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1.  Antimicrobial Resistance of Campylobacter Isolates from Retail Meat in the United States between 2002 and 2007▿  
Applied and Environmental Microbiology  2010;76(24):7949-7956.
The emergence of antimicrobial resistance in Campylobacter spp. has been a growing public health concern globally. The objectives of this study were to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Campylobacter spp. recovered by the National Antimicrobial Resistance Monitoring System (NARMS) retail meat program. Retail meat samples (n = 24,566) from 10 U.S. states collected between 2002 and 2007, consisting of 6,138 chicken breast, 6,109 ground turkey, 6,171 ground beef, and 6,148 pork chop samples, were analyzed. A total of 2,258 Campylobacter jejuni, 925 Campylobacter coli, and 7 Campylobacter lari isolates were identified. Chicken breast samples showed the highest contamination rate (49.9%), followed by ground turkey (1.6%), whereas both pork chops and ground beef had <0.5% contamination. The most common resistance was to doxycycline/tetracycline (46.6%), followed by nalidixic acid (18.5%), ciprofloxacin (17.4%), azithromycin and erythromycin (2.8%), telithromycin (2.4%), clindamycin (2.2%), and gentamicin (<0.1%). In a subset of isolates tested, no resistance to meropenem and florfenicol was seen. C. coli isolates showed higher resistance rates to antimicrobials, with the exception of doxycycline/tetracycline, than those seen for C. jejuni. Pulsed-field gel electrophoresis (PFGE) fingerprinting resulted in 1,226 PFGE profiles among the 2,318 isolates, with many clones being widely dispersed throughout the 6-year sampling period.
PMCID: PMC3008252  PMID: 20971875
2.  β-Lactam Resistance in Salmonella Strains Isolated from Retail Meats in the United States by the National Antimicrobial Resistance Monitoring System between 2002 and 2006▿  
Applied and Environmental Microbiology  2009;75(24):7624-7630.
Ampicillin-resistant (Ampr) Salmonella enterica isolates (n = 344) representing 32 serotypes isolated from retail meats from 2002 to 2006 were tested for susceptibility to 21 other antimicrobial agents and screened for the presence of five beta-lactamase gene families (blaCMY, blaTEM, blaSHV, blaOXA, and blaCTX-M) and class 1 integrons. Among the Ampr isolates, 66.9% were resistant to five or more antimicrobials and 4.9% were resistant to 10 or more antimicrobials. Coresistance to other β-lactams was noted for amoxicillin-clavulanic acid (55.5%), ceftiofur (50%), cefoxitin (50%), and ceftazidime (24.7%), whereas less than 5% of isolates were resistant to piperacillin-tazobactam (4.9%), cefotaxime (3.5%), ceftriaxone (2%), and aztreonam (1.2%). All isolates were susceptible to cefepime, imipenem, and cefquinome. No Salmonella producing extended-spectrum beta-lactamases was found in this study. Approximately 7% of the isolates displayed a typical multidrug-resistant (MDR)-AmpC phenotype, with resistance to ampicillin, chloramphenicol, streptomycin, sulfonamide, tetracycline, plus resistance to amoxicillin-clavulanic acid, cefoxitin, and ceftiofur and with decreased susceptibility to ceftriaxone (MIC ≥ 4 μg/ml). Pulsed-field gel electrophoresis results showed that several MDR clones were geographically dispersed in different types of meats throughout the five sampling years. Additionally, 50% of the isolates contained blaCMY, 47% carried blaTEM-1, and 2.6% carried both genes. Only 15% of the isolates harbored class I integrons carrying various combinations of aadA, aadB, and dfrA gene cassettes. The blaCMY, blaTEM, and class 1 integrons were transferable through conjugation and/or transformation. Our findings indicate that a varied spectrum of coresistance traits is present in Ampr Salmonella strains in the meat supply of the United States, with a continued predominance of blaCMY and blaTEM genes in β-lactam-resistant isolates.
PMCID: PMC2794113  PMID: 19854922
3.  Scottish court dismisses a historic smoker's suit 
Tobacco Control  2007;16(5):e4.
The decision in a Scottish smoker's case, McTear v. Imperial Tobacco Limited, that there was no scientific proof of causation between the plaintiff's smoking and his death from lung cancer, accepted all of the traditional arguments that the tobacco industry has made throughout the history of tobacco litigation, including that epidemiology is not an adequate branch of science to draw a conclusion of causation, that the tobacco industry has no knowledge that its products are dangerous to consumers, and that, despite this lack of knowledge, the plaintiff had sufficient information to make an informed decision about the dangers of smoking. This case relied on outmoded methods of reasoning and placed too great a faith in the tobacco industry's timeworn argument that “everybody knew, nobody knows”. Further, the judge found it prejudicial that the plaintiff's expert witnesses were not paid for their services because she was indigent, believing that the lack of payment placed in doubt their credibility and claiming that the paid tobacco expert witnesses had more motive to testify independently because they had been paid, a perverse and novel line of reasoning. The McTear case contrasts unfavourably with the recent decision in United States v. Philip Morris, a United States decision that found the tobacco industry defendants to be racketeers, based both on the weight of a huge amount of internal tobacco industry documents showing that the tobacco industry knew their products were addictive and were made that way purposely to increase sales, and on the testimony of expert witnesses who, like those who testified in McTear, have made the advancement of the public health their life's work and are not “hired guns”. The McTear case's reasoning seems outdated and reminiscent of early litigation in the United States. Hopefully, it will not take courts outside of the United States 40 more years to acknowledge the current scientific knowledge about smoking and health.
PMCID: PMC2598549  PMID: 17897973
4.  Antimicrobial Resistance in Salmonella enterica Serovar Heidelberg Isolates from Retail Meats, Including Poultry, from 2002 to 2006 ▿  
Applied and Environmental Microbiology  2008;74(21):6656-6662.
Salmonella enterica serovar Heidelberg frequently causes food-borne illness in humans. There are few data on the prevalence, antimicrobial susceptibility, and genetic diversity of Salmonella serovar Heidelberg isolates in retail meats. We compared the prevalences of Salmonella serovar Heidelberg in a sampling of 20,295 meats, including chicken breast (n = 5,075), ground turkey (n = 5,044), ground beef (n = 5,100), and pork chops (n = 5,076), collected during 2002 to 2006. Isolates were analyzed for antimicrobial susceptibility and compared genetically using pulsed-field gel electrophoresis (PFGE) and PCR for the blaCMY gene. A total of 298 Salmonella serovar Heidelberg isolates were recovered, representing 21.6% of all Salmonella serovars from retail meats. One hundred seventy-eight (59.7%) were from ground turkey, 110 (36.9%) were from chicken breast, and 10 (3.4%) were from pork chops; none was found in ground beef. One hundred ninety-eight isolates (66.4%) were resistant to at least one compound, and 49 (16.4%) were resistant to at least five compounds. Six isolates (2.0%), all from ground turkey, were resistant to at least nine antimicrobials. The highest resistance in poultry isolates was to tetracycline (39.9%), followed by streptomycin (37.8%), sulfamethoxazole (27.7%), gentamicin (25.7%), kanamycin (21.5%), ampicillin (19.8%), amoxicillin-clavulanic acid (10.4%), and ceftiofur (9.0%). All isolates were susceptible to ceftriaxone and ciprofloxacin. All ceftiofur-resistant strains carried blaCMY. PFGE using XbaI and BlnI showed that certain clones were widely dispersed in different types of meats and meat brands from different store chains in all five sampling years. These data indicate that Salmonella serovar Heidelberg is a common serovar in retail poultry meats and includes widespread clones of multidrug-resistant strains.
PMCID: PMC2576681  PMID: 18757574
5.  Tobacco industry use of judicial seminars to influence rulings in products liability litigation 
Tobacco Control  2006;15(2):120-124.
This paper examines the tobacco industry's efforts to influence litigation by sponsoring judicial seminars.
Thousands of internal tobacco documents were examined, including memos, reports, presentations, and newsletters. Connections to outside organisations were corroborated by examining tobacco industry financial records, budgets, and letters pledging funds. Facts about outside organisations were triangulated through examining their websites and publicly‐filed financial records, and verifying facts through their representatives' statements in newspaper and law review articles.
There are direct financial ties between the tobacco industry and groups that organise judicial seminars in an effort to influence jurisprudence, and judges who attend these seminars may be breaching judicial ethics either by not inquiring about the source of funding or by ignoring funding by potential litigants.
The tobacco industry's attempts to clandestinely influence judges' decisions in cases to which they are a party endangers the integrity of the judiciary.
PMCID: PMC2563562  PMID: 16565460
ethics; judges; litigation
6.  Working conditions and fatigue in professional truck drivers at Israeli ports 
Injury Prevention  2005;11(2):110-114.
Background: Trucks represent 6% of all vehicles, but truck crashes account for 20% of road deaths in Israel, even though travel distances are usually short (<200 km) and overnight travel is uncommon.
Objective: To determine occupational and individual predictors of fatigue, falling asleep at the wheel, and involvement in crashes with injuries and deaths in truck drivers.
Setting and methods: We carried out field interviews of 160 port truck drivers regarding driver characteristics, workplace and driving conditions, employer-employee relations, medical conditions, sleep quality and fatigue, falling asleep at the wheel, and involvement in road crashes.
Results: One day before interview, 38.1% of the drivers had worked more than the 12 hour legal limit. More than 30% reported falling asleep at the wheel recently, and 13% had prior involvement in a sleep related crash. Sixty seven (41.9%) drivers said that their employer forced them to work beyond the legal 12 hour daily limit. Involvement in a crash with casualties was associated with poor sleep quality (adjusted OR = 2.9; p = 0.042) and frequent difficulty finding parking when tired (OR = 3.7; p = 0.049). Self assessment of fatigue underestimated fatigue from the Pittsburgh Sleep Quality Questionnaire. However fatigue occurred in many drivers without sleep problems and many crashes occurred without fatigue.
Conclusions: Prevention requires measures to reduce work stresses, screening drivers, speed control, and modal shifts. The work risks and adverse outcomes of truck drivers in large countries with long overnight journeys occur in a small country with small distances, relatively short work journeys, and little overnight travel.
PMCID: PMC1730197  PMID: 15805441
7.  Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis 
Gut  2005;54(1):142-151.
Background: Hepatic stellate cells (HSCs) are a major fibrogenic cell type that contributes to collagen accumulation during chronic liver disease. With increasing interest in developing antifibrotic therapies, there is a need for cell lines that preserve the in vivo phenotype of human HSCs to elucidate pathways of human hepatic fibrosis. We established and characterised two human HSC cell lines termed LX-1 and LX-2, and compared their features with those of primary human stellate cells.
Methods and results: LX-1 and LX-2 were generated by either SV40 T antigen immortalisation (LX-1) or spontaneous immortalisation in low serum conditions (LX-2). Both lines express α smooth muscle actin, vimentin, and glial fibrillary acid protein, as visualised by immunocytochemistry. Similar to primary HSCs, both lines express key receptors regulating hepatic fibrosis, including platelet derived growth factor receptor β (βPDGF-R), obese receptor long form (Ob-RL), and discoidin domain receptor 2 (DDR2), and also proteins involved in matrix remodelling; matrix metalloproteinase (MMP)-2, tissue inhibitor of matrix metalloproteinase (TIMP)-2, and MT1-MMP, as determined by western analyses. LX-2 have reduced expression of TIMP-1. LX-2, but not LX-1, proliferate in response to PDGF. Both lines express mRNAs for α1(I) procollagen and HSP47. Transforming growth factor β1 stimulation increased their α1(I) procollagen mRNA expression, as determined by quantitative reverse transcription-polymerase chain reaction. LX-2, but not LX-1, cells are highly transfectable. Both lines had a retinoid phenotype typical of stellate cells. Microarray analyses showed strong similarity in gene expression between primary HSCs and either LX-1 (98.4%) or LX-2 (98.7%), with expression of multiple neuronal genes.
Conclusions: LX-1 and LX-2 human HSC lines provide valuable new tools in the study of liver disease. Both lines retain key features of HSCs. Two unique advantages of LX-2 are their viability in serum free media and high transfectability.
PMCID: PMC1774377  PMID: 15591520
fibrosis; wound healing; liver; myofibroblast; stellate cells
8.  Target discovery in the postgenomic era 
Breast Cancer Research : BCR  2003;5(Suppl 1):58.
PMCID: PMC3300178
9.  Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture. 
Journal of Clinical Investigation  1994;94(4):1563-1569.
A consistent response to liver injury is the activation of resident mesenchymal cells known as lipocytes (Ito, fat-storing cells) into a proliferating cell type. In cultured lipocytes, platelet-derived growth factor (PDGF) is the most potent proliferative cytokine, but requires the activation-dependent expression of its receptor protein (Friedman, S. L., and M. J. P. Arthur. 1989. J. Clin. Invest. 84:1780-1785); the role of PDGF receptor (PDGFR) in liver injury is unknown. We have examined PDGFR gene expression in freshly isolated lipocytes during liver injury and correlated these findings with a culture model of cellular activation. Whereas lipocytes from normal rats had no detectable transcript for the beta-PDGFR subunit, this mRNA was induced within 1 h after a dose of carbon tetrachloride (CCl4). In contrast, alpha subunit mRNA was detected in normal cells, but was unchanged after liver injury. Similar results were observed in lipocytes from bile duct-obstructed rats, although beta-PDGFR induction was less marked. By immunoblot, induction of beta-PDGFR protein in lipocytes isolated from CCl4-treated animals correlated with mRNA increases. In contrast to lipocytes, endothelial cells from normal liver expressed low levels of alpha- and beta-receptor subunit mRNA, which did not increase with injury. Using a beta-PDGFR antibody, receptor protein could be identified within fibrotic septa in CCl4-treated animals in regions where cells expressed proliferating cell nuclear antigen (PCNA). In cultured lipocytes activated by growth on uncoated plastic, beta-PDGFR transcripts appeared within 3 d after plating, which coincided with the onset of cellular proliferation. In contrast, quiescent cells in suspension culture had no detectable beta-PDGFR mRNA. These results indicate that beta-PDGF receptor induction by lipocytes is an early event during hepatic injury in vivo and in primary culture.
PMCID: PMC295310  PMID: 7929832
10.  Transfusion-associated bacterial sepsis. 
Clinical Microbiology Reviews  1994;7(3):290-302.
The incidence of sepsis caused by transfusion of bacterially contaminated blood components is similar to or less than that of transfusion-transmitted hepatitis C virus infection, yet significantly exceeds those currently estimated for transfusion-associated human immunodeficiency and hepatitis B viruses. Outcomes are serious and may be fatal. In addition, transfusion of sterile allogenic blood can have generalized immunosuppressive effects on recipients, resulting in increased susceptibility to postoperative infection. This review examines the frequency of occurrence of transfusion-associated sepsis, the organisms implicated, and potential sources of bacteria. Approaches to minimize the frequency of sepsis are discussed, including the benefits and disadvantages of altering the storage conditions for blood. In addition, the impact of high levels of bacteria on the gross characteristics of erythrocyte and platelet concentrates is described. The potentials and limitations of current tests for detecting bacteria in blood are also discussed.
PMCID: PMC358326  PMID: 7923050
11.  Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. 
Journal of Clinical Investigation  1993;92(4):1795-1804.
Hepatic lipocytes are perisinusoidal cells that have been thought to be analogous to tissue pericytes, a cell type with purported vasoregulatory properties. However, we and others have recently demonstrated that lipocytes acquire markers of smooth muscle cells or myofibroblasts only after liver injury, via a process termed "activation." In this study, we document lipocyte contractility on collagen lattices and examine the importance of activation in this process. In culture, lipocytes became contractile only after spreading and activating, coincident with expression of smooth muscle alpha actin, a marker of activation (1990. Virchows Arch. B Cell Pathol. 59:349). After 5 d in culture, lipocytes induced rapid and sustained contraction of collagen lattices (to 43.7 +/- 2.3% of their original size 24 h after detachment). There was no contraction of lattices containing hepatocytes. Scanning electron microscopy demonstrated intimate associations of lipocyte cell membranes and collagen fibrils. Reduction in cell volume during contraction was also prominent. Lattice contraction by lipocytes was proportional to cell number. Serum was a potent stimulator of lipocyte contraction, as were endothelin types 1, 2, and 3; the effect of serum and endothelin 1 were additive. Neither thrombin, angiotensin-II, serotonin, nor the cytokines PDGF and TGF beta induced contraction. Cytochalasin B treatment resulted in concentration-dependent inhibition of contraction. As a test of the in vivo relevance of the culture findings, lipocytes were isolated from fibrotic animals and examined immediately after adherence. Whereas lipocytes from normal liver were initially compact, smooth muscle alpha actin negative and noncontractile, cells from animals with hepatic injury due to CCl4 displayed an activated appearance, expressed smooth muscle alpha actin, and were contractile immediately after adherence. Additionally, IFN-gamma, an agent which blocks lipocyte activation (1992. Hepatology. 16:776), inhibited lipocyte contraction. The data document that normal (i.e., quiescent) lipocytes are not contractile, but that activation is associated with the development of contractility. These findings suggest that a role for lipocytes in organ contraction or vasoregulation may be confined to injured, not normal liver.
PMCID: PMC288342  PMID: 8408632
12.  Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1. Implications for regulation of matrix degradation in liver. 
Journal of Clinical Investigation  1992;90(1):282-287.
Hepatic lipocytes play a central role in the pathogenesis of liver fibrosis, both via production of extracellular matrix proteins and through secretion of matrix metalloproteinases. In this study, we have characterized lipocyte expression and release of tissue inhibitor of metalloproteinases-1 (TIMP-1), an important inhibitor of metalloproteinase activity, whose role in liver has not previously been examined. TIMP-1 was immunolocalized to human lipocytes, and secretion of TIMP-1 was confirmed by ELISA of culture media; (mean +/- SD) 159 +/- 79 ng of TIMP-1/10(6) cells per 24 h. Evidence for functional inhibitory activity of released TIMP-1 was obtained by (a) reverse zymography that demonstrated a single inhibitor band, M(r) 28 kD, that co-migrated with a TIMP-1-positive control sample; and (b) unmasking of inhibited gelatinase activity in lipocyte medium by separating it from TIMP-1 using gelatin sepharose chromatography; gelatinase activity in chromatographed medium increased more than 20-fold, compared with unfractionated medium, and could be reinhibited by adding back fractions that contained inhibitor. By Northern analysis, freshly isolated human lipocytes exhibited low levels of mRNA expression for TIMP-1, but this increased markedly relative to beta-actin expression with lipocyte activation during cell culture. We conclude that human hepatic lipocytes synthesize TIMP-1, a potent metalloproteinase inhibitor, and that TIMP-1 expression increases with lipocyte activation. These data indicate that hepatic lipocytes can regulate matrix degradation in the liver, and suggest that expression of TIMP-1 by activated lipocytes may contribute to the progression of liver fibrosis.
PMCID: PMC443094  PMID: 1634616
13.  The relationship of structural brain imaging parameters to antipsychotic treatment response: a review. 
Over the last decade, a number of studies have attempted to relate brain morphology to treatment response to neuroleptics. This approach has scientific potential to define subtypes of schizophrenia as well as potential clinical utility. In the present report, a review of 33 studies, including a meta-analysis, is provided. Although the overall test of the effect was not significant, the analysis revealed marked heterogeneity in the results of the various studies. The following factors were significant predictors of effect size: age, illness duration and age of onset of the patient cohort, the percentage of patients with marked structural abnormality included in the study overall, the duration of treatment and the degree of symptom improvement in the study overall. The following factors were unrelated to study effect size: date of study, gender, and the presence of a washout period. In future studies, attention to the parameters utilized in the meta-analysis should help to clarify the strength and generality of the relationship between brain morphology and treatment response.
PMCID: PMC1188400  PMID: 1353369
14.  Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. 
Journal of Clinical Investigation  1989;84(6):1780-1785.
Hepatic lipocytes appear to be central to the pathogenesis of hepatic fibrosis, undergoing activation during inflammation to a matrix-producing, proliferative cell type. We have studied the activation process in culture by examining the response of lipocytes to conditioned medium from hepatic macrophages (Kupffer cells). Lipocytes exposed to Kupffer cell medium (KCM) exhibited cellular and nuclear enlargement associated with up to a threefold increase in collagen and total protein synthesis per cell. Cell proliferation was also stimulated as measured by [3H]thymidine incorporation and direct cell counting. The latter effect was serum dependent and inhibited by antibodies to platelet-derived growth factor (PDGF). Proliferation could be stimulated by recombinant PDGF, but only after preincubation of cells with KCM. These findings suggested that KCM was eliciting expression of the PDGF receptor in lipocytes, and this was confirmed by immunoblot analysis with antibodies to the PDGF receptor. DNA synthesis in lipocytes exposed to KCM occurred at 48 h, which reflected the time required for PDGF receptor expression (24 h) plus initiation of [3H]thymidine incorporation (24 h). These results indicate that KCM has multiple stimulatory effects on cultured lipocytes similar to activation of these cells observed in vivo.
PMCID: PMC304055  PMID: 2556445
15.  Lipocytes from normal rat liver release a neutral metalloproteinase that degrades basement membrane (type IV) collagen. 
Journal of Clinical Investigation  1989;84(4):1076-1085.
We report a proteinase that degrades basement-membrane (type IV) collagen and is produced by the liver. Its cellular source is lipocytes (fat-storing or Ito cells). Lipocytes were isolated from normal rat liver and established in primary culture. The cells synthesize and secrete a neutral proteinase, which by gelatin-substrate gel electrophoresis and gel filtration chromatography, has a molecular mass of 65,000 D. The enzyme is secreted in latent form and is activated by p-aminophenylmercuric acetate but not by trypsin. Enzyme activity in the presence of EDTA is restored selectively by zinc and is unaffected by serine-protease inhibitors. In assays with radiolabeled soluble substrates, it degrades native type IV (basement membrane) collagen but not interstitial collagen types I or V and exhibits no activity against laminin or casein. At temperatures causing partial denaturation of soluble collagen in vitro, it rapidly degrades types I and V. Thus, it is both a type IV collagenase and gelatinase. The enzyme may play a role in initiating breakdown of the subendothelial matrix in the Disse space as well as augmenting the effects of collagenases that attack native interstitial collagen.
PMCID: PMC329763  PMID: 2551922
16.  Collagen measured in primary cultures of normal rat hepatocytes derives from lipocytes within the monolayer. 
Journal of Clinical Investigation  1988;82(2):450-459.
The cellular origin of hepatic collagen is under active investigation. Several recent studies using cells in primary culture suggest that hepatocytes are the source of much of the collagen in normal rat liver. In view of other data indicating that lipocytes produce substantial amounts of this protein, we have reexamined collagen biosynthesis in hepatocyte cultures that have been carefully characterized with respect to the presence of lipocytes. We find that routinely prepared hepatocyte isolates contain, by number, approximately 10% lipocytes. Lipocytes in early culture are difficult to visualize by phase-contrast microscopy but after 4 d proliferate and eventually replace the parenchymal cells. The size of the lipocyte subpopulation in these cultures correlates positively with collagen production. Similarly, removal of lipocytes by further processing of the initial hepatocyte isolate significantly reduces collagen production. Moreover, the only cells within hepatocyte cultures that display type I collagen by immunohistochemistry are lipocytes. We conclude that lipocytes are the principal source of collagen in primary hepatocyte cultures. The findings indicate also that these cells are the previously described "fibroblast" that appear in relatively long-term hepatocyte cultures.
PMCID: PMC303534  PMID: 3042806
17.  Teratological research using in vitro systems. II. Rodent limb bud culture system. 
This review represents a compilation of information related to the rodent limb bud culture system from approximately 80 publications after 1969 and conversations with workers in the field. Most of these papers and book chapters refer exclusively to studies with the mouse limb bud. Sections in this review include historical review, end point measurements, activating systems, types of compounds studied and dose response, reproducibility, statistical analysis, equipment and personnel requirements, mechanisms, and summary.
PMCID: PMC1474665  PMID: 3304997
18.  Binding of Escherichia coli heat-stable enterotoxin to rat intestinal cells and brush border membranes. 
Infection and Immunity  1984;43(2):622-630.
The association of heat-stable enterotoxin (STa) produced by enterotoxigenic Escherichia coli 431 with isolated rat intestinal epithelial cells and brush border membranes was characterized. Specific binding of strain 431 125I-STa to a single class of specific high-affinity receptors was saturable and temperature dependent and reached a maximum between 5 and 10 min. A 1,000-fold excess of unlabeled 431 STa competitively displaced 90 to 95% of radiolabeled enterotoxin bound to brush border membranes. In contrast, specific binding of 431 125I-STa to intestinal cells ranged from 40 to 65%. The number of STa-specific receptors on rat intestinal cells determined by Scatchard analysis was 47,520 +/- 14,352 (mean +/- standard error of the mean) per cell, with affinity constants (KaS) of 2.55 X 10(11)and 4.32 x 10(11) liters/mol determined for intestinal cells and brush border membranes, respectively. Villus intestinal cells appeared to possess about twice as many STa receptors as did crypt cells. Dissociation of specifically bound 431 125I-STa from intestinal cells and brush border membranes was minimal (2 to 5%). In addition, neither the rate nor the extent of dissociation was increased by a 1,000-fold excess of unlabeled homologous 431 Sta. Binding experiments with 431 125I-STa and brush border membranes showed that purified unlabeled STas from enterotoxigenic E. coli strains 667 (class 1 porcine enteropathogen), B-41 (bovine enteropathogen), and human strains 213C2 (Mexico) and 153961-2 (Dacca, Bangledesh) exhibited patterns of competitive inhibition similar to those of homologous unlabeled 431 STa (class 2 enteropathogen). A lipid extract which contained gangliosides and glycolipids exhibited dose-dependent competitive inhibition of heat-labile enterotoxin binding to brush border membranes but did not inhibit binding of 431 125I-STa. Purified heat-labile enterotoxin from strain 286C2 did not inhibit binding of 431 STa to brush border membranes. Pronase treatment of brush border membranes reduced binding of 431 125I-STa by about 30%, suggesting that the STa receptor was a protein or a glycoprotein. The putative STa receptor was radiolabeled with 431 125I-STa and solubilized with sodium deoxycholate. One major radioactive band was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by radioautography. These data suggested that STas bind essentially irreversibly to a specific receptor on the cell surface of intestinal cells before activation of guanylate cyclase.
PMCID: PMC264345  PMID: 6537947
20.  Colchicine suppression of corneal healing after strabismus surgery. 
Two patients who had previously undergone uneventful operations for strabismus showed healing of corneal dellen and erosion after withdrawal of colchicine therapy. It is suggested that the exhibition of colchicine therapy for familial Mediterranean fever in these two cases was responsible for initial persistence of these two postoperative complications.
PMCID: PMC1043020  PMID: 889763
21.  Prostacyclin in pregnancy. 
British Medical Journal  1980;280(6231):1581-1582.
PMCID: PMC1601850  PMID: 7000245
22.  Approaches to the formulation of standards for carcinogenic substances in the environment. 
After having agreed that standards are necessary for carcinogens that cannot be completely eliminated from the environment, two exchange groups in the U.S.S.R.-U.S. Cooperative present their different approaches to the problem. The Russian groups has recommended a benzypyrene standard of 0.1 microgram/100m3 of atmospheric air over populated regions and gives its experimental basis and theoretical rationale in the first part of this joint paper. Lifetime experiments in adult rats over a wide range of dose levels permit the determination of a largest ineffective dose level with respect the theoretical time of first tumor as well as incidence. The standard is set by extrapolation based on body weight and uses a safety factor of 10 to account for the additional susceptibility in embryogenesis and childhood. The U. S. group presents a mathematical model of time-to-tumor occurrence which permits the prediction of population incidence and life span shortening from time-to-tumor data in animals or man. It assumes the distribution of mortality-corrected time to tumor is lognormal with the nth power of time inversely proportional to dose and with dose independence of the variability of the logarithm of time to tumor. The prediction is made by combining this distribution, fitted to the data, with population mortality tables. Both groups emphasize that substantial research efforts are necessary to improve the scientific basis for setting standards.
PMCID: PMC1637722  PMID: 446461
24.  Factors influencing the incidence of neonatal jaundice. 
British Medical Journal  1978;1(6122):1235-1237.
A retrospective study of 12 461 single births confirmed an association between maternal oxytocin infusion and neonatal jaundice. The effect of oxytocin on jaundice was independent of gestational age at birth, sex, race, epidural anaesthesia, method of delivery, and birth weight, each of which was significantly associated with neonatal jaundice. The effect of oxytocin was, however, small, producing a calculated mean increase in peak plasma bilirubin concentration of 8.6 mumol/1 (0.5 mg/100 ml); this excess was independent of sex and less than the effect of the baby being born one week earlier.
PMCID: PMC1604617  PMID: 647211
25.  Atypical isolate of Cryptococcus neoformans cultured from sputum of a patient with pulmonary cancer and blastomycosis. 
Journal of Clinical Microbiology  1978;7(3):316-318.
Cryptococcus neoformans was isolated repeatedly from a patient with epider-moid carcinoma and pulmonary blastomycosis. The isolate was atypical in that it had only a minute capsule, caused persistent infection but no perceptible disease in mice, and initially appeared not to assimilate trehalose. Only after an incubation of 2 to 3 weeks did utilization of this substrate become apparent.
PMCID: PMC274926  PMID: 348724

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