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Biomedical subjects

R I Walker

Publications and source records attributed to R I Walker.

At least 37 records · Page 2Linked to original sources
PubMed1989

Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock.

Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses of viable or formalin-killed bacteria. Cardiovascular function of conscious animals was studied using simultaneous radionuclide heart scans and thermodilution cardiac outputs. Serial plasma endotoxin levels were measured. S. aureus produced a pattern of reversible cardiovascular dysfunction over 7-10 d that was concordant (P less than 0.01) with that of E. coli. Although this cardiovascular pattern was not altered by formalin killing (S. aureus and E. coli), formalin-killed organisms produced a lower mortality and less myocardial depression (P less than 0.01). S. aureus, compared to E. coli, produced higher postmortem concentrations of microorganisms and higher mortality (P less than 0.025). E. coli produced significant endotoxemia (P less than 0.01), though viable organisms (versus nonviable) resulted in higher endotoxin blood concentrations (P less than 0.05). Significant endotoxemia did not occur with S. aureus. Thus, in the absence of endotoxemia, S. aureus induced the same cardiovascular abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality.

Animals↗
PubMed1988

Prospects for management of gastrointestinal injury associated with the acute radiation syndrome.

The effect of total-body ionizing radiation on the digestive tract is dose-dependent and time-dependent. At low doses (1.5 Gy), one observes only a short prodromal syndrome consisting of nausea, vomiting, and gastric suppression. At doses greater than 6 Gy, the prodromal syndrome is more marked, and it is followed after a 2-5-day remission period by a subacute syndrome, characterized by diarrhea and hematochezia. This gastrointestinal syndrome is superimposed onto a radiation-induced bone marrow suppression. The combination of intestinal and hemopoietic syndromes results in dehydration, anemia, and infection, leading eventually to irreversible shock and death. The treatment of prodromal symptoms is based on the administration of antiemetics and gastrokinetics, although an effective treatment devoid of side effects is not yet available for human therapy. The treatment of the gastrointestinal subacute syndrome remains difficult and unsuccessful after exposure to total body doses greater than 8-10 Gy. Supportive therapy to prevent infection and dehydration may be effective if restoration or repopulation of the intestinal and bone marrow stem cells does occur. In addition, bone marrow transplantation may improve the prospect of treating the hemopoietic syndrome, although the experience gained in Chernobyl suggests that this treatment is difficult to apply in the case of nuclear accidents. Administration of radioprotectants before irradiation decreases damage to healthy cells, while not protecting cancerous tissues. In the future, stimulation of gastrointestinal and hemopoietic progenitor cells may be possible using cell growth regulators, but much remains to be done to improve the treatment of radiation damage to the gastrointestinal tract.

Accidents↗
PubMed1988

Requirements of radioprotectors for military and emergency needs.

Uncontrolled exposure to radiation from nuclear weapons, space, or accidents presents challenges unlike those met in radiotherapy. For example, the time and quality of exposure are uncertain. Thus it is necessary to develop radioprotectors that can be given chronically (e.g. as vitamin combinations), or shortly before exposure (e.g. as WR-2721 and related compounds), or after exposure (e.g. as immunomodulators) to cover all possible situations of use. Also, for military purposes, performance capability, as well as survival from acute effects, must be maintained. In contrast to clinical and experimental exposure, it is likely that stem cells will survive in military and accident situations, making supportive therapy (e.g. fluids, antibiotics) of real value. Radioprotectors that can increase cell survival or enhance repopulation by the remaining cells can reduce the time required for supportive therapy and enhance its effectiveness. First-generation agents to accomplish this may be combinations of agents to mitigate free radical damage such as dietary supplements or WR-2721 and related compounds. Immunomodulators, either microbial agents (e.g. glucan, TDM) or recombinant cytokines (e.g. interleukin-1, colony-stimulating factor), can enhance hematopoietic and functional cell recovery after irradiation. Synergistic effects can be demonstrated with some combinations of these agents. This is important because agents with individual DRFs of less than two can be significant radioprotectors in combinations. Whether these combinations are effective against combined injury remains to be determined. Future research into mechanisms of radiation-induced damage and natural repair mechanisms should lead to even better second-generation radioprotectants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effect of antimicrobial therapy on bowel flora and bacterial infection in irradiated mice.

Mice exposed to 10 Gy cobalt-60 radiation were given intramuscular antimicrobial therapy of gentamicin, or metronidazole, or a combination of the two. Mortality in the mice treated with metronidazole alone or in combination with gentamicin occurred earlier than in the controls (P less than 0.001). Microorganisms were recovered from the blood, spleen, and liver of the metronidazole-treated mice earlier than from other groups. The predominant organisms recovered from these animals were Enterobacteriaceae. Quantitative cultures of the ileal flora showed a decrease in the number of aerobic, facultative anaerobic and strict anaerobic bacteria after irradiation, and a subsequent increase only in the number of strict aerobic bacteria. As compared to untreated mice, a rapid decrease (by 8.8 logs) in the number of anaerobic flora occurred in the mice treated with metronidazole 5 days after irradiation. This was followed by a rapid increase in the number of aerobic organisms which coincided with the earlier mortality in this group. These data suggest that antimicrobial agents that decrease the number of the strict anaerobic component of the gut flora enhance systemic infection by aerobic or facultative anaerobic bacteria, and this facilitates mortality after irradiation.

Animals↗
PubMed1988

Mucosal and systemic immunity to Campylobacter jejuni in rabbits after gastric inoculation.

The mucosal and systemic immune responses to Campylobacter jejuni were studied in rabbits receiving gastric inoculation with live organisms. A lavage procedure was used to facilitate repeated monitoring of the intestinal immune response to C. jejuni. Immunity to C. jejuni was determined by secondary challenge by using the removable intestinal tie adult rabbit diarrhea (RITARD) model and monitoring for resistance to colonization and bacteremia. Oral-gastric inoculation of normal rabbits produced a transient intestinal colonization without diarrhea. C. jejuni serotypes differed in their ability to colonize the intestines of rabbits and to stimulate primary intestinal and serum antibody responses. Animals previously colonized were resistant to recolonization and the development of bacteremia after homologous challenge by the RITARD procedure but were not resistant to heterologous challenges. Anticampylobacter intestinal and serum IgA titers before this secondary infection were the most reliable predictors of resistance to colonization and bacteremia.

Animals↗
PubMed1988

Selective association and transport of Campylobacter jejuni through M cells of rabbit Peyer's patches.

M cells in the Peyer's patches may facilitate transport of pathogens such as Campylobacter jejuni from the intestine. We evaluated this hypothesis by using electron microscopy to examine Peyer's patches in ligated adult rabbit ileal loops inoculated with 5-mL suspensions of 10(9) cfu/mL of Campylobacter jejuni. Peyer's patches taken at intervals from 15 min to 2 h after inoculation of loops in anaesthetized rabbits provided evidence that Campylobacter jejuni selectively adhered to M cells as opposed to absorptive epithelial cells and was transported, apparently intact, into the M cell follicle. Although intercellular organisms were seen within the follicle, many others were phagocytosed by lymphoid cells. The proximity of the lymphatic and blood circulatory systems to the M cell follicle makes this a probable route for systemic spread of Campylobacter jejuni.

Animals↗
PubMed1988

Cardiovascular performance with E. coli challenges in a canine model of human sepsis.

We investigated cardiovascular dysfunction by injecting lethal and nonlethal bacterial challenges into conscious dogs. E. coli bacteria of varying numbers were placed in a peritoneal clot. Cardiovascular function was studied with simultaneous radionuclide scans and thermodilution cardiac outputs. In surviving animals, the number of bacteria in the clot increased as the corresponding systolic cardiac function decreased (P = 0.01). Cardiac function was measured by left ventricular (LV) ejection fraction (EF) and LV function curves [LV stroke work index (LVSWI) vs. end-diastolic volume index (EDVI), and peak systolic pressure vs. end-systolic volume index]. Furthermore, the diastolic volume-pressure relationship of survivors shifted progressively to the right [i.e., increasing EDVI (P less than 0.02) with minimal change (P = NS) in LV filling pressure]. This increase in LV size was associated with maintenance of measures of cardiac performance [stroke volume index (SVI) and stroke work index (SWI)] at similar levels. Death occurred only in the group with the highest bacterial dose. Compared with survivors receiving the same number of bacteria, nonsurvivors had a decrease in (P less than 0.05) LV size, a leftward shift (P less than 0.01) in LV diastolic volume-pressure relationship, and a decrease in both LVSWI and SVI (possibly related to volume and/or LV functional status). Data from survivors suggest that increasing the number of bacteria produces changes in myocardial compliance and contractility. These changes increase LV size (preload), a major determinant of cardiac performance that possibly enhances survival.

Animals↗
PubMed1987

Dieldrin toxicity in housed merino sheep.

An outbreak of nervous disease with deaths and reproductive failure was investigated in a fully housed flock of 640 super fine wool (Sharlea) Merino sheep. During the 4 months after the flock was dipped in dieldrin, 70 adult sheep died and no live lambs were produced by the ewes. The diagnosis of poisoning with dieldrin was based upon the presence of characteristic clinical signs, pathological findings and the detection of residues of dieldrin in tissues. Deficiency of vitamin A was confirmed in 2 sheep and may have contributed to the reproductive failure.

Animals↗
PubMed1987

Intestinal mucus gel and secretory antibody are barriers to Campylobacter jejuni adherence to INT 407 cells.

An in vitro mucus assay was developed to study the role of mucus gel and secretory immunoglobulin A (sIgA) in preventing attachment of Campylobacter jejuni to INT 407 cells. An overlay of rabbit small intestinal mucus was found to impede the attachment of C. jejuni to a monolayer of INT 407 cells. Mucus from rabbits previously colonized with C. jejuni was found to completely inhibit bacterial adherence to the underlying cells. Anti-Campylobacter sIgA was readily detected in mucus samples from previously exposed rabbits and was responsible for eliminating bacterial adherence to the INT 407 cells. This was shown by loss of inhibition after mucus absorption with Campylobacter cells. sIgA-containing mucus caused aggregation of the C. jejuni cells within the mucus layer of the assay system. Nonimmune mucus and sIgA alone were unable to cause bacterial aggregation, suggesting a cooperative role for mucus and sIgA. Antibodies responsible for adhesion inhibition were cross-reactive among several Campylobacter strains and were not directed solely against flagellar antigens.

Animals↗
PubMed1986

Changes in the cell wall of Clostridium species following passage in animals.

Morphological changes in clostridial isolates after animal passage with other flora in mixed infections were studied by utilizing a subcutaneous abscess model in mice. We used 26 isolates of 7 clostridial species, and one isolate each of Bacteroides fragilis and Klebsiella pneumoniae. Abscesses were induced by all 7 Clostridium perfringens and 3 Clostridium butyricum isolates and by some of the other isolates. A thick granular wall prior to animal inoculation was shown only in C. perfringens, C. butyricum, and C. difficile. This structure was observed in other clostridia only following their animal passage alone or when co-inoculated with K. pneumoniae or B. fragilis.

Animals↗
PubMed1986

Pathogenicity of Clostridium species with other bacteria in mixed infections.

The relationship of clostridial isolates with other bacteria in mixed infections was studied by means of a subcutaneous abscess model in mice. We used 26 isolates of seven clostridial species, two Bacteroides spp., eight Gram-positive facultative or anaerobic cocci and three enteric Gram-negative aerobic rods. Abscesses were induced by all seven Clostridium perfringens and three C. butyricum isolates and by some of the others. Selective antimicrobial therapy experiments showed that enteric Gram-negative rods were of equal or greater significance in the formation of abscesses than were clostridial strains in mixed infections. Enhancement or suppression of each component of the mixed infection was studied by comparing the number of each bacterium to its number when injected alone. Enhancement was observed mainly with C. perfringens in mixed infections. By contrast, other Clostridium spp. were less able to induce enhancement. Clostridium difficile and C. sporogenes often inhibited other bacterial species. This study demonstrated the synergistic and antagonistic relationship between clostridial species and other bacteria.

Abscess↗
PubMed1986

The relationship between Fusobacterium species and other flora in mixed infection.

Mixed infections with three Fusobacterium species and seven other bacterial species were studied in a subcutaneous abscess model in mice. Fifteen Fusobacterium isolates (eight F. nucleatum, four F. necrophorum, and three F. varium) and one isolate each of Bacteroides fragilis, B. asaccharolyticus, Staphylococcus aureus, Group A beta-haemolytic streptococcus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were studied. Electronmicrographs showed the presence of a thin mucopolysaccharide wall before and after inoculation into mice in 12 isolates which included all of 11 Fusobacterium isolates that induced subcutaneous abscesses. After co-inoculation of Fusobacterium isolates with other species and selective therapy with antimicrobial agents, S. aureus and K. pneumoniae were found to be of equal or greater importance in abscess induction than were Fusobacterium isolates, while Fusobacterium isolates were found to be more important than Group A streptococci and E. coli. Mutual enhancement of the numbers of organisms in mixed infections was observed with Fusobacterium spp. and K. pneumoniae, P. aeruginosa or Bacteroides spp. Suppression of Fusobacterium spp. was noticed only when they were co-inoculated with Group A streptococci. The additive or synergistic capabilities of Fusobacterium species highlighted their potential pathogenicity in infection.

Abscess↗
PubMed1986

Identification and characterization of two Campylobacter jejuni adhesins for cellular and mucous substrates.

Campylobacter jejuni is able to colonize the human intestinal mucosa and cause disease. For this reason, it was important to investigate mechanisms by which C. jejuni adheres to epithelial cells and intestinal mucus gel. All strains of C. jejuni used were able to adhere to INT 407 epithelial cells and mucus, but high adherence to one substrate did not necessarily indicate comparable adherence to the other. The adherence of C. jejuni to cells was inhibited partially by treating the bacterial cells with proteases or glutaraldehyde or by adding a certain carbohydrate (fucose or mannose) to the medium. The flagellum of C. jejuni was identified as a potential adhesin by comparing adherence of flagellated and aflagellated variants. Shearing of the bacterial cells to remove the flagella reduced bacterial adhesion, whereas immobilization of the flagellum with KCN increased adhesion. Purified flagella showed specific, fucose-resistant binding to epithelial cells but not to intestinal mucus. The presence of a second, nonproteinaceous adhesin was suggested because no single treatment of the bacteria completely inhibited adhesion. Lipopolysaccharide (LPS) was identified as another C. jejuni adhesin. [3H]LPS specifically bound to epithelial cells, and this phenomenon was inhibited by periodate oxidation of the LPS or glutaraldehyde fixation of the epithelial cells. LPS, unlike flagella, was fucose sensitive and inhibited binding of whole bacterial cells to INT 407 cells. LPS was also able to bind to intestinal mucus gel. These data indicate that both flagella and LPS are important in adhesion to the mucosal surface.

Adhesiveness↗
PubMed1986

Effect of radiation dose on the recovery of aerobic and anaerobic bacteria from mice.

The presence of aerobic and anaerobic bacteria in the blood, spleen, and liver was investigated in mice that were exposed to 7, 8, 9, or 10 Gy 60Co radiation. Microorganisms were detected more often in animals exposed to higher doses of radiation. The number of mice that were culture positive and the number of isolates in one site increased with increasing dose. Bacteria were recovered in mice killed at various times after radiation, in 3 of 100 mice exposed to 7 Gy, in 13 of 100 irradiated with 8 Gy, in 23 of 90 exposed to 9 Gy, and in 34 of 87 irradiated with 10 Gy. The predominant organisms recovered were Escherichia coli, anaerobic Gram-positive cocci, Proteus mirabilis, Staphylococcus aureus, and Bacteroides spp. Escherichia coli and anaerobes were more often isolated in animals exposed to 10 Gy, while S. aureus was more often recovered in those irradiated with 9 Gy. These data demonstrate a relationship between the dose of radiation and the rate of infection due to enteric aerobic and anaerobic bacteria.

Animals↗