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Biomedical subjects

I Diamond

Publications and source records attributed to I Diamond.

At least 109 records · Page 6Linked to original sources
PubMed1983

Biochemical pharmacology and toxicology of formycin alone and in combination with 2'-deoxycoformycin (pentostatin).

The toxicology and pharmacology of formycin both as a single agent and combined with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) were examined in outbred Swiss mice heterozygous for the nude gene (nu/+). The LD10 for formycin alone given on a daily x 5 schedule was 21 mg/kg. When the animals were pretreated with 1 mg/kg of dCF 1 hour prior to each dose of formycin, toxicity was approximately doubled, ie, LD10 was reduced to 10 mg/kg. Death was associated with hepatic toxicity in both treatment regimens; suppression of leukocyte counts was mild except at doses greater than the LD10. Formycin nucleotides were detected by high-performance liquid chromatography in the livers of mice treated with formycin either alone or combined with dCF. When isolated rat hepatocytes were incubated for 2 hours with either formycin or dCF plus formycin, analog nucleotides accumulated in the cells. Cellular ATP decreased to below the limits of detection, whereas a large peak corresponding to formycin-5'-triphosphate was present. This replacement of cellular ATP by formycin-5'-triphosphate may help explain the hepatic toxicity observed.

Adenosine Deaminase Inhibitors↗
PubMed1982

Biochemical pharmacology and toxicology of 8-azaadenosine alone and in combination with 2'-deoxycoformycin (pentostatin).

The toxicology and metabolism of 8-azaadenosine (8-azaAdo) were examined both as a single agent and in combination with the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF). The LD10 (mice) for 8-azaAdo alone on a once daily for 5 days (q.d. x 5) schedule was 30 mg . kg-1 . day-1. When the animals were pretreated with 0.1 mg . kg-1 . day-1 of dCF, the LD10 dose was reduced to 10 mg . kg-1 . day-1 x 5. The major organ toxicity seen was hepatic. Bone marrow cellularity was only slightly altered at the LD10 dose. 8-AzaAdo nucleotides were detected in the livers of treated mice as determined by high performance liquid chromatography. Further, after 2 hr of incubation, isolated rat hepatocytes accumulated 8-azaATP to levels of 2.2 mumoles/g of cells with 8-azaAdo (1 mM) alone and to 4.3 mumoles/g of cells when 8-azaAdo was used in combination with dCF (1 microgram/ml). ATP levels decreased to below the limits of detection after 2 hr in cells treated with the combination. The replacement of cellular ATP by 8-azaATP may provide an explanation for the hepatotoxicity observed in the murine toxicology studies.

Adenosine↗
PubMed1982

Specificity and localization of the acetylcholine receptor kinase.

Acetylcholine receptor-phosphorylation has been compared in sealed and lysed right-side-out membrane vesicles prepared form Torpedo californica electric organ. Phosphorylation was increased 5- to 12-fold in hypotonically lysed vesicles as compared with untreated vesicles. Control experiments confirm that this enhancement is a result of increased permeability of the membrane to ATP. These data suggest that the acetylcholine receptor kinase is located on the cytoplasmic side of the plasma membrane. Results with detergent lysis support this conclusion. Although the acetylcholine receptor constitutes less than 10% of the total protein in these membranes, the kinase was found to be highly specific for polypeptides corresponding in molecular weight to acetylcholine receptor subunits.

Adenosine Triphosphate↗
PubMed1982

The cost of quality control.

Quality control and quality assurance increasingly are under evaluation. The number of procedures required to guarantee the medical reliability of the data generated by clinical laboratories has grown steadily with little or no signs of abating. Laboratorians would do well to anticipate the cost/benefit questions that appear inevitable. In this article, the author adduces some cost data.

Cost-Benefit Analysis↗
PubMed1982

2'-Deoxycoformycin-induced hemolysis in the mouse.

2'-Deoxycoformycin (dCF), a tight-binding inhibitor of adenosine deaminase, has recently been entered into clinical trials. Toxicity has included lymphopenia, seizures, coma, conjunctivitis, renal failure, and hemolysis. Mice treated with dCF on a variety of schedules exhibited massive hemolysis. Hemolysis was brief, lasting about 20 hours, and did not recur upon readministration of the drug unless readministration was delayed for at least 6 days after initial exposure, which suggests that a sensitive subpopulation of cells was selectively destroyed. Splenectomy failed to protect the animals from dCF-induced hemolysis. Administration of adenosine or 2'-deoxyadenosine without dCF did not cause hemolysis, and use of these two agents with dCF did not potentiate the observed hemolysis. ATP and dATP levels were measured in erythrocytes, and changes in levels of these nucleotides did not correspond with the development of hemolysis.

Animals↗
PubMed1982

Inhibition of the growth of human colon cancer xenografts by polar solvents.

The effects of N,N-dimethylformamide (DMF) and N-methyl-formamide (NMF) on the growth of two human colon cancer cell lines xenografted in nude mice were assessed. Toxicological studies with mice heterozygous for the nu/nu gene showed that with both compounds the limiting organ toxicity was hepatic. The 10% lethal doses for DMF and NMF given i.p. daily for 21 days were 2219 and 374 mg/kg, respectively. Nude mice (10/group) received s.c. transplants of HCT-15 or DLD- 2 human colon cancer cells. Mice were treated i.p. with the approximate 10% lethal doses of either DMF (daily for 21 days) or NMF (daily for 19 days) or with 0.9% NaCl solution when tumors became palpable. With the HCT-15 tumor, a growth inhibition of 65% was obtained using DMF compared to 0.9% NaCl solution-treated controls. Two independent experiments with DLD-2 demonstrated that DMF effected growth inhibitions of 45 and 67%. NMF treatment produced 48 and 75% growth inhibitions of HCT-15 and DLD-2 tumors, respectively. Weight loss of groups of treated mice in all experiments was between 2 and 14%, within the acceptable range for 10% lethal drug doses. Results indicate that some human cancer xenografts respond to the polar solvent DMF and to its metabolite NMF and that DMF may be acting at least in part by its metabolism to NMF. Furthermore, the data should alert clinical investigators to the possibility of hepatotoxicity when polar solvents are tested in Phase I clinical trials.

Animals↗
PubMed1981

The performance of protein, lactic dehydrogenase, and alkaline phosphatase electrophoresis as part of a hospital admission screening procedure.

The practice of pre-admission hospital laboratory testing has been criticized as inefficient and cost ineffective. Laboratory screening is frequently condemned without regard for the possibility that a particular screening protocol may be poorly conceived and inadequate. To increase the specificity of our screening procedure to answer some questions raised by results of total enzyme and protein results, we have adapted the Nerenberg "sandwich" technique for multi-sample, simultaneous electrophoresis of sera for proteins, lactic dehydrogenase, and alkaline phosphatase. Twenty-six samples can be analyzed per hour by one technician at a total cost of about $1.00 per specimen. Results are interpreted visually without densitometry. Addition of the technique to our laboratory screening procedure has produced a demonstrable increase in test specificity and sensitivity. There is also a potential for a significant reduction in laboratory costs through anticipation and reduction of individually-performed electrophoretic techniques.

Alkaline Phosphatase↗
PubMed1981

Identification of a mitochondrial phosphoprotein in brain synaptic membrane preparations.

A 41,000-dalton phosphoprotein in crude synaptosomal membrane fractions is characterized by its unique divalent and monovalent cation regulation. It is identified by two-dimensional gel electrophoresis as the phosphoprotein whose phosphorylation is enhanced by repetitive electrical stimulation of hippocampal brain slices. After sucrose-gradient ultracentrifugation, this phosphoprotein is found in the mitochondrial subfraction. This suggests that the electrically produced changes in the level of phosphorylation of the 41,000-dalton polypeptide are probably effects on cellular energetics rather than on specialized neural membrane function.

Animals↗
PubMed1981

Sweet syndrome with involvement of the female genital tract.

Acute febrile neutrophilic dermatosis, otherwise known as Sweet syndrome, usually occurs in women after prior respiratory infections. The first case of Sweet syndrome with involvement of the female genital tract is reported here. The woman recovered completely, and no evidence of other underlying disease has appeared.

Acute Disease↗
PubMed1980

Membrane-bound protein kinase activity in acetylcholine receptor-enriched membranes.

Membrane protein phosphorylation may be a general regulatory mechanism mediating the response of cells to exogenous metabolic and physical signals. We have determined that the membrane-bound acetylcholine receptor is the major substrate phosphorylated in situ by a nearby membrane protein kinase. Moreover, these same membranes also contain phosphoprotein phosphatase activity which dephosphorylates the membrane-bound receptor. These findings suggest that reversible phosphorylation of the actylcholine receptor may be critical for receptor function at the synapse. Therefore, it is necessary to define the properties of the enzymes which mediate this phosphorylation-dephosphorylation mechanism. In this report we describe the properties of the first component of this system, the membrane-bound protein kinase in receptor-enriched membranes from the electric organ of Torpedo californica. Only ATP is effective as a phosphate donor for this cyclic AMP-independent membrane kinase; GTP does not support phosphorylation of the receptor. Both casein and histone can also be phosphorylated by the membrane protein kinase, but casein is a better substrate. Although phosphorylation of the receptor appears to be regulated by cholinergic ligands and K+, casein phosphorylation is not specifically affected by these agents. Moreover, while phosphorylation of the acetylcholine receptor is maximal in receptor=enriched membranes, casein phosphorylation is similar in all membrane fractions prepared from the electric organ. Taken together, these findings suggest that the membrane protein kinase activity in receptor-enriched membranes is similar to most other membrane kinases. Therefore, the unique characteristics of membrane-bound acetylcholine receptor phosphorylation appear to be determined by the receptor and its availability as a substrate for the membrane kinase.

Acetylcholine↗
PubMed1980

Reversible phosphorylation of the membrane-bound acetylcholine receptor.

We have found that the acetylcholine receptor (AChR) of Torpedo californica is phosphorylated and dephosphorylated in situ by a membrane-bound protein kinase and phosphatase [1]. There is increasing evidence that other neurotransmitters [2], light [3-6], polypeptide hormones [7], and growth factors [8-12] also may act by regulating the level of phosphorylation of membrane proteins. These observations suggest that membrane protein phosphorylation may be a general regulatory mechanism affecting the response of cells to exogenous metabolic and physical signals. To understand the role of membrane protein phosphorylation, we have chosen to study acetylcholine receptor-enriched membranes purified from the electric organ of T californica. This organ is an ideal model system for such studies since it is a rich source of the acetylcholine receptor. Membranes can be purified from the electric organ that are enriched in the AChR[13] and that show cholinergic agonist-dependent changes in cation flux [14]. Moreover, the AChR from T californica has been purified [15[, biochemically characterized [16], and used to generate specific antibodies [17]. Receptor, enriched membranes contain only a few other proteins that are closely associated with the receptor in the postsynaptic membrane. Such associated proteins may play a critical role in regulating the function of the AChR in the postsynaptic membrane. We have taken advantage of these conditions to study phosphorylation of the membrane-bound AChR in this well-defined, homogeneous system.

Adenosine Triphosphate↗
PubMed1980

Simultaneous assay of diazepam, chlordiazepoxide, N-desmethyldiazepam, N-desmethylchloridazepoxide, and demoxepam in serum by high performance, liquid chromatography.

A method is presented for simultaneously determining diazepam and chlordiazepoxide along with their respective major active serum metabolites N-desmethyldiazepam, and N-desmethylchlordiazepoxide and demoxepam. The drugs are extracted from one ml of buffered serum using chloroform containing 5-(p-methylphenyl)-5-phenylhydantoin as an internal standard. The elution is accomplished using a reversed-phase column with a mobile phase consisting of an acetonitrile/methanol/acetate buffer pH 5.0 (200/225/500) at a flow rate of 2.0 ml/min. Absorbance is monitored at 240 nm using a variable wavelength detector. Each chromatographic separation requires approximately 15 minutes at ambient temperature. Of more than twenty drugs tested for possible interference with this procedure, only methaqualone interferes with the internal standard, and phenytoin with demoxepam.

Anti-Anxiety Agents↗
PubMed1980

Cerebral Whipple's disease. Diagnosis by brain biopsy.

Whipple's disease, a multisystem chronic granulomatous disease treatable by antibiotics, usually presents clinically with gastrointestinal or joint symptoms. Usually, the diagnosis is substantiated by small intestinal biopsy. This shows diastase-resistant periodic-acid-Schiff-(PAS)-positive inclusions in the cytoplasm of macrophages within the lamina propria. By electron microscopy, this PAS-positive material consists of 1.5 X 0.2-mum bacilli and fine fibrillar material within macrophage phagolysosomes. Rarely, Whipple's disease presents clinically as a primary neurologic disease without gastrointestinal symptoms. Because untreated cerebral Whipple's disease usually progresses rapidly to death, it is imperative to establish the diagnosis promptly. This report describes a case of cerebral Whipple's disease without gastrointestinal symptoms that was diagnosed early by light-and electron-microscopic study of brain biopsy material.

Biopsy↗
PubMed1980

Quality control revisited.

Quality Control is a way of life for today's clinical laboratory and the direct responsibility of its director. While individual laboratory sections require quality control procedures of ever-growing complexity, there also is need for an overview and the statement of policies that concern the laboratory as a whole. In the August 1977 issue of Pathologist (I & A Center, pp. 442-444), Dr. Diamond, regional commissioner for the northeast, described a guide for a comprehensive quality control statement. The following article is an expansion and development of that statement.

Hospitals↗