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Biomedical subjects

S M Kelly

Publications and source records attributed to S M Kelly.

At least 145 records · Page 8Linked to original sources
PubMed1990

Lack of covalent binding to DNA of di-n-octyltin dichloride (DOTC) in vivo and in vitro.

[14C]Di-n-octyltin dichloride ([14C]DOTC) was administered by oral gavage to male and female rats. After 96 h hepatic and thymic DNA was isolated. All DNA fractions were radioactive, but analysis of DNA hydrolysates by HPLC revealed that the radioactivity was incorporated via biosynthesis and was not due to adduct formation. The limit of detection for adduct formation, expressed in units of the covalent binding index (CBI = mumol chemical bound per mol nucleotides/mmol chemical applied per kg body wt.) was approximately 0.2 for liver DNA and about 0.7 for thymus DNA. This maximum possible DNA-binding ability is about 30,000 times lower than the corresponding value for the strong carcinogen, aflatoxin B1. In addition, [14C]DOTC did not bind covalently to calf thymus DNA in the presence or absence of rat liver S9 or to DNA of V79 Chinese hamster cells. This study therefore gives no indication for genotoxic activity of DOTC mediated by DNA binding.

Animals↗
PubMed1990

Epidermal growth factor stimulates synthesis and secretion of mucus glycoproteins in human gastric mucosa.

1. The effects of epidermal growth factor on the synthesis and secretion by human gastric mucosa of radiolabelled mucus glycoprotein have been studied in organ culture. 2. Addition of epidermal growth factor at a concentration of 5 or 10 ng/ml increased the synthesis of glycoprotein from 84 +/- 16.2 d.p.m./micrograms of protein to 132 +/- 19.5 and 156 +/- 20.2 d.p.m./micrograms of protein, respectively. The same doses increased secretion from 73.75 +/- 17 d.p.m./micrograms of protein to 114.0 +/- 26.4 and 141.5 +/- 31.4 d.p.m./micrograms of protein (P less than 0.001). 3. As glycoproteins are the main constituent of the mucus defence barrier, epidermal growth factor-stimulated mucus production may contribute to gastric cytoprotection.

Epidermal Growth Factor↗
PubMed1990

Selective management of early glottic cancer.

Seventy patients with stage I and II glottic cancer were treated at the University of Utah School of Medicine hospitals from 1980 through 1987. Forty-four patients had stage I cancer and 26 patients had stage II. The overall survival in the stage I group was 82%. Primary site control was 93% with only three deaths due to laryngeal cancer. Local control rates were 93% with CO2 laser excision, 80% with CO2 laser and irradiation, and 67% with radiation alone. Stage II glottic patients had an overall survival of 61.5% with a local control rate of 76%. Twenty-one of 24 patients were treated by full-course irradiation. Of the eight patients who recurred at the primary site, all were irradiation failures who had initial bulky disease and impaired vocal cord mobility. Selective CO2 laser excision was highly effective, whereas radiation therapy results were somewhat disappointing. Open partial laryngectomy should be considered in bulky stage II disease patients.

Adult↗
PubMed1989

Selective delivery of antigens by recombinant bacteria.

The means to attenuate Salmonella and to endow such avirulent strains with the ability to express colonization and virulence antigens from other pathogens has achieved considerable progress during the past several years. One can therefore begin to design and construct strains with specificity to a given animal host and to express in a defined way specific colonization and virulence antigens in a manner to stimulate long-lasting immunity to the Salmonella and to the pathogen supplying the genetic information for the colonization and virulence antigens. Since most pathogens colonize on or invade through mucosal surfaces, the use of recombinant bivalent Salmonella vaccine strains to stimulate a mucosal immune response would induce the development of a first line of defense against a diversity of pathogens. Mucosal immunity should therefore reduce contagious spread of many pathogens since the dose to overcome the mucosal immune barrier would be increased to result in a diminished likelihood of infection. The fact that the recombinant Salmonella vaccine strains also induce humoral and cellular immune responses justifies their use for induction of long-lasting immunity. Although considerable progress has been made in targeting antigens to the GALT by use of avirulent Salmonella, a similar strategy for delivery of antigens to the BALT has yet to be discovered and developed. In addition to constituting a system for induction of immunity against a diversity of pathogens, the recombinant avirulent Salmonella system should provide a means to explore parameters of the mucosal immune response. This would include investigation of the location and duration of memory, the age dependence of induction of mucosal immunity, and the means for the possible induction of oral tolerance with regard to either the mucosal or humoral response to an antigen expressed by the recombinant Salmonella. It is also possible to contemplate using the avirulent Salmonella to target expression of various modulators of the immune system such as interleukin-2 and interferon-gamma to the GALT and thus further enhance the immune response. Lastly, one can introduce into avirulent Salmonella strains genes for putative colonization antigens in order to investigate whether induction of an immune response against the putative colonization antigen does or does not interfere with infection. This system, therefore, permits another means to analyze the relative importance of various bacterial surface attributes in conferring pathogenicity to the microbe.

Animals↗
PubMed1989

Postural changes in spontaneous and evoked regional diaphragmatic activity in dogs.

We addressed the question whether gravity-dependent differences in passive tension and length of the diaphragm are associated with differences in its regional activation. By using intramuscular electrodes, we measured the electromyographic activity of different parts of the diaphragm (Edi) during quiet breathing in several postures in 13 anesthetized mongrel dogs. The Edi of the left and right costal hemi-diaphragm was compared between the left and right lateral decubitus postures, whereas that from the substernal and crural regions was compared between the supine and prone positions. On changing posture, the Edi of the dependent part of the diaphragm decreased in both cases, whereas that of the non-dependent part increased. The results were consistent with reflex modulation of regional diaphragm activation in response to postural changes in local resting length. However, these changes in Edi persisted after bilateral vagotomy, cordotomy (C7-T1) and dorsal rhizotomy of the C5-C7 roots. Compound muscle action potentials, recorded in different regions of the diaphragm and evoked by supramaximal stimulation of the phrenic nerves, were altered with changes in posture in the same direction as Edi. Because the stimuli were supramaximal, these changes reflected systematic changes in the recording conditions with posture, possibly because of a combination of 1) changes in the electrical environment surrounding the intramuscular electrodes and 2) passive changes in muscle length. Our results demonstrate systematic, reproducible, posture-dependent changes in regional Edi that may not be due to different neural drive.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1988

Avirulent Salmonella typhimurium delta cya delta crp oral vaccine strains expressing a streptococcal colonization and virulence antigen.

Salmonella typhimurium SR-11 strains lacking adenylate cyclase and the cyclic AMP receptor protein (CRP) due to deletion (delta) mutations in the cya and crp genes, respectively, are avirulent for mice and induce high level protective immunity against subsequent challenge with wild-type virulent S. typhimurium SR-11 cells. The avirulence of these delta cya delta crp mutants has been enhanced by elimination of the 100 kb virulence plasmid pStSR100 without impairing immunogenicity. The present report confirms the avirulence and immunogenicity of these mutant strains, demonstrates that immunization of both four- and eight-week-old mice has no adverse effect on weight gain, and that immunity lasts at least ninety days following initial immunization. Avirulent S. typhimurium strains have been endowed with the ability to produce several streptococcal colonization and virulence antigens for the purpose of constructing recombinant bivalent oral vaccine strains. Important antigenic determinants of the Streptococcus sobrinus surface protein antigen A (SpaA), presumed to be a critical colonization antigen of S. sobrinus, are expressed at high level by the delta cya delta crp S. typhimurium strains. The recombinant vaccine strains are stable in vitro and in animals (for a period of at least eight days) where they localize to the gut-associated lymphoid tissue (GALT).

Administration, Oral↗
PubMed1987

Effect of expiratory glottic constriction on lung volume and pattern of breathing in adult dogs.

We examined the effect of laryngeal constriction on the pattern of breathing in 4 anaesthetized adult mongrel dogs. By means of a T-shaped tracheostomy tube the larynx could be repeatedly excluded or included in the breathing circuit. Marked expiratory activity of the thyroarytenoid muscle (TA), the main glottic constrictor, was induced by injection of 100-400 ml of air into the pleural space or by inhalation of histamine aerosol (2 dogs) which resulted in rapid shallow breathing. In 21 pairs of runs in the 4 dogs switching from tracheostomy breathing to oral breathing decreased mid-expiratory flow and frequency by 85 +/- 2% (P less than 0.001) and 48 +/- 4% (P less than 0.001), respectively. Although expiratory duration (TE) increased, end-expiratory lung volume also increased by 40 +/- 8 ml or 21 +/- 4% of the tidal volume (VT) during tracheostomy breathing (P less than 0.001). In contrast, VT remained unchanged (P = 0.9). Instantaneous ventilation decreased due to both the prolongation of TE and an increase in inspiratory duration. Our results indicate that laryngeal braking can be recruited in adult dogs and interacts with reflex mechanisms that modulate respiratory timing, thereby significantly influencing end-expiratory lung volume, ventilation and the pattern of breathing. Simulation of the laryngeal mechanism by expiratory resistive loading at the tracheostomy below the larynx points to a non-reflex mechanical effect of the larynx as a resistance in series.

Aerosols↗
PubMed1987

Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic.

Salmonella typhimurium SR-11 mutants with cya::Tn10 or crp::Tn10 mutations were found to be avirulent and immunogenic for BALB/c mice. Fusaric acid-resistant derivatives with deletions of the Tn10 and adjacent DNA sequences were constructed in S. typhimurium SR-11 strains with or without the virulence plasmid pStSR100. These delta cya delta crp strains grew more slowly than wild-type strains. They possessed wild-type ability to attach to, invade, and persist in gut-associated lymphoid tissue for up to a week but exhibited a diminished ability to reach mesenteric lymph nodes and the spleen. Mice 4 to 8 weeks old were resistant to oral infection with 10(9) cells of several different delta cya and delta cya delta crp strains (the equivalent to 10(4) 50% lethal doses of wild-type S. typhimurium SR-11) and 30 days after immunization became resistant to oral challenge with 10(3) to 10(4) 50% lethal doses of wild-type S. typhimurium SR-11.

Adenylyl Cyclases↗
PubMed1987

Effect of cardiogenic gas mixing on arterial O2 and CO2 tensions during breath holding.

To examine the effect of cardiogenic gas mixing on gas exchange we measured arterial tension of O2 (PaO2) and arterial tension of CO2 (PaCO2) during 3- to 5-min breath holds (BH) before and after infusing 50 ml of saline into the pericardial space (PCF) of seven anesthetized, paralyzed, mechanically ventilated dogs. During BH the ventilator was disconnected and a bias flow of 50% O2 at 4-5 l/min was delivered through the side ports of a small catheter whose tip was positioned 1 cm cephalad of the carina. Paired runs, alternately with and without PCF, were performed in triplicate in each dog. Initial PaO2 was similar for control runs [81 +/- 3 mmHg (SE)] and PCF runs (78 +/- 3 mmHg; P greater than 0.1). After 3-min BH, PaO2 in PCF runs (33 +/- 3 mmHg) was less than that in control runs (58 +/- 4 mmHg) (P less than 0.001). In contrast, the pattern of PaCO2 during BH did not differ with PCF. After 3-min BH, PaCO2 was 49 +/- 3 mmHg with PCF and 49 +/- 2 mmHg in the control runs (P greater than 0.7). In two dogs, repeated 50-ml reductions in lung volume, produced by rib cage compression, did not alter the time course of PaO2 during BH. Although cardiac output decreased slightly with PCF, hemodynamic changes due to PCF were unlikely to account for the observed fall in PaO2. Our results indicate a substantial effect of cardiogenic gas mixing on O2 uptake when tracheal gas is O2 enriched during breath holding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Hyporesponsiveness to aerosolized but not to infused methacholine in cigarette-smoking dogs.

Seven beagles were exposed via a tracheostomy to smoke from 10 cigarettes/day, 5 days/wk for 10 months; 2 other dogs were exposed for 6 months only. Four dogs served as sham-exposed control animals. Mucus was collected 2 times/wk prior to and during the exposure period by resting a cytology brush on the lower trachea for 2 to 5 min. At least once prior to and as often as 3 times during exposure, transpulmonary pressure and flow were monitored under anesthesia to determine resistance RL. Two airway responses to methacholine were determined: the infusion response delta Ri, the increment in RL 4 to 6 min after infusion of 4 micrograms/kg/min, and the aerosol response delta Ra, the increment in RL 2 min after aerosolization of 2 mg/ml, the highest common dose reached. Eight of 9 smoking dogs developed persistent mucus hypersecretion. In 5 dogs, tracheal mucus flux increased 5- to 10-fold; in 3 dogs, the increase was 2 to 3 times that of control animals. One of the sham-exposed dogs developed moderate hypersecretion. After 10 months of smoke exposure, delta Ri increased to 2.24 times that of the initial value (+/- 0.47 SE) (n = 7, p less than 0.05), whereas delta Ra decreased to 0.28 times that of the control value (+/- 0.21 SE) (n = 6, p less than 0.02). The difference between aerosol and infusion response, delta Rai = delta Ra - delta Ri, is an index of relative hyporesponsiveness to methacholine aerosol.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1986

A prospective comparison of anoscopy and fiberendoscopy in detecting anal lesions.

With the increase in rectal and perianal disease, thorough examination of this area is necessary in every patient with colorectal complaints. We compared the current fibersigmoidoscope and colonoscope with routine anoscopy in the detection rate of perianal pathology in 115 consecutive patients. Straight withdrawal and retroflexion in the rectum of the fiberoptic instruments led to lesion detection rates of 78% and 54%, respectively. The anoscope showed 99% of lesions. Anoscopy was easily learned and required less than a minute to perform. We conclude that anoscopy should be performed in every patient undergoing fibersigmoidoscopy or colonoscopy. Instructions in this procedure should be provided in all training programs.

Adult↗
PubMed1984

Inspiratory muscle strength and body composition in patients receiving total parenteral nutrition therapy.

We examined the relationship between inspiratory muscle strength and body composition in 59 patients receiving total parenteral nutrition (TPN). Inspiratory muscle strength was assessed by measuring maximal inspiratory pressure (Pm) after a tidal expiration, with the patient supine and the nose occluded. Body composition was determined by multiple isotope dilution. Body cell mass (BCM) and extracellular mass were estimated by measuring total exchangeable potassium (Ke) and total exchangeable sodium (Nae), respectively; Nae/Ke, an index of the nutritional state, was calculated from these values. The effect of changes in muscle mass was evaluated in 29 of the patients by simultaneous determination of Pm and body composition, prior to and at 2-wk intervals during TPN therapy. The Pm was lower (mean +/- 1 SE:33.5 +/- 2.8 cm H2O) in malnourished patients than in those who were in the normal Nae/Ke range (45.3 +/- 4.8 cm H2O, p less than 0.05). Loss of strength was related to reduction in muscle mass because BCM was also reduced in malnourished patients (15.6 +/- 0.8 kg) when compared to those with normal Nae/Ke (19.3 +/- 0.9 kg), (p less than 0.05), and Pm was positively correlated with BCM (r = 0.27, p less than 0.01). Changes in BCM were accompanied by appropriate changes in Pm during the study period (r = 0.44, p less than 0.01); the majority (21 patients) showed improvement in both BCM and Pm.(ABSTRACT TRUNCATED AT 250 WORDS)

Body Composition↗
PubMed1982

The oxygen cost of breathing in patients with cardiorespiratory disease.

We measured the oxygen cost of breathing (VO2resp) in 13 patients with cardiorespiratory disease requiring artificial ventilation as the difference between the oxygen consumption during spontaneous respiration (VO2tot) and that during artificial ventilation (VO2nonresp). Average VO2tot was 312 +/- 90 ml/min (mean +/- 1 SD), whereas VO2nonresp was 246 +/- 38 ml/min (p less than 0.01). Average VO2resp was 75 +/- 82 ml/min (range, 8 to 286), representing 24% of VO2tot or 8.7 +/- 8.9 ml O2/L ventilation. In normal resting adults, VO2resp in 5 to 10 ml/min, about 1 to 3% VO2tot, or 0.25 to 2.5 ml O2/L ventilation. The VO2resp had an exponential relationship with FEV1 (r = 0.97) in 6 patients who had had prior spirometry. Because minute ventilation was normal in our patients (8.8 +/- 2.2 L/min), the elevated VO2resp represented an increase in the work of breathing as well as a decrease in the efficiency of the respiratory muscles. These results suggest that, where O2 transport is compromised, artificial ventilation may release substantial quantities of oxygen for use by other body systems.

Adult↗
PubMedDate not supplied

Stabilization of recombinant avirulent vaccine strains in vivo.

Salmonella strains attenuated by various mutational alterations and expressing heterologous colonization and virulence antigens specified by cloned genes have begun to be widely used as vaccines for oral immunization to induce protective immunity against the pathogens supplying the genes for the colonization or virulence antigens. Problems associated with plasmid instability and/or poor expression of cloned gene products have frequently been encountered and regulatory agencies are now banning use of antibiotic resistance markers in live attenuated vaccine strains. We have therefore developed a balanced lethal host-vector system in which the chromosome of the attenuated vaccine strain contains a deletion mutation that impose a requirement for diaminopimelic acid (DAP), an essential constituent of the rigid layer of the cell wall of all Gram-negative and some Gram-positive microbes. The plasmid cloning vector contains the wild-type allele for this gene allowing the recombinant avirulent Salmonella to be independent of DAP. Since DAP is not prevalent in nature, especially in the animal host, essentially 100% of the surviving avirulent Salmonella recovered from an immunized animal host still contain the recombinant plasmid and express the foreign colonization or virulence antigen. Occasional loss of the plasmid renders the avirulent Salmonella DAP-requiring, which quickly results in DAPless death with lysis of the bacterium to release its antigenic contents, an occurrence which might further enhance the immune response to the foreign colonization or virulence antigen. We describe below strains of bacteria, recombinant vectors and the methods to make use of this system in a diversity of situations for development of live recombinant avirulent vaccines as well as for other potential applications.

Amino Acid Sequence↗