oxygen.