Biomedical subjects
Publications and source records attributed to S D Davis.
A false aneurysm that formed after injury by a Swan-Ganz catheter to the pulmonary artery in a patient on long-term anticoagulant therapy is reported. The lesion was demonstrated both by computed tomography and pulmonary angiography. The case is unique in that the patient was successfully treated with percutaneous transcatheter embolization.
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Proteases are involved in the pathogenesis of Pseudomonas aeruginosa infections of the cornea. Although there are many potential roles for these enzymes, involvement in corneal stroma destruction with subsequent descemetocele formation and/or corneal perforation is an important example. This study examined the relationship of elastase and alkaline protease to corneal destruction as indicated by descemetocele formation. The protease content of the overnight Mueller-Hinton broth cultures of various strains of P. aeruginosa correlated with the production of descemetoceles both in the rabbit trauma model of Pseudomonas keratitis and upon intrastromal injection of filtrates of the overnight culture media. The levels of alkaline protease correlated better with descemetocele formation than those of elastase. The influx of inflammatory cells was not correlated with descemetocele formation within 24 to 48 hrs.
We investigated whole kidney function and electrolyte transport in the loop of Henle of surface nephrons using micropuncture in rats pretreated for 5-7 days with cyclosporine A (CSA, 15 mg/kg). We also studied whether the kidney was able to increase K+ excretion acutely after a period of acute i.v. KCl loading (37 mumol/min.kg body weight). For Henle loop studies we microperfused the late proximal tubule downstream from an immobile wax block at two perfusion rates (15 and 40 nl/min). The fluid at the beginning distal tubule was collected and analyzed for inulin, Na+, K+, Cl-, Ca++, and Mg++. Plasma levels of CSA in our model ranged from 254 and 971 ng/ml and showed no relation to the obtained measurements. The pretreatment with CSA did not significantly change whole kidney or Henle loop electrolyte transport compared to drug free controls. Also, the CSA-pretreated rats were able to excrete an acute KCl load although this was at the expense of a marginally higher plasma K+ concentration and also a smaller urine flow increase during KCl loading. Thus CSA-pretreated rats showed only a mildly impaired response to KCl challenge in the absence of GFR impairment.
The movement of polymorphonuclear leukocytes (PMNLs) into inflamed corneas was studied using a quantitative technique to measure PMNL chemotaxis in vivo. Our studies suggested that, in this model, most PMNLs enter the cornea through limbal vessels. A variety of bacterial agents, including viable bacteria, killed bacteria, culture filtrates, and endotoxin, were found to induce a significant corneal inflammatory response. Of the agents tested, viable Pseudomonas aeruginosa produced greatest inflammation. Host factors (serum, PMNLs) also induced movement of PMNLs into corneas, but only after preincubation with activating agents. Normal serum, resting PMNLs, and PMNL lysates derived from resting cells did not promote PMNL corneal ingress. These studies provide further insight into the movement of PMNLs into the inflamed cornea and information that may be of use in developing techniques to inhibit the corneal inflammatory response.
Previous studies established that naloxone reverses hypotension in endotoxin, hemorrhagic, and spinal shock. We studied endotoxin shock in hypophysectomized (Hx) rats, which have little circulating beta-endorphin. Hx or intact rats received surgically implanted jugular catheters for drug injection and aortic catheters for arterial blood pressure (MAP) recording. On the second day after implantation, rats were pretreated with either naloxone or saline. Two minutes later each rat received endotoxin. Following endotoxin, all rats showed a brief biphasic hypertensive-hypotensive response followed by stabilization of MAP near baseline. Within 20 min, all Hx rats, regardless of pretreatment, and the saline-treated intact rats, showed progressive hypotension (P less than 0.005). Only the naloxone-pretreated intact rats maintained a stable MAP. Plasma endorphin measured at 20 min was undetectable in Hx rats in contrast to intact rats (P less than 0.001); plasma corticosterone levels were likewise suppressed in the Hx rats (P less than 0.01). Thus (1) naloxone protected only the rats with an intact pituitary-adrenal-sympathetic system, and (2) pituitary endorphin is not required to generate endotoxin shock in hypophysectomized rats.
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An in vivo model of Pseudomonas aeruginosa sepsis was developed with normal and neutropenic guinea pigs injected intravenously with a strain of Pseudomonas demonstrated in vitro to be synergistically susceptible to ticarcillin and tobramycin. Therapy with ticarcillin, tobramycin, or a combination of the two starting 4 hr after intravenous injection of microorganisms was administered every 2 hr for periods up to 40 hr. Each therapy was associated with significant reductions in bacterial counts in blood, liver, spleen, and kidney compared with untreated animals. In no tissue in either normal or granulocytopenic animals did therapy with a combination of ticarcillin and tobramycin reduce bacterial counts significantly more effectively than did the better single antibiotic agent alone. These findings suggest that when ticarcillin and tobramycin are administered to animals at doses equivalent to therapeutic doses given in humans, a synergistic effect in reduction of bacterial counts in parenchymal organs and blood is not observed. These studies may help explain clinical reports in humans describing a lack of synergistic activity of combination antibiotic therapy in patients with Pseudomonas sepsis.
Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.
We evaluated the efficacy of topical gentamicin prophylaxis for experimental Pseudomonas keratitis in rabbits by applying gentamicin in concentrations of 0.3 and 4 mg/100 ml, in both solution and ointment vehicles, one or four hours after a superficial stromal scratch was infected topically with Pseudomonas organisms. Under these conditions the most effective prophylaxis was that given early, in solution, and in high concentration.
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Vitamin A-deficient rabbits were used to evaluate the role of secondary bacterial infection in the development of keratomalacia and to describe the resultant clinical and morphologic alterations. The conjunctival sacs of vitamin A-deficient rabbits at different stages of corneal involvement were inoculated with Pseudomonas aeruginosa topically. Approximately two weeks after inoculation, corneal ulceration with stromal melting developed in one of three eyes with severe punctate keratitis and in four of seven eyes with xerosis. Ulceration did not develop in any of the eight eyes with early epithelial graying or mild punctate keratitis. Inflammatory cells (primarily polymorphonuclear leukocytes) infiltrated the anterior corneal stroma of infected corneas. Liquefaction of collagen was observed in association with bacteria alone, as well as in association with polymorphonuclear leukocytes. No signs of infection were observed after conjunctival inoculation of Pseudomonas in the eyes of nine control rabbits.
Uniformly severe corneal infections were produced in rabbits by intracorneal injection of a few viable Pseudomonas aeruginosa. The bacteria multiplied rapidly, and within 24 hr, about 10 million organisms were present. The numbers remained stable thereafter. Polymorphonuclear leukocytes (PMNs) began to infiltrate peripheral stroma 24 hr after inoculation. By 32 hr, ring-shaped dense accumulations of PMNs were apparent in the anterior stroma with moderate stromal edema. By 48 hr, the anterior one third of central stroma was severely involved with abscess formation and loss of epithelium, and PMNs had invaded full corneal thickness. The area of liquefactive necrosis eventually involved the entire cornea from limbus to limbus, and collagen staining was lost. Transmission electron microscopy revealed the accumulation of small electron-dense particles in association with collagen fibrils and degranulating PMNs.
A model for the study of polymorphonuclear leukocyte (PMN) migration after transfusion employing induction of keratitis in guinea pigs was developed. Initial studies demonstrated that compared with other agents, intracorneal injection of Pseudomonas aeruginosa following in vivo labelling of PMN by administration of 3H-thymidine produced the greatest influx of radiolabelled PMN into corneas. In subsequent studies, donor peritoneal PMN were radio-labelled by injection of donors with 3H-thymidine. Neutropenia was induced in recipients by whole body irradiation, and they were infected intracorneally with Pseudomonas prior to transfusion. Corneal radioactivity was assayed 24 h after induction of keratitis and the number of donor PMN in corneas was calculated. Half-life of transfused PMN in non-neutropenic recipients was 1.9 h. Arrival of labelled PMN at infected corneas in recipient animals ranged between 0.1-1.0% of transfused cells. Exposure of donor PMN to sonication or to 45 degrees C for 20 min reduced the proportion of PMN arriving at infected corneas (P less than 0.001). Storage of PMN for 24 h at 4 degrees C led to a greater ingress of donor PMN compared with storage at 37 degrees C (P less than 0.01). This model allows quantitation of in vivo PMN function after transfusion and should allow assessment of the effects of most aspects of PMN transfusion technique upon such function.
In a quantitative model of experimental Pseudomonas aeruginosa keratitis in guinea pigs, topical solutions of amikacin, gentamicin and tobramycin were equally effective. Solutions of 20 mg/ml were more effective than solutions of 3 mg/ml.
The effectiveness of cryotherapy alone and in combination with topical tobramycin sulfate therapy for experimental Pseudomonas keratitis was determined in guinea pigs and rabbits. Results were evaluated quantitatively by determining numbers of viable bacteria surviving in corneas. A brass probe cooled to--79 degrees C and applied directly to infected corneas for six seconds resulted in an immediate 99.9% reduction in bacteria. One freeze-thaw cycle followed by topical tobramycin therapy was significantly more effective than tobramycin therapy alone in five of six strains tested. None of the corneas treated with tobramycin alone demonstrated no growth, whereas 24 of 42 of these infected corneas showed no growth after the combination treatment. We conclude that cryotherapy alone had a rapid bactericdal effect on experimental Pseudomonas keratitis and that it significantly potentiated topical antibiotic therapy for most strains.
We determined the efficacy of tobramycin administered by topical, intramuscular, and subconjunctival routes in guinea pigs and rabbits with experimental Pseudomonas keratitis. The topical route of administration was consistently more effective than either subconjunctival or intramuscular routes. Subconjunctival injection of antibiotic did not enhance the effectiveness of topical therapy in either guinea pigs or rabbits. Intramuscular tobramycin was more effective than saline in guinea pigs with keratitis but not in rabbits with keratitis.
Quantitative techniques were used to determine the relative concentrations of viable bacteria and polymorphonuclear leukocytes (PMNs) in the corneas of neutropenic and non-neutropenic guinea pigs with experimental bacterial keratitis induced with three strains of Pseudomonas aeruginosa. Neutropenia was produced by whole-body X-irradiation 1 week before infection. Significantly greater numbers of bacteria were present in the cornea of neutropenic animals 48 h after infection than were present in the corneas of non-neutropenic animals. The same was true 24 and 48 h after infecting animals with Staphylococcus aureus. Examination of histological sections showed that fewer PMNs were present in the corneas of infected neutropenic animals than in the corneas of infected non-neutropenic animals. Radiolabeling of PMNs confirmed a significant reduction in PMN concentration in the corneas of infected neutropenic animals. Tears and the corneal epithelium appear to be the most important elements protecting the cornea against local invasion by bacteria. However, once bacterial keratitis is established, PMNs play a role in limiting bacterial multiplication.