Error analysis of one sample clearance methods.
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Biomedical subjects
Publications and source records attributed to C D Russell.
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A captopril renal study performed with both radiohippuran and 99mTc-MAG3 demonstrated the typical changes of a hemodynamically significant renal artery stenosis in a hypertensive renal allograft recipient. Arteriography demonstrated high grade stenosis not of the renal artery but of the iliac artery. After successful angioplasty, the patient's hypertension resolved.
Twelve patients with metastatic colorectal cancer participated in a Phase I trial of 131I-labeled chimeric B72.3 (human IgG4). Consecutive groups of patients received 18 mCi/m2, 27 mCi/m2 and 36 mCi/m2. No acute side effects related to antibody administration were noted. Bone marrow suppression was the only side effect; it was dose-dependent and correlated with whole-body radiation dose estimates. The lowest dose level produced no marrow suppression, whereas 27 mCi/m2 resulted in Grade 1 and 2 marrow suppression in two of three patients. The maximum tolerated dose was 36 mCi/m2 with all six patients at this dose level having at least Grade 1 and two patients with Grade 3 and 4 marrow suppression. Eight of 12 patients had radioimmune imaging of tumor sites at 5-22 days. Seven patients had an antibody response to initial infusion. On retreatment, whole-body kinetics and imaging were altered for patients with a high anti-ch-B72.3 response. Thus, chimeric B72.3 (IgG4) has limited utility as a means of delivering multiple therapeutic doses of 131I in the majority of patients; alternative strategies including second generation anti-TAG-72 monoclonal antibodies, other radioisotopes and other chimeric human isotypes will need to be pursued.
Hypertension in renal transplant recipients is an important risk factor for graft function and cardiovascular morbidity and mortality. The mechanisms of posttransplant hypertension are not well understood. Most of the time, the nature of this hypertension is multifactorial. Rejection, both acute and chronic, recurrent renal disease, graft renal artery stenosis, native kidney disease and drug therapy with steroids and cyclosporin have all been implicated. Where a single cause can be identified, the therapy can be rational and often very successful. For this reason, the diagnosis of graft renal artery stenosis is important, because percutaneous transluminal angioplasty or surgery can lead to the cure of hypertension and improvement of the graft function. Noninvasive testing, using captopril renography for the diagnosis of hemodynamically significant renal artery stenosis, presently yields encouraging results.
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Development and validation of simplified renal clearance methods has required a research data base of multiple blood samples drawn over a substantial time interval, which is difficult to obtain for children. While the medical risks entailed in drawing multiple samples may be negligible, the problems of parental and institutional consent make such studies more difficult in the pediatric population. Scaling for patient size permits combining data from patients of different age and limits the number of studies required. A scaling technique is presented and evaluated here. With scaling, adult data can be used successfully to predict pediatric responses and to develop pediatric methods based on adult data alone. Inclusion of pediatric data improves the fit and permits development of generic methods that work with both adults and children.
Pharmacokinetics, immunogenicity, and biodistribution of a 131I-labeled mouse/human chimeric monoclonal antibody (C-17-1A) was studied in six metastatic colon cancer patients. Pharmacokinetics obtained from serum radioactivity or chimera concentration were identical after 5 mCi of 131I-C-17-1A with mean alpha half-lives of 17.6 +/- 2.3 and 19.7 +/- 2.9 and mean beta half-lives of 100.9 +/- 16.1 and 106.4 +/- 14.1 hr, respectively. HPLC analysis documented the monomeric chimeric 17-1A without evidence of immune complexes or free 131I. None of the patients developed antibody after 131I-chimeric 17-1A exposure. Radiolocalization occurred in known areas of disease greater than 4 cm in all patients. The half-life of total-body radioactivity was 58 +/- 7 hr by whole-body counts and 64 +/- 13 hr by urine measurements. Whole-body and bone marrow dose estimates ranged from 0.75-1.03 and 0.76-1.05 rad/mCi, respectively. These studies confirm the prolonged circulation and reduced immunogenicity of chimeric 17-1A versus murine 17-1A. Marrow radiation exposure using antibodies with prolonged circulation is a critical factor in planning for radioimmunotherapeutic applications.
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Renal parenchymal transit time of the recently introduced radiopharmaceutical 99mTc-MAG3 (mercaptoacetylglycylglycinel) was measured in 37 kidneys, using factor analysis to separate parenchymal activity from that in the collecting system. A new factor algorithm was employed, based on prior interpolative background subtraction and use of the fact that the initial slope of the collecting system factor time-activity curve must be zero. The only operator intervention required was selection of a rectangular region enclosing the kidney (by identifying two points at opposite corners). Transit time was calculated from the factor time-activity curves both by deconvolution of the parenchymal factor curve and also by measuring the appearance time for collecting system activity from the collecting system factor curve. There was substantial agreement between the two methods. Factor analysis led to a narrower range of normal values than a conventional cortical region-of-interest method, presumably by decreasing crosstalk from the collecting system. In preliminary trials, the parenchymal transit time did not well separate four obstructed from seventeen unobstructed kidneys, but it successfully (p less than 0.05) separated six transplanted kidneys with acute rejection or acute tubular necrosis from 10 normal transplants.
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The reduction of [99Tc]pertechnetate was studied as a function of pH in complexing media of pyrophosphate, methylene diphosphonate (MDP), and ethane-1, hydroxy-1, and 1-diphosphonate (HEDP). Tast (sampled d-c) and normal-pulse polarography were used to study the reduction of pertechnetate, and normal-pulse polarography (sweeping in the anodic direction) to study the reoxidation of the products. Below pH 6 TcO4-was reduced to Tc(III), which could be reoxidized to Tc(IV). Above pH 10, TcO4-was reduced in two steps to Tc(V) and Tc(IV), each of which could be reoxidized to TcO4-. Between pH 6 and 10 the results differed according to the ligand present. In pyrophosphate and MDP, TcO4- was reduced in two steps to Tc(IV) and Tc(III); Tc(III) could be reoxidized in two steps to Tc(IV) and TcO4-. In HEDP, on the other hand, TcO4- was reduced in two steps to Tc(V) and Tc(III), and could be reoxidized to Tc(IV) and TcO4-. Additional waves were observed; they apparently led to unstable products.
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A method previously established in the experimental animal for predicting the acute response to either metabolic stress (bicarbonate administration) or respiratory stress(manipulation of oxygenator gas during cardiopulmonary bypass) has been extended to man. The method is based on a single nomogram. The accuracy of the nomogram is demonstrated using data from 13 patients on cardiopulmonary bypass. Similar agreement obtains between the nomogram and data reported by others. The nomogram can be used to estimate the therapeutically required dose of bicarbonate.
99mTc-pertechnetate scanning is now recognized as a useful means of detecting Meckel's diverticula. When these contain gastric mucosa and present with ulceration and bleeding, the ectopic gastric mucosa can be identified by its secretion of 99mTc-pertechnetate. However, the secretions of normal gastric and salivary glands can pool in the gut and simulate a Meckel's diverticulum. We believe the diagnostic procedure of choice to include both continuous nasogastric suction and continuous sequential gamma camera images. To support this view, we present cases illustrating 1) that 99mTc-pertechnetate can appear in the bowel within the first few minutes of administering 99mTc-pertechnetate, even in the absence of a Meckel's diverticulum; 2) that rapid sequential camera views are helpful but not definitive in distinguishing such bowel activity from a Meckel's diverticulum; and 3) that continuous nasogastric suction most successfully eliminates this interference.
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A focal avascular defect in an enlarged spleen, clearly shown both by 99mTc-sulfur colloid scanning and by celiac angiography, could not be associated with any gross pathologic abnormality at splenectomy. Vascular lesions can probably produce focal defects on the scan in the absence of infarction.