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Biomedical subjects

M G Williams

Publications and source records attributed to M G Williams.

At least 55 records · Page 3Linked to original sources
PubMed1989

Identification and genetic mapping of the structural gene for an essential Escherichia coli membrane protein.

Attempts to isolate conditionally lethal recB and recC mutations of Escherichia coli K-12 by P1 localized mutagenesis led to the identification of the structural gene for an essential membrane protein. Located on a 1.5-kilobase-pair DNA fragment which physically mapped immediately 5' to the thyA gene, the product of the umpA (unidentified membrane protein) gene is a 25,000 Mr membrane-associated polypeptide. These results provide an explanation for why several research groups have been unable to obtain chromosomal deletions of the entire thyA gene. A possible interaction between the umpA and thyA genes is also discussed.

Escherichia coli↗
PubMed1989

Usefulness of combined light and electron microscopy: evaluation of sputum samples for asbestos to determine past occupational exposure.

Ferruginous bodies (FB) in sputa are recognized as an indicator of past exposure to asbestos. However, a great variability exists in FB production, even in individuals with a history of occupational exposure. A further complication in interpreting the presence of FBs in sputa is that all individuals in modern society are exposed to asbestos and, in lung tissue studies, have been shown to harbor appreciable numbers of asbestos fibers. Thus, some of these individuals should occasionally produce FBs in their sputa. The present study was undertaken to determine if uncoated asbestos fiber content could be used to better discriminate occupationally exposed individuals from the general population. Randomly selected sputum samples from 12 former workers in an amosite asbestos plant and 12 controls were studied. The samples were prepared for the study by digesting the sputa in sodium hypochlorite. The digests were filtered through 0.2-microns polycarbonate filters for collection of particulates. The filters were screened for FBs by light microscopy at 200 X, and the presence or absence of uncoated asbestos fibers was determined at 5000 X in an AMRAY 1000A scanning electron microscope. The use of electron microscopy revealed the presence of commercial amphiboles in the sputa of the occupationally exposed individuals and enabled a differentiation of these samples from those of the general population.

Adult↗
PubMed1989

Animal behavioral and neurochemical effects of the CNS toxic amino acid antitumor agent, acivicin.

The investigational amino acid antitumor agent, acivicin, has been reported to cause dose-related and reversible CNS toxicity in humans characterized by sedation, ataxia, hallucinations, personality changes, and other symptoms. In a series of studies aimed at characterizing this toxicity, we investigated several species as potential animal models, determined the effects of acivicin on neuronal action potentials, and measured drug effects on the brain content of several putative amino acid neurotransmitters. In mice, we were unable to demonstrate any effects of acivicin in a battery of tests used in identifying and classifying CNS-active agents of potential therapeutic utility. In rats, unlike phencyclidine and certain other psychotomimetic drugs, acivicin produced no impairment of shock avoidance or brightness discrimination in animals trained on an automated Y-maze. In contrast to the rodent species, acivicin effects were perceived as resembling those of cyclazocine by rhesus monkeys trained to discriminate between psychoactive drugs and saline by food reinforcement. Cats treated with acivicin exhibited dose-related symptoms of sedation, somnolence, and ataxia. Iontophoretically applied acivicin was shown to have no effect on the spontaneous firing rate of dorsal horn interneurones in spinal cats. At the time of peak CNS symptoms in cats treated with 100 mg/kg acivicin, content of gamma-aminobutyric acid (GABA; nmoles/mg protein) was elevated from 57-140% in cerebellum, diencephalon, midbrain, and corpus callosum compared to control animals. Brain contents of glutamate, glutamine, and aspartate were not altered in cats experiencing neurotoxicity. These studies have shown that some symptoms of acivicin CNS toxicity are shared by humans and higher non-human species such as the cat and the monkey but not by rodents. Acivicin itself is apparently not a CNS excitant or depressant, but metabolites of the drug could be. Acivicin may also cause increases in the GABA content of localized regions of brain.

Action Potentials↗
PubMed1988

Evaluation of DNA binding characteristics of some CC-1065 analogs.

The factors influencing the binding of CC-1065 to DNA were examined using racemic analogs with varying chain lengths. The ability of these agents to bind DNA appeared to be related to cytotoxic potency, however this did not appear to be a direct quantitative correlation. Two enantiomers of a bis-indole analog of CC-1065 were studied for DNA binding and cytotoxic activity. The agent with the same stereochemical configuration as CC-1065 was a potent cytotoxin, but its enantiomer was essentially inactive. Both enantiomers showed significant binding to DNA, but the biologically less active isomer showed less overall binding. In all cases, the agents preferred AT-rich DNA, and all bound to similar regions in DNA as evidenced by positions of drug-initiated thermal breaks in single end-labelled fragments of phi X 174RF DNA. The overall similarity in site specificity for binding of the structurally diverse agents suggests that much of the specificity observed in binding of the agent to DNA lies in the DNA itself. Thus, it may be difficult to change minor groove specificity for agents of this type simply by designing structures that can encompass guanine or cytosine residues. Other modifications, such as changing the specificity of the alkylating moiety, may be required to achieve this goal.

Animals↗
PubMed1988

Comparison of light and electron microscopy for defining occupational asbestos exposure in transbronchial lung biopsies.

Since asbestos burden in the lung can very among areas, the usefulness of small tissue samples for identifying past occupational exposure is examined. Simulated transbronchial biopsy samples and open lung biopsy samples were collected from autopsy material from 12 former amosite asbestos workers and ten persons from the general population. Tissue evaluation included (1) paraffin embedment and light microscopy screening for fibrosis and ferruginous bodies, and (2) tissue digestion, which was analyzed by the combination of (A) light microscopy screening for ferruginous bodies and (B) electron microscopy (EM) screening for uncoated fibers. Using standard pathology techniques to classify the small samples was generally unsuccessful, the samples being too small or their size compounding other random sampling problems. The most reliable method of establishing which transbronchial biopsy tissue samples were from the occupationally exposed group occurred when light and EM analyses were used to evaluate digested tissue. The combined data from the EM analysis of two samples per subject indicated controls had two or fewer observed asbestos fibers, while the amosite asbestos workers had six or more fibers. This distinction was valid even in those who, 21 years before sampling, had worked for only a few weeks in the asbestos plant.

Adult↗
PubMed1988

A comparison of asbestos burden in non-urban patients with and without lung cancer.

Asbestos is a recognized carcinogen which is widely available for environmental exposure. Since all members of our society are exposed to asbestos containing environments and, indeed, have asbestos fibres in their lungs, the concern exists as to its significance in contributing to the incidence of lung cancer in such populations. The asbestos burden was compared in lung tissue from control and lung cancer patients who had resided in a non-urban environment. There were no significant differences between the asbestos burdens in both age matched groups; however, the proportions of amphiboles to chrysotile were different from those reported in previous urban based studies. This difference was suggested to be attributable to chrysotile exposure in urban air. All patients had appreciable non-asbestos fibres within their lungs. The results indicate that when comparing any dust burden in lungs, it is necessary to have data from regional control populations before attempting to explore causal-disease relationships.

Adult↗
PubMed1987

Expression of arg genes of Escherichia coli during arginine limitation dependent upon stringent control of translation.

The transcription and translation of operons for arginine biosynthetic enzymes after arginine removal (arginine down shift) were studied in relA and relA+ strains of Escherichia coli. After arginine down shift, derepression of synthesis of the arginine biosynthetic enzymes ornithine carbamoyltransferase (argF) and argininosuccinate lyase (argH) began at about 15 min in relA+ cells but was delayed in relA cells for more than 2 h. However, both relA+ and relA cells accumulated high levels of argCBH mRNA, as shown by dot blot hybridization, after arginine down shift. After 15 min of arginine limitation, the proportion of ribosome-bound argCBH mRNA was equivalent in both relA+ and relA cells. During the 15 min after the arginine down shift, relA+ cells produced a significant burst of argF and argH enzyme synthesis when arginine was added back to the culture, whereas relA cells did not produce this burst of enzyme synthesis. The relA cells regained the ability to produce a burst of argF and argH enzyme synthesis when alpha-methylglucose-induced glucose starvation was combined with arginine limitation. Significant guanosine 5'-diphosphate 3'-diphosphate accumulated in relA cells under this condition. Our results support the view that during periods of severe amino acid limitation guanosine 5'-diphosphate 3'-diphosphate acts in some way to ensure the translation of argCBH mRNA.

Arginine↗
PubMed1986

An ultrastructural study of acute and long-term lung response to commercial diatomaceous earth.

The acute pulmonary effects of intratracheally instilled particles of calcined diatomaceous earth were found to include a pronounced neutrophil invasion of the bronchioles by 4 h after exposure which remained well developed through 1 day post-exposure. The number of macrophages and neutrophils in the alveoli continued to increase through 1 day post-exposure and remained above control values through 7 days post-exposure. The number of macrophages, many of which contained diatomaceous earth, remained elevated for the duration of the experiment. Most phagocytosis of the particles was carried out by macrophages, with minor participation by neutrophils. Many of the reactive macrophages in the groups with post-exposure periods longer than 2 h showed various types of pathological alterations. A few particles were found in type I epithelial cells. Oedematous changes were observed in some type I epithelial cells and proliferation of type II epithelial cells was evident in some alveoli, particularly those near the respiratory bronchioles. Mild diffuse fibrosis was first observed at 6 months and was still present at 15 months but remained confined to the areas containing the diatomaceous earth.

Animals↗
PubMed1986

Umbilical versus peripheral tobramycin administration.

This study evaluated the disposition of tobramycin (T) after umbilical artery catheter (UAC), intravenous (i.v.), and intramuscular administration to a group of 12 premature neonates. Patients varied in gestational age (31-42 weeks) and weight (1.76-3.98 kg). Each neonate received a 2 mg/kg dose of T at 12-h intervals for 2-15 days. Multiple blood samples after the first and last doses of T, as well as daily measurements, were made during the course of therapy. Analysis of drug concentration data revealed a biphasic distribution of T, which required a two-compartment model for description. Mean values for the alpha and beta elimination phases, t1/2 beta, Vc, and Vdss after the first dose of T were 7.604 h-1, 0.087 h-1, 11.18 h, 0.214 L/kg, and 0.645 L/kg, respectively. Average drug clearance (ClT) increased during therapy from 71 to 103 ml/min, associated with an increase in the renal function of patients. Serum concentrations of T were out of the therapeutic range in 50% of study patients. The variability of drug clearance in the neonate requires the measurement of T concentration in order to ensure safe and effective therapy.

Female↗
PubMed1985

A comparison of the ferruginous body and uncoated fiber content in the lungs of former asbestos workers.

Tissue samples from 12 former asbestos workers were digested and analyzed for ferruginous body and uncoated fiber populations. It was noted that there were large numbers of nonasbestos fibers in each of the samples. In some samples, these fibers constituted over 80% of the total uncoated fibers, and they could greatly influence the data as to asbestos content of the tissue unless differentiated by light and electron microscopic techniques, such as X-ray energy-dispersive analysis. There were great variations in the numbers of uncoated fibers per ferruginous body between the individual workers. The digested samples from lungs of 2 workers yielded no ferruginous bodies by light microscopy, even though these samples by electron microscopy contained respective loads of 780,000 and 1.2 million uncoated amphibole fibers per gram. Light microscopy examination of adjacent tissues confirmed mild fibrosis in both workers. Ferruginous bodies serve as a general marker for asbestos exposure. However, our data suggest that their absence in tissue with interstitial fibrosis from a worker with previous occupational exposure may not be sufficiently conclusive to rule out asbestos-induced disease. Rather, as shown by our data, individual exceptions may require correlated analysis by analytical electron microscopy in order to define particulate load and support the diagnosis of the disease.

Asbestos↗
PubMed1985

Ferruginous body formation on a nonasbestos mineral.

Tissue from a lung biopsy specimen was submitted for electron microscopy and x-ray energy-dispersive analysis of ferruginous bodies. The presence of these entities had been used as a factor in concluding an asbestos-related tissue response. A 62-year-old man had worked for over 25 years in an iron reclamation and manufacturing facility that had no known sources of asbestos in the work environment. He had no history of recurrent respiratory problems. Combined studies in tissue sections as well as on digested specimens revealed that the core of a majority of the ferruginous bodies was an iron-rich fiber. The source of the fibers was traced to a material used in packing and insulation of the metal during the tempering process. While there is a widespread regional potential for exposure in both environmental and occupational settings, the question as to whether the dust is actually a health hazard or more of a nuisance pollutant remains unanswered. It is evident, however, that the fibrous mineral should be recognized as a stimulus for ferruginous body formation in humans.

Asbestosis↗
PubMed1984

Asbestos content in lungs of occupationally and nonoccupationally exposed individuals.

Previous reports have indicated that a majority of the population has asbestos bodies within their lungs. These studies generally have been carried out using cohorts from urban environments. The present study compares the asbestos body levels from three unique cohorts: (1) a nonoccupationally exposed group from a large urban environment having a relatively low asbestos content, (2) patients with lung cancer from a nonurban setting, and (3) amosite asbestos workers, who worked and lived in a rural setting. The number of asbestos bodies in both the urban nonoccupationally exposed group and the patients with lung cancer was generally found to be low or below limits of detectability, with the exceptions being those persons in whom an occupational exposure was eventually found. The ferruginous body content of the occupationally exposed group varied considerably between individuals as well as between sites within the same individual.

Adult↗
PubMed1984

The influence of amosite asbestos exposure on lung permeability.

The effect of amosite asbestos on permeability of the blood/air barrier in the lung was studied using an acute animal model. The ultrastructural tracer selected for the study was horseradish peroxidase which was given intravenously in animals that had been exposed intratracheally to asbestos. The acute period of study was either 1/2, 1, 2, 3, or 4 hr, or 1-7 or 14 days postexposure. The barrier in the normal lung was at the level of the alveolar epithelial lining. Leakage of exudate and tracer occurred through the altered barriers following asbestos exposure and the extent of leakage related directly to the degree of alveolitis and the asbestos present in the area. A trend toward recovery of the barrier occurred with the reestablishment of a more normal-appearing epithelial lining during the second week postexposure.

Animals↗
PubMed1984

An ultrastructural study of the blood/air barrier in the guinea-pig.

Horseradish peroxidase (HRP) was intravenously injected into guinea-pigs to ultrastructurally examine the permeability of the blood/air barrier. Adults were given 300 mg/kg of the tracer in a small volume of saline, anesthetized and sacrificed at intervals by either intratracheal filling or right ventricular perfusion with 3% glutaraldehyde. The reaction product had passed through endothelial clefts and accumulated in the interstitium as early as 1.5 min after injection. This same degree of penetration occurred with either fixation method used. Tight junctions between pneumocytes prevented passage of the reaction product into alveoli. Pinocytotic vesicles were numerous in both endothelial and epithelial cells, but did not significantly contribute to tracer transport. Ten minutes post-injection was selected as optimal for this model since the highest concentration of tracer was found in the tissues at this time.

Animals↗
PubMed1983

Acute lung response to amosite asbestos: a morphological study.

The acute morphological response to amosite asbestos in the guinea pig was studied by light microscopy and by transmission, scanning, and scanning transmission electron microscopy. Fiber identification was carried out by energy dispersive X-ray analysis. Animals were studied at postinjection intervals of 2, 4, and 12 hr and 1-7 days. Three groups of test animals were studied for each time interval. These consisted of a vascularly perfused parenchymal group and a free cell lavaged group. The information obtained was compared with saline-injected and normal control animals. The acute tissue response was characterized by intraalveolar, not interstitial, events. The early phagocytic response was shared between polymorphs and macrophages, while in the longer intervals, the macrophages were the phagocytic cell type. Packaging differences within the two types of phagocytes were seen. Endothelial stability was noted, while some edematous type I pneumocytes were observed. Fibrotic involvement was limited to some intraalveolar fibrin deposits. It is suggested that the term "free asbestos fibers" refers to an extracellular event, while intracellular fibers are coated with either a membranous sheath, a siderosome, or a classical ferruginous coating.

Acute Disease↗