The sophistry of the term "Legionnaires' Disease".
Explore the source record for details and available documents.
Centers for Disease Control and Prevention, U.S.↗
Biomedical subjects
F W Sunderman
Publications and source records attributed to F W Sunderman.
Platinum in blood mononuclear cells from patients after cisplatin therapy.
The feasibility of monitoring cisplatin chemotherapy by measuring platinum (Pt) concentrations in blood mononuclear cells was tested in six patients (four with squamous cell carcinomas of the head and neck, one with non-Hodgkin's lymphoma, and one with lung carcinoma). Blood samples (20 to 40 mL) were collected at intervals from 6 min to 21 days after an iv infusion of cisplatin (80 or 100 mg per m2). Blood mononuclear cells were harvested on a Ficoll-Hypaque gradient, washed repeatedly, counted, and homogenized by sonication in 0.5 mL of saline solution. Pt was analyzed in duplicate 40 microL samples of plasma (N = 26) or cell homogenates (N = 23) by electrothermal atomic absorption spectrophotometry with Zeeman background correction. Immediately after the cisplatin infusion, plasma Pt concentrations averaged 2.6 (SD +/- 0.2) mg per L and mononuclear cell Pt concentrations averaged 2.5 +/- 0.5 ng per 10(6) cells. At 24 to 26 hr post-infusion, plasma Pt concentrations averaged 1.6 +/- 0.2 mg per L and mononuclear cell Pt concentrations averaged 2.3 +/- 0.6 ng per 10(6) cells. Plasma Pt disappearance followed two-compartment kinetics in all patients; the plasma Pt disappearance half-time (T1/2, mean +/- SD) was 148 +/- 41 hours. The Pt concentrations in blood mononuclear cells diminished gradually during the period of observation; the T1/2 could not be reliably determined, but was estimated to be longer than two weeks. This study shows that Pt can be measured in mononuclear cells of patients after cisplatin treatment and that Pt disappears more slowly from blood mononuclear cells than from plasma of these patients.
Adult↗
Clinical response to therapeutic agents in poisoning from mercury vapor.
Exposure to mercury vapors for an hour per working day over a period of 13 years produced in a thermometer manufacturer severe signs and symptoms of mercury poisoning. Complete disability developed insidiously over the last six months of employment. During the first two months of observation, the patient was treated in succession with three chelating agents: 2,3-dimercapto-l-propanol (BAL), D-penicillamine and sodium diethyldithiocarbamate (Dithiocarb). Each agent was administered initially for a period of approximately two weeks. A second course of therapy with BAL was administered for three days. Of the three complexing agents used, BAL gave the most dramatically favorable clinical response and yielded the highest urinary excretions of mercury. Dithiocarb was partially effective; d-pencillamine proved to be essentially ineffective. Analyses of the patient's sweat indicated that appreciable amounts of mercury were excreted by this route. Following the alleviation of the severe symptoms by BAL, the patient was placed on a regimen of daily sweats and physio-therapy for a protracted period of several months. On this latter regimen, the mercury levels in the urine, blood serum and sweat were decreased to within the normal ranges of values. The patient made a complete and uneventful recovery. In patients encountering psychotic and neurological disorders of undetermined etiology, consideration should be given to unsuspected or masked chronic exposure to mercury vapors as a possible cause.
Adult↗
Use of sodium diethyldithiocarbamate in the treatment of nickel carbonyl poisoning.
This presentation is primarily concerned with the use of sodium diethyldithiocarbamate (Dithiocarb) in the treatment of acute nickel carbonyl poisoning. Reference will be made to earlier studies pertaining to diagnosis in relation to treatment. In addition, recent studies will be briefly considered on the administration of Dithiocarb to rats developing tumors following the muscular implantations of nickel subsulfide (Ni3S2).
Animals↗
Efficacy of sodium diethyldithiocarbamate (dithiocarb) in acute nickel carbonyl poisoning.
A brief historical resume is presented on the use of dithiocarbamates for the treatment of persons exposed to nickel carbonyl. The specificity of the treatment is demonstrated in an industrial accident in which four men were simultaneously exposed to nickel carbonyl vapors. Three of the men received dithiocarb within 24 hours after exposure and the fourth was hospitalized by his family physician and treated for bronchopneumonia with antibiotics and without benefit of dithiocarb. The three workmen who received dithiocarb became symptomless and returned to work within 72 hours after exposure. The fourth man who had not received dithiocarb died within five days after exposure.
Animals↗
The clinical biochemistry of 5'-nucleotidase.
This review delineates the subcellular distribution, biochemical characteristics, and metabolic functions of 5'-nucleotidase (5'NT), summarizes the analytical biochemistry of 5'NT, and assesses the clinical significance of 5'NT determinations in body fluids, cells, and tissues. Salient aspects of the clinical biochemistry of 5'NT, discussed herein, are as follows: (A) Serum 5'NT activity is generally elevated in hepatobiliary diseases, especially with intrahepatic obstruction, but, unlike serum alkaline phosphatase, serum 5'NT activity is not increased in infancy, childhood, pregnancy, or osteoblastic disorders. (B) In cancer patients, elevated serum 5'NT activity does not always indicate hepatobiliary involvement; in some cases, 5'NT may be released into serum from the primary tumor or local metastases. (C) Genetic deficiency of erythrocyte pyrimidine 5'NT activity is a common cause of hereditary non-spherocytic hemolytic anemia. (D) Acquired deficiency of erythrocyte pyrimidine 5'NT activity occurs in patients with beta-thalassemia and lead poisoning. (E) 5'NT activity is low in circulating monocytes, increases markedly upon their differentiation to tissue macrophages, and subsequently diminishes during macrophage activation. (F) Lymphocyte ecto-5'NT activity, a plasma membrane marker of cell maturation, is generally low in immunodeficiency states, and undergoes characteristic changes in patients with certain lymphomas and leukemias.
5'-Nucleotidase↗
Chromosomal abnormalities and gene amplification in renal cancers induced in rats by nickel subsulfide.
Nickel subsulfide (alpha Ni3S2) was administered to male Fischer-344 rats by unilateral intrarenal (i.r.) injection (20 mg per rat) to establish the time-course of alpha Ni3S2-induced erythrocytosis and to identify chromosomal abnormalities and molecular genetic aberrations in ensuing renal cancers. Blood hematocrit values were increased in alpha Ni3S2-treated rats during two to 36 weeks post-injection, attained a maximum of 77 percent (SD +/- 5) at 16 weeks (vs 51 +/- 3 percent in vehicle controls), and returned to baseline at 40 weeks. Within 21 months, malignant neoplasms (five sarcomas, one carcinoma) occurred in the injected kidneys of 6/28 alpha Ni3S2-treated rats (vs 0/13 controls). Cytogenetic analyses of direct preparations or primary cell cultures showed prominent chromosomal aberrations in three neoplasms, with rearranged marker chromosomes, polyploidy, and in one case an homogeneously staining region (HSR). Assays for gene amplification were performed with probes for murine erythropoietin (EPO) gene and H-ras, c-fos, c-myc, and N-myc oncogenes, using deoxyribonucleic acid (DNA) samples isolated from injected kidneys and renal neoplasms, as well as from the contralateral, non-injected kidneys. No consistent pattern was found; in one sarcoma, N-myc was amplified six-fold and c-fos was amplified two-fold; in another sarcoma, H-ras, c-fos, and EPO were amplified two-fold. This study shows that (a) karyotypes of 3/6 renal neoplasms of alpha Ni3S2-treated rats contained prominent marker chromosomes, (b) oncogene amplification was noted in 2/6 renal neoplasms, and (c) the EPO gene was not consistently amplified in DNA from the injected kidneys of alpha Ni3S2-treated rats during the initiation of erythrocytosis, or in subsequent renal neoplasms.
Animals↗
Presence of nickel in alpha-2 macroglobulin isolated from human serum by high performance liquid chromatography.
A two-step procedure was devised for purification of alpha 2-macroglobulin (alpha 2 M) from human serum by high performance liquid chromatography (HPLC) on "Superose 6" gel-filtration medium and "Mono-Q" ion-exchange medium. The isolated protein reacts with specific alpha 2 M-anti-serum upon immunoelectrophoresis, migrates as single protein band on SDS-acrylamide gel electrophoresis, and yields an approximate molecular weight of 7 x 10(5) Mr upon HPLC size-exclusion chromatography. Presence of nickel in the purified serum alpha 2 M was demonstrated by Zeeman electrothermal atomic absorption spectrophotometry, consistent with findings decades ago by less refined and sensitive techniques.
Adult↗
The mechanism of malignant tumor induction by nickel subsulfide.
Experiments were performed to study the earliest changes and their sequence in the development of malignant tumors following implantation of 10 mg of nickel subsulfide (Ni3S2) into the right quadriceps muscle of seven male Fischer rats. Biopsies were performed when nodules reached one to three mm, and, later, when they were five to seven mm, and, finally, at sacrifice, to confirm the fully developed tumor pattern. Light microscopy of the earliest samples showed groups of cells clumped and scattered among degenerating muscle fibers. Mitoses were seen and inflammatory cells were not a feature. Electron microscopy showed individual degenerating muscle fibers, but also cells with characteristic features of myofibroblasts. In many cells osmium, dense fragments suggestive of crystalline material, were seen in the cytoplasm and nuclei. In the second set of biopsy material, myofibroblasts with well defined and dilated rough endoplasmic reticulum, intracellular membrane-bound collagen, and microfilaments with focal "dense bodies" were numerous. Mitoses were frequent. Immunohistochemistry showed strongly positive reaction to Vimentin and muscle-specific Actin in the tumor cells. In the fully developed tumors, the previously described typical storiform cell pattern with spindle and spheroidal cells with frequent mitoses was seen. Vimentin and muscle-specific Actin stains were strongly positive. The long latent period, the evidence of cell degeneration, necrosis, foreign material (probably of nickel composition), cell invasion, and subsequent rapid myofibroblast-type cell development, proliferating to malignant tumors highly suggestive of malignant fibrous histiocytoma, seem to suggest an epigenetic form of carcinogenicity of cytotoxic variety. Whether the tumor cells derive from transformed myofibrils or from activated pluripotential mesenchymal cells, or from both, remains in doubt.
Actins↗
Histopathology of sinonasal and lung cancers in nickel refinery workers.
Histopathological diagnoses were compiled for 100 sinonasal cancers and 259 lung cancers in nickel refinery workers, including cases from Wales, Canada, and Norway. The sinonasal cancers comprised squamous cell carcinomas (48 percent), anaplastic and undifferentiated carcinomas (39 percent), adenocarcinomas (6 percent), transitional cell carcinomas (3 percent), and other malignant tumors (4 percent). The lung tumors comprised squamous cell carcinomas (67 percent), anaplastic, small cell, and oat cell carcinomas (15 percent), adenocarcinomas (8 percent), large cell carcinomas (3 percent), other malignant tumors (1 percent), and cancers not otherwise specified (6 percent). Possible selection bias in these data cannot be excluded, since the histological diagnoses represent 63 percent, 68 percent, and 100 percent of cases of sinonasal cancer and 24 percent, 47 percent, and 86 percent of cases of lung cancer in the Welsh, Canadian, and Norwegian workers. This study suggests that (a) the sinonasal cancers in nickel refinery workers conformed to the usual distribution of histological types observed in the general population (in contrast to the predilection for adenocarcinomas in wood workers), and (b) the lung cancers in nickel-refinery workers showed preponderance of squamous cell carcinomas and deficit of adenocarcinomas, compared to prevalent proportions of these neoplasms, possibly reflecting the paucity of women in the cohorts and temporal trends during the six decades in which the tumors were diagnosed.
Adenocarcinoma↗
A pilgrimage into the archives of nickel toxicology.
Explore the source record for details and available documents.
Accidents↗
Direct analysis of platinum in plasma and urine by electrothermal atomic absorption spectrophotometry.
An improved technique is described for analysis of platinum (Pt) concentrations in plasma and urine by electrothermal atomic absorption spectrophotometry (EAAS). The method is intended for use in therapeutic monitoring of cancer patients treated with platinum-containing antitumor drugs. Samples (0.1 ml) of plasma, urine, or Pt standards are diluted to two ml with a matrix solution that contains diammonium edetate, ammonium dihydrogen phosphate, ammonium hydroxide, and octoxynol detergent. Concentrations of Pt in the diluted samples are determined directly by EAAS analysis with Zeeman background correction. Standard additions are unnecessary; Pt concentrations are read from a calibration chart of peak heights, which is linear up to 1.6 mg per liter. The detection limit is 0.02 mg of Pt per liter. Day-to-day precision (coefficient of variation, based on 21 consecutive runs) ranges from 4.2 to 11.7 percent, depending upon the Pt concentration in the plasma and urine specimens. Recovery of Pt added to plasma and urine specimens averages 103 +/- 8 and 99 +/- 6 percent, respectively. Concentrations of Pt are stable in plasma and urine specimens stored at 4 degrees C or -20 degrees C for four weeks. Analyses of Pt concentrations in serial plasma and urine specimens from cancer patients receiving cisplatin chemotherapy demonstrate the clinical utility of the technique.
Cisplatin↗
Serum nickel concentrations in hemodialysis patients with environmental exposure.
Nickel was analyzed by electrothermal atomic absorption spectrophotometry in serum specimens from 22 healthy hospital workers and 30 patients with end-stage renal disease treated by extracorporeal hemodialysis, who resided in Sudbury, Ontario, Canada, a city with extensive nickel mines and smelters. Samples of tap water from Sudbury contained 109 +/- 46 micrograms Ni per L (P less than 0.01 vs 0.4 +/- 0.2 micrograms Ni per L in corresponding water samples from Hartford, Connecticut). Serum nickel concentrations averaged 0.6 +/- 0.3 micrograms Ni per L in Sudbury hospital workers (P less than 0.05 vs 0.2 +/- 0.2 micrograms Ni per L in corresponding serums from 43 healthy hospital workers in Hartford). In serums collected post-treatment from Sudbury hemodialysis patients, nickel concentrations averaged 8.5 +/- 2.8 micrograms Ni per L, (i.e., 14-times the corresponding mean in Sudbury hospital workers, P less than 0.01), but were not significantly higher than the nickel concentrations in serums from 42 Hartford hemodialysis patients (7.2 +/- 2.2 micrograms Ni per L). This study confirms the presence of hypernickelemia in hemodialysis patients, but does not suggest that hemodialysis patients have significantly increased risk of nickel toxicity in Sudbury, compared to Hartford, despite the high nickel concentrations in Sudbury tap water. This favorable outcome attests to the efficient deionization of water used to prepare hemodialysis solutions in Sudbury.
Environmental Exposure↗
Finger-loops, oncogenes, and metals. Claude Passmore Brown memorial lecture.
Certain DNA-binding proteins that regulate gene expression contain single or multiple copies of short polypeptide sequences, approximately 30 residues long, consisting of combinations of four Cys or His residues at defined spacing, so that Zn++ is complexed in tetrahedral coordination with the respective thiol-sulfur and/or imidazole-nitrogen atoms. The Zn++ ion evidently serves as a strut that stabilizes folding of the domain into a 'finger-loop', which is capable of site-specific binding to double-stranded DNA. This article reviews the evidence (a) that finger-loop domains have been highly conserved during evolution, (b) that they furnish one of the fundamental mechanisms for regulating gene expression, and (c) that a metal ion (e.g., Zn++) is required for binding of finger-loops to DNA and for their biological functions. The authors' search of amino acid sequences of 38 transforming proteins identified possible finger-loop domains in the myc, fms, fps, raf-1, rfp, src, syn, yes, erbA, int-1, and TGF-alpha gene-products. The search incidentally revealed possible finger-loop domains in human insulin receptor, which may provide a mechanistic explanation for recent observations that insulin, after binding to its cell surface receptor, is translocated to hepatocyte nuclei and becomes bound to chromatin. Zn++-coordination sites in finger-loop domains are proposed as potential targets for metal toxicity; substitution of Ni++, Co++, or Cd++ for Zn++ in finger-loops of transforming proteins is suggested as an hypothetical mechanism for metal carcinogenesis.
Amino Acid Sequence↗
Nickel-induced malignant tumors.
A series of malignant tumors experimentally induced by implanting Ni3S2 in gelatin capsules into the right hind limb of Fischer 344 rats is described. In this series, histology and ultrastructure revealed two major cell types. These are described as fibroblast-like and histiocyte-like. In addition, numerous giant cells, including large bizarre multinucleate giant cells with granular cytoplasm, were also seen. In this preliminary report, no more precise diagnosis will be given for this tumor than "malignant tumor of pluripotential origin". Further work is proposed to define more specifically its histogenesis. The appearances of the experimentally produced tumor are compared with certain tumors found in humans and also in experimentally induced tumors by Maruyama et al designated as malignant fibrous histiocytoma (MFH).
Animals↗
Hepatic toxicity of nickel chloride in rats.
Enhanced lipid peroxidation was observed in livers of rats killed 24 hr after sc injection of nickel chloride (NiCl2) (750 mumol per kg), as evidenced by 13-fold increase of conjugated dienes in microsomal lipids and 4-fold increase of thiobarbituric acid (TBA) chromogens in hepatic cytosol. Histologic examination of livers from rats killed one to three days after NiCl2 injection (500 mumol per kg) showed microvesicular fatty metamorphosis, mild hydropic degeneration, and foci of inflammation. Microvesicular steatosis of hepatocytes was confirmed by electron microscopy. Dose-related increases of serum aspartate aminotransferase (ALT) activity (up to 7-fold vs controls) and alanine aminotransferase (ALT) activity (up to 3-fold vs controls) were observed 24 hr after injection of NiCl2 (125 to 750 mumol per kg); diminished serum alkaline phosphatase activity (up to 72 percent reduction vs controls) was seen at NiCl2 dosages from 375 to 750 mumol per kg. Diethyldithiocarbamate did not influence the effects of NiCl2 on TBA-chromogens in liver homogenates or on serum AST and ALT activities but acted synergistically with NiCl2 to diminish serum alkaline phosphatase activity and to increase serum bilirubin concentration. This study demonstrates that parenteral administration of NiCl2 to rats produces acute hepatic toxicity, with enhanced lipid peroxidation, microvesicular steatosis, and increased serum AST and ALT activities.
Alanine Transaminase↗