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D K Johnson

Publications and source records attributed to D K Johnson.

At least 73 records · Page 4Linked to original sources
PubMed1989

Synthesis of novel bifunctional chelators and their use in preparing monoclonal antibody conjugates for tumor targeting.

Bifunctional derivatives of the chelating agents ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, in which a p-isothiocyanatobenzyl moiety is attached at the methylene carbon atom of one carboxymethyl arm, was synthesized by reductive alkylation of the relevant polyamine with (p-nitrophenyl)pyruvic acid followed by carboxymethylation, reduction of the nitro group, and reaction with thiophosgene. The resulting isothiocyanate derivatives reacted with monoclonal antibody B72.3 to give antibody-chelator conjugates containing 3 mol of chelator per mole of immunoglobulin, without significant loss of immunological activity. Such conjugates, labeled with the radioisotopic metal indium-111, selectively bound a human colorectal carcinoma implanted in nude mice when given intravenously. Uptake into normal tissues was comparable to or lower than that reported for analogous conjugates with known bifunctional chelators. It is concluded that substitution with a protein reactive group at this position in polyaminopolycarboxylate chelators does not alter the chelating properties of these molecules to a sufficient extent to adversely affect biodistribution and thus provides a general method for the synthesis of such chelators.

Animals↗
PubMed1989

Molecular mapping within the mouse albino-deletion complex.

Induced germ-line deletion mutations in the mouse provide a malleable experimental system for in-depth molecular and functional analysis of large segments of the mammalian genome. To obtain an initial bank of molecular probes for the region of mouse chromosome 7 associated with the albino-deletion complex, random anonymous DNA clones, derived from a library constructed from flow-sorted chromosomes, were screened on DNAs from Mus musculus-Mus spretus F1 hybrids carrying large, multilocus, lethal albino deletions. Clones falling within a given deletion interval can easily be recognized because hybridization bands that represent restriction fragment length polymorphisms specific for the mutant (deleted) chromosome inherited from the M. musculus parent will be absent. Among 72 informative clones used as probes, one, which defines the locus D7OR1, mapped within two deletions that are 6-11 centimorgans in length. Submapping of this anonymous clone across a panel of 27 smaller deletions localized D7OR1 distal to a chromosomal subregion important for survival of the preimplantation embryo, proximal to globin [beta-chain (Hbb)], and near the shaker-1 (sh-1) locus. The results of these deletion-mapping experiments were also confirmed by standard three-point linkage analysis. This strategy for selection and rapid mapping of anonymous DNA probes to chromosomal segments corresponding to germ-line deletion mutations should contribute to the generation of more detailed physical and functional maps of genomic regions associated with mutant developmental phenotypes.

Animals↗
PubMed1989

Dual isotope study of iodine-125 and indium-111-labeled antibody in athymic mice.

Monoclonal antibody B72.3 was coupled to a benzylisothiocyanate derivative of diethylenetriaminepentaacetic acid (DTPA). The maximum substitution achievable without loss of immunoreactivity was three DTPA groups per immunoglobulin molecule. The resulting conjugate was labeled with 111In by brief incubation with 111InCl3, giving a mean radiochemical yield of 111In-labeled antibody of 96%. The [111In]B72.3 preparation was mixed with an [125I] B72.3 preparation, obtained by the chloramine-T method, and the mixture administered to athymic mice bearing subcutaneous LS174T colon carcinoma xenografts. There were no significant differences (p greater than 0.1) in the biodistributions of the two labels at 1, 2, 5, and 7 days postinjection. These results are contrasted with prior studies showing elevated levels of 111In in liver, spleen, and kidneys using B72.3-DTPA conjugates prepared via the bicyclic anhydride. It is concluded that protein cross-linking and/or the formation of unstable chelate sites in anhydride coupled conjugates underlie these disparities.

Animals↗
PubMed1985

Pseudomembranous colitis in spinal cord injury.

Pseudomembranous colitis is a well-known disease associated with antibiotic administration and caused by the Clostridium difficile toxin. Clinical presentation is usually marked by watery diarrhea, crampy abdominal pain, and fever. Since early appropriate therapy can reduce morbidity and mortality, it is important for health care professionals to be aware of this disease. Patients with spinal cord injury have a relatively high incidence of respiratory and urinary tract infections that are treated with antibiotics. Therefore, these patients theoretically have a higher risk of contracting pseudomembranous colitis. This article presents a case report of a spinal cord injured patient with this disease who has several of the common difficulties encountered in the diagnosis and treatment, such as indeterminate assays and relapses. The clinical presentation, diagnosis, and treatment of pseudomembranous colitis are described.

Adult↗
PubMed1984

The National Institutes of Health animal handlers medical surveillance program.

The medical surveillance program for animal caretakers, technicians, and other personnel having contact with animals at the National Institutes of Health is described. The program classifies workers according to the groups of animals with which they work. It includes preplacement physical examinations, preventive immunizations, testing, and monitoring of health status. This program helps to protect the workers' health from diseases acquired from animals and to prevent ill employees from adversely affecting the health of the animals with which they work.

Animals↗
PubMed1983

U.S. laws, regulations, and policies important to managers of nonhuman primate colonies.

The various animal welfare laws, regulations, policies, accreditation standards, and welfare groups have an obvious impact on the activities of managers of nonhuman primate colonies. Federal organizations such as the Department of Health and Human Services, Department of Interior, the Department of Agriculture, the Department of Transportation, and the Justice Department regulate many aspects of animal management. Pertinent guidance is available through scientific organizations such as the American Association for Accreditation of Laboratory Animal Care and the National Academy of Sciences. Finally, the recommendations of responsible animal welfare organizations should also receive careful consideration.

Accreditation↗
PubMed1982

The effects of estrogen on cortisol metabolism in female baboons.

We examined cortisol (F) dynamics in female baboons (Papio anubis) treated with diethylstilbestrol (DES) or estradiol (E2) and compared values with those previously measured in nonpregnant and pregnant animals. Five regularly menstruating baboons (12-18 kg, BW) were administered 5 mg DES daily via fruit or 0.5 mg E2/0.1ml oil sc for 30 days. Blood samples, obtained before and after treatment, were assayed for serum F concentrations and serum cortisol binding capacity (CBC). The metabolic clearance (MCR) and production rate (PR) of F and the catabolism of i.v. administered [3H] F were examined 25 and 30 days after initiation of estrogen treatment. Compared with values in nonpregnant baboons, F metabolism in estrogen treated animals is significantly altered and is characterized by increased formation of unconjugated metabolites, decreased glucuronylation, increased excretion of unconjugated F, cortisone, and highly polar metabolites, and increased CBC. These changes induced by estrogen are similar to those observed in intact pregnant baboons and permit the suggestion that the pattern of F metabolism and the level of CBC in baboon pregnancy are the result of elevated estrogen production. However, estrogen also caused a significant decrease in the MCR and PR of F, parameters which, by contrast, are similar in intact pregnant and nonpregnant baboons. These findings indicate that while estrogen also influences the rate of F clearance and F production, these effects of estrogen are not apparent during pregnancy. Collectively, these findings allow the suggestion that estrogen is a major factor which alters F metabolism and increases serum CBC in baboon gestation. However, additional factors are operative in primate pregnancy which maintain PR and MCR of F at levels similar to those of nonpregnant baboons.

Animals↗
PubMed1982

Hepatocyte iron kinetics in the rat explored with an iron chelator.

The hepatocyte metabolism of 59Fe-labelled ferritin, haemoglobin-haptoglobin and transferrin has been examined in rats. All three forms of 59Fe became transiently available to desferrioxamine (DF) at the time they would otherwise have entered storage or alternative pathways of iron metabolism. However, differences in both the patterns of spontaneous 59Fe reutilization by normal and iron deficient rats and the partition of chelate iron excretion between bile and urine, suggested that iron in transit within hepatocytes did not behave as a single common pool. Ferritin 59Fe, entering a pool of non-radioactive iron the size of which is determined by liver iron stores, was chelated predominantly into the bile. Transferrin 59Fe was distinguished by a greater reflux to the erythron in iron deficient rats, and by excretion of a larger proportion of 59Fe chelated by DF in the urine. Haemoglobin-haptoglobin 59Fe followed a metabolic pathway which was relatively independent of both the iron stores and DF. If the heterogeneous behaviour of rat hepatocyte transit iron has a parallel in man, alterations in the size of similar chelatable iron pools could explain the dependence of DF-induced urine and faecal iron excretion on both liver iron stores and the level of erythropoiesis.

Animals↗
PubMed1982

An in vivo evaluation of iron-chelating drugs derived from pyridoxal and its analogs.

Chelating agents related to the newly described iron binding drug, pyridoxal isonicotinoyl hydrazone, were screened for their effects on iron excretion in the rat, employing a new and highly sensitive radioisotopic procedure. Pyridoxal itself induced significant iron excretion when given either parenterally or orally, the excreted iron being derived from the same pool as that tapped by the drug currently used in treating iron overload in man, desferrioxamine B. Schiff base derivatives of pyridoxal produced varying amounts of iron excretion, the hydrazone derivatives being much more effective than pyridoxal alone. These data suggested a number of possible mechanisms for the chelation of endogenous iron by such agents. Pyridoxal benzoyl hydrazone induced approximately 50% more iron excretion than did an equivalent dose of the parent isonicotinoyl analog and bile cannulation studies showed this difference to be associated with a prolonged duration of action of the benzoyl derivative. When give i.v., the benzoyl and isonicotinoyl hydrazones of pyridoxal and the benzoyl hydrazone of salicylaldehyde all produced levels of iron excretion which exceeded that seen with an equivalent dose of desferrioxamine B. It is concluded that the range of active Schiff base derivatives is likely to be large and that some of these, although not necessarily any of the particular compounds described here, may prove to be of clinical use.

Animals↗
PubMed1981

A rapid assay for evaluation of iron-chelating agents in rats.

The animal assay of potential new iron-chelating agents is at present dependent on cumbersome and imprecise iron balance studies in hypertransfused rodents. We report the development of a radioisotope assay in intact rats based on the transient labeling by ferritin 59Fe of the main source of chelatable iron within hepatocytes. The isotope was maximally available to chelators during the first 6 hr after its injection, nearly all the excretion being in the bile. The bile 59Fe/total iron ratio was independent of both the chelator and its dose. However, in iron-loaded rats, the ratio was reduced, and the isotope excretion was a less sensitive measure of intrahepatic chelation. In the proposed assay, test chelators were given to normal rats 2 hr after an intravenous injection of 59Fe-ferritin. Four hours later, the radioiron in the liver and in the gut gave a sensitive measure of the mobilization of hepatic iron to the bile. In addition, chemical iron determinations identified a small alternative source of urinary chelate with agents known to promote urine excretion in man. The assay gave a rapid and precise screen for chelators given by parenteral and oral routes.

Animals↗
PubMed1980

Single system ectopic ureteroceles with anomalies of the heart, testis and vas deferens.

We report a series of 7 children with single system ectopic ureteroceles. Our study included 6 boys, unlike the more common duplicated system ectopic ureterocele, that occurs 4 to 6 times more often in female patients. The presenting symptoms or signs were related to infection or obstruction in only 2 of our 7 patients. An ipsilateral non-functioning hypoplastic dysplastic kidney was present in 5 children (71%). Of the 7 children 4 had major congenital cardiac anomalies. Three boys had abdominal testes, including 2 with bilateral non-union of the vas deferens, 1 of whom represents the first reported case of bilateral atresia of the vas deferens with abdominal testes.

Child↗
PubMed1980

The changing role of cystoscopy in the pediatric patient.

Cystoscopy is used too often in the pediatric patient and frequently is without diagnostic or therapeutic benefit to the child. Cystoscopy is of little proved benefit in the evaluation and treatment of recurrent cystitis, primary enuresis and most cases of hematuria. In children initially diagnosed with vesicoureteral reflux therapeutic determinations generally can be made on the basis of response to appropriate antimicrobial therapy and from uroradiographic findings. Cystoscopy remains a valuable tool to evaluate urinary obstruction and severe congenital defects, such as intersex and cloacal anomalies, and to help place percutaneous suprapubic tubes for bladder cycling before urinary undiversion and for urodynamic evaluation.

Child↗
PubMed1980

Atherosclerosis in the Erythrocebus patas, an old world monkey.

Fifty monkeys of the species Erythrocebus patas were fed a control monkey chow, a semi-synthetic diet containing 25% lard, or a semisynthetic diet containing 25% lard and 0.5% cholesterol for 2 years. The patas monkeys had naturally occurring atherosclerosis that was greatly accelerated by feeding a diet containing cholesterol. The atherosclerosis involved the aorta, predominantly the abdominal portion, the coronary arteries, and various peripheral vessels. Histologically, the atherosclerosis was characterized by intimal proliferative lesions associated with intra- and extracellular lipid deposition. Complicated lesions that developed after 2 years on the cholesterol-containing diet were associated with lipid crystals, necrosis, mineralization, and encroachment upon the media. Adventitial reactions characterized by increased vascularity and the presence of inflammatory cells were seen. All of these observations have been described as components of the human atherosclerotic disease process. The similarity of the patas monkey atherosclerosis to human atherosclerosis, the relatively large size and easy handling of the animals, and the fact that previous studies have shown the lipoproteins of both control and cholesterol-fed monkeys to resemble human lipoproteins all contribute to making the patas monkey a useful model for the study of experimental atherosclerosis.

Animals↗