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Biomedical subjects

W G Sorenson

Publications and source records attributed to W G Sorenson.

At least 19 recordsLinked to original sources
PubMed2002

Infant animal model of pulmonary mycotoxicosis induced by Stachybotrys chartarum.

In recent years cases of often fatal pulmonary hemorrhage in infants have been associated with water damaged homes and the toxigenic fungus Stachybotrys chartarum. The fungal spores contain mycotoxins which could be injurious to the rapidly developing lung. In order to understand the developmental pathophysiology of this disease we developed an infant rat model of stachybotrytoxicosis describing the effects of fungal spores on survival, growth, histopathology of the lung and respiration. Conidia of S. chartarum were instilled intratracheally (1.0-8.0 x 10(5)/gm wt.) in 4-d old Sprague-Dawley rat pups. Two control groups received either sterile PBS or a suspension of spores extensively extracted with ethanol to remove toxins. Lethal dose response was determined (LD50 = 2.7 x 10(5) spores/gm wt.). All dead pups had extensively hemorrhagic lungs. Growth of surviving animals was impaired in a dose-dependent manner. Changes of pulmonary function parameters in rats treated with 1.1 x 10(5) spores/g were consistent with an increased respiratory resistance. Histology of lungs revealed fresh hemorrhage, sparse hemosiderin-laden macrophages, and evidence of inflammation including thickened alveolar septa infiltrated by lymphocytes and mononuclear cells and intra-alveolar macrophages. Significant increases (p = 0.001) in numbers of macrophages (2-fold), lymphocytes (5-fold) and neutrophils (7-fold) were found in BAL fluid. Hemoglobin was elevated 2-fold (p = 0.004). Proinflammatory mediator IL-1beta increased more than 6-fold and TNF-alpha 30-fold (p = 0.001). Extracted spores had a minimal effect on all examined parameters in BAL fluid indicating that mycotoxins are primarily responsible for the hemorrhagic and inflammatory response.

Animals↗
PubMed2002

Clinical profile of 30 infants with acute pulmonary hemorrhage in Cleveland.

Between 1993 and 2000, 30 infants were hospitalized with acute pulmonary hemorrhage at Rainbow Babies and Children's Hospital in Cleveland. Most infants presented with severe pulmonary symptoms requiring intensive support, but a few infants had less severe hemorrhage. Three quarters of the patients required ventilator support and blood transfusions. Eleven patients had transitory hemoglobinuria. Five patients died, but infants who survived did well. There are currently no specific treatment modalities, although we have advised moving to a different home and avoiding environmental tobacco smoke. Subsequently, rebleeding from the lower respiratory tract has decreased from 5 of 7 infants to 1 in 21. On the basis of decreased subsequent fatal hemorrhage, high dose glucocorticoids seem to be of some value. Several patients revealed continued low-grade alveolar hemorrhage for months after their initial bleed, even after removal from their original home environments.

Acute Disease↗
PubMed2000

Tyrosine kinase activation in response to fungal spores is primarily dependent on endogenous reactive oxygen production in macrophages.

Studies from our laboratory (Shahan, T. A., Sorenson, W. G., and Lewis, D. M. (1994) Environ. Res. 67, 98-104) demonstrated that spores from different fungal species differentially activate rat alveolar macrophages as detected by the measurement of superoxide anion and cytokine production (Shahan, T. A., Siegel, P. D., Sorenson, W. G., Kuschner, W. G., and Lewis, D. M. (1998) Am. J. Respir. Cell Mol. Biol. 18, 435-441). Spores from Aspergillus candidus stimulated production of the highest levels of superoxide anion (5.2 nmol/1.0 x 10(6) alveolar macrophages (AMs)/30 min), followed by those from Aspergillus niger (2.4 nmol/1.0 x 10(6) AMs/30 min) and Eurotium amstelodami (0.4 nmol/1.0 x 10(6) AMs/30 min). The mechanism of this differential activation was studied. Our data demonstrate that the tyrosine kinases p56(Hck), p72(Syk), p77(Btk), p62(Yes), p56(Lck), and p59(Fyn) were specifically activated in response to spores from A. candidus, whereas spores from either A. niger or E. amstelodami activated p56(Hck), p72(Syk), and p77(Btk). Kinetic analysis of specific tyrosine kinases demonstrated that p56(Hck), p72(Syk), and p77(Btk) were activated faster and to a greater extent by spores from A. candidus as compared with spores from E. amstelodami. These data suggest a relationship between reactive oxygen species and tyrosine kinase activation. Treatment of AMs with H(2)O(2) (1 mM) caused the activation of p72(Syk) only, whereas treatment with superoxide dismutase and catalase before treatment with the spores had no effect on tyrosine kinase activation. Incubation with NADPH oxidase inhibitors inhibited both superoxide anion production and the activation of p56(Hck), p72(Syk), and p77(Btk) in response to fungal spores. These data indicate that endogenous reactive oxygen species are necessary for the activation of p56(Hck), p72(Syk), and p77(Btk) by spores; they also indicate that some species of spores are capable of activating tyrosine kinases independent of superoxide anion.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2000

Acute pulmonary haemorrhage in an infant during induction of general anaesthesia.

Pulmonary haemorrhage is a rare, life-threatening complication of anaesthesia. This report describes the anaesthetic management of an infant who developed laryngospasm and pulmonary haemorrhage during general anaesthesia. The infant was subsequently found to have prior exposure to a fungus, Stachybotrys chartarum, which produces mycotoxins that may have produced capillary fragility in the infant's rapidly growing lungs.

Acute Disease↗
PubMed1999

Highly sensitive protein translation assay for trichothecene toxicity in airborne particulates: comparison with cytotoxicity assays.

Screening assays for environmental mycotoxins in bulk samples currently use cytotoxicity in cell cultures, but their application to air particulate samples often lacks sensitivity and specificity for fungal spores. An assay based on inhibition of protein synthesis using translation of firefly luciferase in a rabbit reticulocyte system has been developed for the detection of trichothecene mycotoxins found in the spores of toxigenic fungi. Ethanol extracts of air particulates trapped on polycarbonate filters are ultrafiltered and applied at several dilutions to a translation reaction mixture. The activity of translated luciferase is measured directly in a luminometer, eliminating the need for radioisotopes and time-consuming sample processing. Parallel standard curves using a commercially available trichothecene provide for expression of the results in T-2 toxin equivalents per cubic meter of air. The assay can be completed in 2 h and is readily applicable to multiple samples. Comparison to the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide cytotoxicity assay indicates a 400-fold increase in sensitivity of trichothecene detection in addition to a much higher specificity for these toxins. Initial field testing indicates a strong correlation between the measured level of toxicity and the presence of toxigenic fungi detected with microbiological methods. In conclusion, this luciferase translation assay offers a rapid and highly sensitive and specific method for quantitative detection of trichothecene mycotoxin activity in air particulate samples.

Air Pollutants↗
PubMed1999

Hemolysis, toxicity, and randomly amplified polymorphic DNA analysis of Stachybotrys chartarum strains.

Stachybotrys chartarum is an indoor air, toxigenic fungus that has been associated with a number of human and veterinary health problems. Most notable among these has been a cluster of idiopathic pulmonary hemorrhage cases that were observed in the Cleveland, Ohio, area. In this study, 16 strains of S. chartarum isolated from case (n = 8) or control (n = 8) homes in Cleveland and 12 non-Cleveland strains from diverse geographic locations were analyzed for hemolytic activity, conidial toxicity, and randomly amplified polymorphic DNA banding patterns. In tests for hemolytic activity, strains were grown at 23 degrees C on wet wallboard pieces for an 8-week test period. Conidia from these wallboard pieces were subcultured on sheep's blood agar once a week over this period and examined for growth and clearing of the medium at 37 or 23 degrees C. Five of the Cleveland strains (all from case homes) showed hemolytic activity at 37 degrees C throughout the 8-week test compared to 3 of the non-Cleveland strains. Five of the Cleveland strains, compared to two of the non-Cleveland strains, produced highly toxic conidia (>90 microgram of T2 toxin equivalents per g [wet weight] of conidia) after 10 and 30 days of growth on wet wallboard. Only 3 of the 28 strains examined both were consistently hemolytic and produced highly toxic conidia. Each of these strains was isolated from a house in Cleveland where an infant had idiopathic pulmonary hemorrhage.

DNA, Bacterial↗
PubMed1999

Fungal spores: hazardous to health?

Fungi have long been known to affect human well being in various ways, including disease of essential crop plants, decay of stored foods with possible concomitant production of mycotoxins, superficial and systemic infection of human tissues, and disease associated with immune stimulation such as hypersensitivity pneumonitis and toxic pneumonitis. The spores of a large number of important fungi are less than 5 microm aerodynamic diameter, and therefore are able to enter the lungs. They also may contain significant amounts of mycotoxins. Diseases associated with inhalation of fungal spores include toxic pneumonitis, hypersensitivity pneumonitis, tremors, chronic fatigue syndrome, kidney failure, and cancer.

Animals↗
PubMed1999

Review of methods applicable to the assessment of mold exposure to children.

This article presents discussion of the assessment of the exposure of children to fungi, substances derived from fungi, and the environmental conditions that may lead to exposure. The principles driving investigations of fungal contamination and subsequent exposure are presented as well as guidelines for conducting these investigations. A comprehensive description of available research sampling and analysis techniques is also presented.

Air Pollution, Indoor↗
PubMed1999

Overview of investigations into pulmonary hemorrhage among infants in Cleveland, Ohio.

Idiopathic pulmonary hemorrhage was diagnosed in 37 infants in the Cleveland, Ohio, area between 1993 and 1998. This rare disorder has been related to 12 deaths, including 7 originally thought to be sudden infant death syndrome. Thirty of the infants were African American, all of whom lived in a limited geographic area of eastern metropolitan Cleveland, an area of older housing stock. An investigation led by the Centers for Disease Control and Prevention has found an association with household exposure to a toxigenic mold, Stachybotrys chartarum, and other fungi. The rapidly growing lungs of young infants appear to be especially vulnerable to the toxins made by toxigenic molds. Environmental tobacco smoke was frequently present in the infants' homes and may be a trigger precipitating the acute bleeding. Stachybotrys, although not thought to be a common mold, is known to have a wide geographic distribution. An additional 101 cases of acute, idiopathic pulmonary hemorrhage have been reported in infants in the United States over the past 5 years. In this overview, the investigations are summarized, the clinical profile is described, the toxicity of S. chartarum is discussed, and pathophysiologic concepts are presented.

Animals↗
PubMed1998

Acute pulmonary hemorrhage in infants associated with exposure to Stachybotrys atra and other fungi.

BACKGROUND: A geographic cluster of 10 cases of pulmonary hemorrhage and hemosiderosis in infants occurred in Cleveland, Ohio, between January 1993 and December 1994. STUDY DESIGN: This community-based case-control study tested the hypothesis that the 10 infants with pulmonary hemorrhage and hemosiderosis were more likely to live in homes where Stachybotrys atra was present than were 30 age- and ZIP code-matched control infants. We investigated the infants' home environments using bioaerosol sampling methods, with specific attention to S atra. Air and surface samples were collected from the room where the infant was reported to have spent the most time. RESULTS: Mean colony counts for all fungi averaged 29 227 colony-forming units (CFU)/m3 in homes of patients and 707 CFU/m3 in homes of controls. The mean concentration of S atra in the air was 43 CFU/m3 in homes of patients and 4 CFU/m3 in homes of controls. Viable S atra was detected in filter cassette samples of the air in the homes of 5 of 9 patients and 4 of 27 controls. The matched odds ratio for a change of 10 units in the mean concentration of S atra in the air was 9.83 (95% confidence interval, 1.08-3 X 10(6)). The mean concentration of S atra on surfaces was 20 X 10(6) CFU/g and 0.007 x 10(6) CFU/g in homes of patients and controls, respectively. CONCLUSION: Infants with pulmonary hemorrhage and hemosiderosis were more likely than controls to live in homes with toxigenic S atra and other fungi in the indoor air.

Acute Disease↗
PubMed1998

Study of toxin production by isolates of Stachybotrys chartarum and Memnoniella echinata isolated during a study of pulmonary hemosiderosis in infants.

A cluster of cases of pulmonary hemosiderosis among infants was reported in Cleveland, Ohio, during 1993 and 1994. These unusual cases appeared only in infants ranging in age from 1 to 8 months and were characterized by pulmonary hemorrhage, which caused the babies to cough up blood. A case-control study identified major home water damage (from plumbing leaks, roof leaks, or flooding) as a risk factor for development of pulmonary hemorrhage in these infants. Because of an interest in the possibility that trichothecene mycotoxins might be involved in this illness, a number of isolates of Stachybotrys chartarum were grown in the laboratory on rice, and extracts were prepared and analyzed both for cytotoxicity and for specific toxins. Two isolates of Memnoniella echinata, a fungus closely related to S. chartarum, were also included in these studies. S. chartarum isolates collected from the homes were shown to produce a number of highly toxic compounds, and the profiles of toxic compounds from M. echinata were similar; the most notable difference was the fact that the principal metabolites produced by M. echinata were griseofulvins.

Animals↗
PubMed1998

Concentration- and time-dependent upregulation and release of the cytokines MIP-2, KC, TNF, and MIP-1alpha in rat alveolar macrophages by fungal spores implicated in airway inflammation.

Inhalation of fungal spores has been shown to cause primary or secondary infection and respiratory inflammation and diseases such as allergic alveolitis, atopic asthma, and organic dust toxic syndrome, which are rarely reported in the absence of predisposing factors. Biochemical and molecular markers of inflammation were measured in rat bronchial alveolar lavage cells (> 95% macrophages) following stimulation with fungal spores isolated from pathogenic and nonpathogenic fungi that have been implicated in airway inflammation. The results of this study demonstrate that mRNA transcripts for the C-X-C branch of the PF4 superfamily are differentially upregulated over those of the C-C mediators in a time- and concentration-dependent manner. Macrophage inflammatory protein (MIP)-2 and KC were differentially upregulated over the acute phase inflammatory cytokines MIP-1alpha and tumor necrosis factor-alpha (TNF-alpha) in rat alveolar macrophages stimulated with fungal spores from Aspergillus candidus, Aspergillus niger, Eurotium amstelodami, and Cladosporium cladosporioides. Spores from Aspergillus terreus and Penicillium spinulosum failed to stimulate an increase of any cytokine mRNA, whereas those from Aspergillus fumigatus stimulated the upregulation of MIP-2, KC, TNF-alpha, and MIP-1alpha mRNAs. Over time, A. fumigatus stimulated increasing KC production until 24 h, when production levels increased slightly, then leveled off when measurements ceased at 36 h. Latex spheres stimulated modest amounts of MIP-2 and transforming growth factor-beta only. These observations suggest that the inflammatory cytokines MIP-2 and KC may be involved in the inflammation arising from the inhalation of fungal spores in a time- and concentration-dependent manner.

Animals↗
PubMed1998

Cell wall preparations from environmental yeasts: effect on alveolar macrophage function in vitro.

Organic dust toxic syndrome (ODTS) is associated with inhalation of high concentrations of organic materials and is a noninfectious illness characterized by fever, malaise, myalgia, and neutrophilic inflammation of the lower respiratory tract. Studies in our laboratory of fungi in fresh lumber have demonstrated that yeasts may predominate and have raised the issue of potential exposure of sawmill workers to yeasts. Zymosan, a cell wall preparation from Saccharomyces cerevisiae, is a potent stimulator of alveolar macrophages (AM). In the present study, preparations from the cell walls of Pichia fabianii, Candida sake, Trichosporon capitatum, Rhodotorula glutinis, and Cryptococcus laurentii were compared with zymosan and beta-1,3-glucan for their ability to stimulate AM and activate complement. All species activated complement. P. fabianii, C. sake, T. capitatum, R. glutinis, C. laurentii, as well as zymosan and glucan, stimulated superoxide anion and leukotriene B4 production in a dose-dependent fashion, but R. glutinis and C. laurentii were much less active. Zymosan, glucan, P. fabianii, and R. glutinis treatment of AM resulted in increased phagocytosis of labeled sheep RBCs, whereas there was no effect with C. sake or C. laurentii and T. capitatum significantly inhibiting phagocytosis. These results suggest that exposure to high concentrations of yeast could provoke pulmonary inflammation resulting in an episode of ODTS.

Agricultural Workers' Diseases↗
PubMed1996

Toxigenic molds in water-damaged buildings: dechlorogriseofulvins from Memnoniella echinata.

An investigation of a cluster of cases of pulmonary hemosiderosis in infants in Cleveland, OH, led to the isolation of many isolates of Stachybotrys atra and two isolates of a related toxigenic fungus, Memnoniella echinata. M. echinata produces two cytotoxic trichothecene mycotoxins, trichodermol (1a) and trichodermin (1b), as well as several griseofulvins. Dechlorogriseofulvin (2a) and epidechlorogriseofulvin (2b) were the major compounds isolated. This is the first report of a fungus outside the Penicillium genus producing griseofulvins.

Griseofulvin↗
PubMed1995

Chemotaxis of alveolar macrophages and neutrophils in response to microbial products derived from organic dust.

The inhalation of organic dust has been implicated to cause a large number of occupational lung diseases. A common event in these diseases is an inflammatory reaction affecting airway and alveolar tissue that is characterized by the recruitment of different types of inflammatory cells. Mechanisms of chemotaxis of alveolar macrophages (AMs) and neutrophils (PMNs) in response to microbial products derived from organic dust were studied. Seven agents known to be etiological agents causing respiratory symptoms (extract and endotoxin of Enterobacter agglomerans, extracts from Thermoactinomyces vulgaris and Aspergillus fumigatus, thermophilic protease, and two preparations of glucans) were used for experiments. These agents were evaluated for their ability to directly attract AMs and PMNs and to stimulate alveolar macrophages to release chemotactic factors for other AMs and PMNs. The microbial products were able to attract both AMs and PMNs directly in a dose-dependent manner and the exposure of cultured AMs to most agents were stimulatory for production of chemotactic activity for AMs and PMNs. The generation and release of this activity by AMs may provide a mechanism for the initiation and amplification of inflammatory reactions in the lung after inhalation of organic dust. Results of these in vitro studies may be relevant to the pathogenesis of alveolitis in organic dust-induced lung diseases.

Air Microbiology↗
PubMed1994

A sensitive new bioassay for tumor necrosis factor.

Tumor necrosis factor is an important cytokine involved in inflammation and assay of this cytokine in biological fluids may be important in the understanding of several disease processes. This report describes an improved TNF bioassay employing a newly isolated subclone of the cell line NCTC-clone 929 as well as a novel fluorescence indicator system for detecting viability of the target cells. The limit of detection for the TNF hypersensitive cell line with this fluorescence viability assay was 68 +/- 2.5 fg/ml, which is approximately 3 x more sensitive than the parental clone and approximately 10 x more sensitive than that reported by Branch et al. (1991) using the neutral red indicator system. The hypersensitivity of the clone gradually declined over a 45-day period and at regular intervals new cells were cultivated from frozen stocks. Two different serum sources, bovine fetal serum and horse serum, and four different serum concentrations (5, 10, 15, 20%) were evaluated to optimize sensitivity. No difference was found between serum sources but sensitivity was significantly reduced if < 15% serum was used.

Animals↗
PubMed1994

Superoxide anion production in response to bacterial lipopolysaccharide and fungal spores implicated in organic dust toxic syndrome.

High amounts of fungal spores, bacteria, and bacterial endotoxin have been found in dust associated with the poorly characterized syndrome, organic dust toxic syndrome (ODTS). As part of an ongoing investigation to determine the etiopathogenesis for ODTS, this study has focused on activation of guinea pig bronchial alveolar lavage (BAL) cells as evidenced by the production of superoxide anion in response to fungal spores and lipopolysaccharide (LPS). Fungal spores from Aspergillus candidus, Aspergillus terreus, Aspergillus niger, Aspergillus fumigatus, Eurotima amstelodami, Penicillium spinulosum, and Cladosporium cladosporioides were all shown to increase superoxide anion production, each with different potencies. LPS stimulated little superoxide anion production in BAL cells, but when cells were pretreated with LPS prior to stimulation with fungal spores, superoxide anion production was increased over that induced by either spores or LPS alone. These results suggest that the inhalation of LPS together with fungal spores could possibly provoke abnormal lung pathologies.

Air Microbiology↗