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Biomedical subjects

A L Smith

Publications and source records attributed to A L Smith.

At least 145 records · Page 8Linked to original sources
PubMed1995

Aerosol administration of antibiotics.

Aerosol administration of antibiotics is an attractive approach to the treatment of the recurrent respiratory infections experienced by patients suffering from cystic fibrosis (CF). Through aerosol administration, drugs can, theoretically, be delivered directly to the target site of infection, i.e. the lumen of the lower respiratory tract, thus enabling smaller doses to be given. This, in turn, should result in reduced costs and decreased potential for systemic toxicity. The efficacy of aerosol antibiotic therapy is, however, influenced by numerous variables, including the type of nebulizer device used to deliver the aerosol, the drug's physical properties, its concentration in the aerosol and particle size, carrier gas and patient factors. The efficacy of aerosol antibiotics in the treatment of CF is controversial. This appears to be due mainly of problems and inconsistencies with clinical trials. However, various antibiotics, including beta-lactams, polymyxins and aminoglycosides, have demonstrated clinical benefits when administered by inhalation to CF patients.

Administration, Inhalation↗
PubMed1995

Persistent rat virus infection in juvenile athymic rats and its modulation by immune serum.

In contrast to euthymic juvenile rats, which develop acute, self-limiting infection with rat virus (RV), RV infection of juvenile athymic rats was persistent for up to 12 weeks as demonstrated by recovery of infective virus, transmission to cagemates, and detection of viral DNA in the lungs. Administration of RV antiserum at the time of virus inoculation prevented persistent infection in five of six rats. Among rats given RV antiserum 1 week after virus, the interval at which euthymic rats begin to seroconvert, RV was not detected 1 week later but was recovered from four of six rats 3 weeks later. Results of these studies confirm that T-cell deficiency facilitates persistent RV infection and indicate that antibody provides significant protection from persistent infection only if it is present at the time of virus inoculation. The results support the concept that factors which prevent persistent infection in euthymic rats act early after virus inoculation and may include cellular immunity.

Animals↗
PubMed1995

NMDA-receptor antagonists disrupt the formation of the auditory space map in the mammalian superior colliculus.

In the ferret (Mustela putorius) the map of auditory space in the deeper layers of the superior colliculus (SC) matures over a period of several postnatal weeks, a process known to be guided by both visual and auditory experience. The auditory responses are initially very broadly tuned, and gradually become more selective for specific sound locations that coincide with the visual receptive fields recorded in the same region of the SC. To investigate the possible involvement of NMDA-type glutamate receptors in the postnatal development of this auditory representation, we have reared ferrets in which 400 microns thick sheets of the slow-release polymer Elvax, containing the NMDA receptor antagonists MK801 or APV, were placed on the dorsal surface of the SC. The Elvax was implanted on postnatal day (P) 25-27, just before the onset of hearing, and removed 5-6 weeks later, just prior to recording from the SC on around P61-70. In vitro measurements with Elvax containing 3H-MK801 revealed that the amount of drug released declined sharply over the first 10 d and then stabilized at a fairly constant rate for the following 5 weeks. These in vitro data were found to parallel the in vivo release of MK801 from implanted Elvax slices. Diffusion of MK801 from the implant was measured and significant levels were found within 800 microns of the SC surface, suggesting that the action of MK801 was restricted to the superficial and intermediate layers of the nucleus. Extracellular recordings were made from visual and auditory units in the SC in response to free-field stimulation. The visual responses of units recorded in the superficial layers appeared to be unaffected by either of the drug treatments, and formed a normal, adult-like map of visual azimuth along the rostrocaudal axis of the SC in all animals. Most of the auditory single-unit responses recorded at this age in normal, unoperated controls were spatially tuned and topographically organized, although the map of sound azimuth was less precise than that in adult ferrets. Data from age-matched control animals that had been reared with drug-free Elvax implants were not statistically different from the unoperated juvenile ferrets. However, in animals reared with APV or MK801 Elvax implants, there was an increase in the relative numbers of auditory units that were ambiguously tuned to two or more locations.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1995

Enzyme-linked immunosorbent assay for detection of antibody to lymphocytic choriomeningitis virus in mouse sera, with recombinant nucleoprotein as antigen.

An enzyme-linked immunosorbent assay (ELISA) was developed for the detection of antibody to lymphocytic choriomeningitis virus (LCMV) in mouse sera. This assay is based on recombinant LCMV nucleoprotein generated in a baculovirus system. Sera from experimentally and naturally infected as well as noninfected mice were tested, and the results were compared with those obtained from an established immunofluorescence assay (IFA) that uses infected cells as antigen. An excellent correlation was found; the ELISA specificity and sensitivity were calculated to be 100 and 95% respectively. Unlike the IFA, this ELISA does not require the handling of infective virus. It eliminates the need to work with a zoonotic agent in the laboratory while allowing effective screening of laboratory mouse populations for LCMV antibody.

Animals↗
PubMed1994

Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.

BACKGROUND: Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, which results in recurrent, symptomatic exacerbations. The viscoelasticity of the secretions can be reduced in vitro by recombinant human deoxyribonuclease I (rhDNase), a bioengineered copy of the human enzyme. METHODS: We performed a randomized, double-blind, placebo-controlled study to determine the effects of once-daily and twice-daily administration of rhDNase on exacerbations of respiratory symptoms requiring parenteral antibiotics and on pulmonary function. A total of 968 adults and children with cystic fibrosis were treated for 24 weeks as outpatients. RESULTS: One or more exacerbations occurred in 27 percent of the patients given placebo, 22 percent of those treated with rhDNase once daily, and 19 percent of those treated with rhDNase twice daily. As compared with placebo, the administration of rhDNase once daily and twice daily reduced the age-adjusted risk of respiratory exacerbations by 28 percent (P = 0.04) and 37 percent (P < 0.01), respectively. The administration of rhDNase once daily and twice daily improved forced expiratory volume in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. None of the patients had anaphylaxis. Voice alteration and laryngitis were more frequent in the rhDNase-treated patients than in those receiving placebo but were rarely severe and resolved within 21 days of onset. CONCLUSIONS: In patients with cystic fibrosis, the administration of rhDNase reduced but did not eliminate exacerbations of respiratory symptoms, resulted in slight improvement in pulmonary function, and was well tolerated.

Adolescent↗
PubMed1994

Differences in eucaryotic cell binding of Pseudomonas.

The lungs of cystic fibrosis (CF) patients are frequently chronically colonized by Pseudomonas aeruginosa. Recently there has been an increase in colonization by another pathogen Pseudomonas cepacia, which can cause a rapid decline in clinical condition or death of the patient. The nature of the factor(s) which predispose CF patients to colonization by one or both of these opportunistic pathogens is unknown. It has been suggested that the genetic defect in CF patients results in an increase in the number of epithelial cell receptors available to P. aeruginosa in the lung, thus rendering CF patients more susceptible to bacterial colonization than non-CF individuals. In this study, we have examined adherence of several strains of P. aeruginosa and P. cepacia to a variety of continuous cell lines, as well as primary cultures of CF and non-CF nasal polyp cells. The results suggested that there may be a decrease in the number of receptors available to both strains of Pseudomonas on cells of canine origin compared to human cells. Both strains appear to use pili as the primary adhesin, but there is also evidence that non-pilus adhesins contribute significantly to eucaryotic cell binding. P. cepacia exhibited microcolony formation on all cell types, which is typical of the localized adherence pattern characteristic of the enteropathogenic Escherichia coli. However, we were unable to demonstrate, with either P. cepacia or P. aeruginosa, a significant increase in adherence to CF compared to non-CF nasal polyp cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adhesins, Bacterial↗
PubMed1994

Distinct laminar differences in the distribution of excitatory amino acid receptors in adult ferret primary visual cortex.

In order to explore the relative contributions of the different ionotropic excitatory amino acid receptor subtypes to signalling in primary visual cortex, we have mapped their distributions in area 17 of adult ferret cerebral cortex by quantitative in vitro autoradiography. D,L-alpha-amino-3-hydroxy-5-methoxy-4-isoxazole propionate (AMPA) and kainate receptors, gating fast, Na(+)-permeable channels, were localized with [3H]dizocilpine maleate ([3H]MK-801). All three radioligands bound to single sites, with KDs of 414 nM [3H]AMPA and [3H]kainate, respectively. Slower-acting N-methyl-D-aspartate receptors, which gate the influx of Ca2+ as well as Na+, were localized with ([3H]AMPA), 78 nM ([3H]kainate) and 16 nM ([3H]MK-801), and each receptor subtype displayed a different laminar distribution pattern within area 17. AMPA receptors were concentrated in superficial layers, with intermediate densities in deep layers and lowest levels in layer IV. Kainate receptor levels were high in layers V and VI and low in all other layers. N-methyl-D-aspartate receptors were more homogeneously distributed than AMPA or kainate receptors, but were expressed at highest levels in layers I and IV and lowest levels in layers V and VI. The binding site densities found in the layers containing most receptors were Bmax = 2812 fmol/mg for [3H]AMPA, Bmax = 626 fmol/mg for [3H]MK-801 maleate and Bmax = 278 fmol/mg for [3H]kainate. Thus, while AMPA receptors were predominant and kainate receptors least abundant in all cortical layers, a complementary relative distribution of excitatory amino acid receptors was apparent, with AMPA receptor density highest in superficial layers, kainate receptor density highest in inferior layers and N-methyl-D-aspartate receptor density highest in the middle granular layer, as well as in layer I. The results indicate that although AMPA receptors are principally involved in excitatory signalling in adult ferret primary visual cortex, kainate receptors in layers V and VI and N-methyl-D-aspartate receptors in layers I and IV may have particularly important roles in mediating synaptic transmission.

Animals↗
PubMed1994

Disposition of drugs in cystic fibrosis. VII. Acetylation of sulfamethoxazole in blood cells: in vitro-in vivo correlation and characterization of its kinetics of acetylation in lymphocytes.

OBJECTIVE: To determine if acetylation of sulfamethoxazole in blood cells is a surrogate measure of its acetylation in vivo. If it is, to use these cells to determine the mechanism(s) by which acetylation of sulfamethoxazole is enhanced in cystic fibrosis. METHODS: Single-point sulfamethoxazole acetylation activity in blood cells obtained from patients with cystic fibrosis (n = 6) and control subjects (n = 7) who had previously participated in our in vivo study was determined. The parameters, Vmax and Km, for acetylation of sulfamethoxazole in lysed lymphocytes obtained from patients with cystic fibrosis (n = 6) and control subjects (n = 5) were also determined. RESULTS: The acetylation activity in cystic fibrosis whole blood, lysed erythrocytes, and lysed peripheral blood mononuclear cells was significantly (p < 0.05) greater than that in cells obtained from control subjects and was highly correlated with acetylation of sulfamethoxazole in vivo (r > 0.80). The apparent Vmax for cystic fibrosis lymphocyte lysate was significantly (p < 0.05) greater than that obtained for control lymphocyte lysate (72.99 +/- 9.07 versus 60.97 +/- 2.26 pmol/mg protein/min), and the apparent Km was significantly (p < 0.05) lower (0.51 +/- 0.07 versus 0.73 +/- 0.06 mmol/L). CONCLUSION: Blood cells may be used as surrogate markers to elucidate the mechanism(s) by which acetylation of sulfamethoxazole (catalyzed by the monomorphic N-acetyltransferase) is enhanced in subjects with cystic fibrosis. Both activation or activation and induction of the monomorphic N-acetyltransferase should be considered as possible mechanism(s) to explain this phenomenon.

Acetylation↗
PubMed1994

Disposition of drugs in cystic fibrosis. VI. In vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin (including P450 3A4) is not enhanced in cystic fibrosis.

OBJECTIVE: To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin is enhanced in cystic fibrosis. DESIGN: Six adult subjects with cystic fibrosis and six healthy control subjects, matched by age and sex, were administered (R)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 192 hours. The concentration of (R)-warfarin in plasma and the concentration of (R)-warfarin and its metabolites in urine were determined by HPLC and GC/MS, respectively. Plasma protein binding of (R)-warfarin was measured by ultrafiltration. RESULTS: The unbound plasma clearance of (R)-warfarin was not significantly (p > 0.05) different between the cystic fibrosis and the control groups (cystic fibrosis, 997 +/- 483 ml/hr/kg; control, 788 +/- 219 ml/hr/kg). The unbound metabolic clearances of (R)-warfarin to its oxidative metabolites--6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin, and 10-hydroxywarfarin (mediated by P450 3A4)--were also similar (p > 0.05) in the two groups (6-hydroxywarfarin: cystic fibrosis: 124.2 +/- 72.8 ml/hr/kg, control: 99.4 +/- 37.3 ml/hr/kg; 7-hydroxywarfarin: cystic fibrosis: 43.8 +/- 32.2 ml/hr/kg, control: 34.5 +/- 10.6 ml/hr/kg; 8-hydroxywarfarin: cystic fibrosis: 80.4 +/- 85.4 ml/hr/kg, control: 69.5 +/- 39.5 ml/hr/kg; 10-hydroxywarfarin: cystic fibrosis: 4.38 +/- 2.72 ml/hr/kg, control: 16.28 +/- 13.71 ml/hr/kg). CONCLUSION: The in vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin, including P450 3A4, is not enhanced in cystic fibrosis.

Adult↗
PubMed1994

Invasive disease caused by Neisseria meningitidis relatively resistant to penicillin in North Carolina.

A case of sepsis and meningitis caused by Neisseria meningitidis with relative resistance to penicillin occurred in North Carolina in August 1992. This isolate was relatively resistant due to decreased affinity of its penicillin-binding protein 2 for penicillin. Such isolates have been reported in Spain, elsewhere in Europe, in South Africa, and in Canada, but invasive disease caused by meningococcal isolates relatively resistant to penicillin was not recognized in the United States before a preliminary report of this case in October 1992. The Centers for Disease Control and Prevention recently retrospectively identified 3 additional cases from 1991. A fifth case occurred in Kentucky in 1993. Surveillance studies of penicillin susceptibility of N. meningitidis isolates suggest such meningococci have existed sporadically in the past. Increases in prevalence and magnitude of penicillin resistance among strains of N. meningitidis would require reconsideration of current clinical practice with regard to treatment of meningococcal disease.

Amoxicillin↗
PubMed1994

The role of natural killer cells in resistance to coccidiosis: investigations in a murine model.

Natural killer (NK) activity, detected by the lysis of Yac-1 target cells, was examined in splenic and mesenteric lymph node (MLN) cells throughout the course of infection with Eimeria vermiformis in BALB/c and C57B1/6 (B6) mice. These strains are, respectively, relatively resistant and susceptible to primary infections, which render them equally, and completely, resistant to challenge. Resting levels of NK activity were higher in B6 than in BALB/c, and B6 responded earlier in the course of infection than BALB/c, but splenic peak values were higher in BALB/c; the pattern of response in MLN cells was similar in both strains, but the peak was higher in BALB/c. At the time (7 days p.i.) of peak NK response in BALB/c mice there was, depending upon the choice of NK-resistant/lymphokine-activated killer (LAK)-sensitive target cells, either little (P388D1), or no (P815) splenic LAK activity. Challenge of immunized BALB/c mice did not evoke a detectable NK response. Although the higher NK activity in BALB/c mice correlated with greater control of primary infection, depletion of NK activity (demonstrated in splenic cells) in vivo by treatment with anti-asialo GM1 antibodies did not greatly affect the course of infection. Furthermore, this treatment did not augment the exacerbation of infection produced by treatment with anti-interferon-gamma (IFN-gamma) MoAb, indicating that, at least in this system, NK cells are not a fundamentally important source of this controlling cytokine of eimerian infections. The results suggest that NK cells may not greatly influence the outcome of coccidial infections.

Animals↗
PubMed1994

Accuracy and cost of antibiotic susceptibility testing of mixed morphotypes of Pseudomonas aeruginosa.

Chronic Pseudomonas aeruginosa colonization of the lower respiratory tract of patients with cystic fibrosis frequently results in pulmonary exacerbations requiring treatment with antimicrobial agents. Multiple morphotypes with different antibiotic susceptibilities are often isolated from a single sputum sample. Determination of MICs of antibiotics for each sputum morphotype is used to guide therapy but is time-consuming and expensive. We explored an alternative assay for determining MICs for all P. aeruginosa morphotypes cultured from a homogenized sputum sample. We sought correlations of those MICs with the MIC for the most resistant morphotypes tested separately. The MICs determined for a mixture of morphotypes correctly predicted the highest MICs (+/- one dilution) determined for isolated morphotypes 73.5% of the time. The MIC for the mixed morphotypes correctly predicted susceptibility in 90.4% of samples. In contrast, determination of the MIC for the mixture of morphotypes correctly predicted resistance in only 57.0%. For sputa containing susceptible isolates, testing the mixed culture may provide adequate susceptibility data with significant laboratory time and cost savings. However, for sputa with resistant strains, the traditional method of testing isolated morphotypes should still be used.

Costs and Cost Analysis↗
PubMed1994

Telecommuting: stress and social support.

Occupational stress and social support were measured in adults, 15 working as telecommuters, 9 working at home, and 14 working in a company office. Analysis showed telecommuters and office workers perceived more support than those working at home. Telecommuters also reported less stress and a stronger preference for this new work option.

Adaptation, Psychological↗
PubMed1994

Automated ventilator testing.

A new era has arrived for the Biomedical Engineering Department at the Royal Women's Hospital in Melbourne. We have developed a system to qualitatively test for intermittent or unconfirmed faults, associated with Bear Cub ventilators. Where previous testing has been inadequate, computer logging is now used to interface the RT200 Timeter Calibration Analyser (TCA) to obtain a real time display of data, which can be stored and graphed. Using Quick Basic version 4.5, it was possible to establish communication between the TCA and an IBM compatible computer, such that meaningful displays of machine performance were produced. From the parameters measured it has been possible to obtain data on Peak Pressure, Inspiratory to Expiratory ratio (I:E ratio) Peak Flow and Rate. Monitoring is not limited to these parameters, though these were selected for our particular needs. These parameters are plotted in two ways: 1. Compressed average versus time, up to 24 hours on one screen 2. Raw data, 36 minutes displayed on each screen. The compressed data gives an overview which allows easy identification of intermittent faults. The uncompressed data confirms that the averaged signal is a realistic representation of the situation. One of the major benefits of this type of data analysis, is that ventilator performance may be monitored over a long period of time without requiring the presence of a service technician. It also allows individual ventilator performance to be graphically compared to other ventilators.

Australia↗
PubMed1993

Chemistry and biology of natural and designed enediynes.

Ever since the initial reports of the enediyne anticancer antibiotics in the late 1980s, researchers from a number of disciplines have been devoting increasing attention to their chemistry, biology, and potential medical applications. Synthetic chemists and molecular designers have been engaged in attempts to synthesize these molecules and to model their unique architecture. Considerable efforts have been directed at understanding and mimicking the various processes involved in the targeting, activation, and DNA cleavage associated with these natural products. This review summarizes the main contributions to the field, with particular emphasis on work from our laboratories. Highlights include studies of the Bergman reaction, which is central to the mechanism of action of enediynes, the design and chemical synthesis of a number of these systems, and biological studies with selected molecules. Finally, the total synthesis of calicheamicin gamma 1I, the most prominent member of this class of naturally occurring compounds, is discussed.

Aminoglycosides↗
PubMed1993

Lethal exacerbation of Pneumocystis carinii pneumonia in severe combined immunodeficiency mice after infection by pneumonia virus of mice.

Mice homozygous for the mutant allele scid (severe combined immunodeficiency) have been described as excellent models for Pneumocystis carinii (Pc) pneumonia (PCP), a major health problem in patients with acquired immune deficiency syndrome (AIDS) and other immunodeficiency states. Other microorganisms have been shown to infect AIDS patients simultaneously with Pc, but whether one opportunist is able to directly influence the pathogenicity of another has not been determined previously. We have deliberately coinfected scid mice (with extent Pc infection) with a variety of primarily pneumotropic viruses and bacteria and have identified pneumonia virus of mice as causing a dramatic increase in the density of Pc organisms and the morbidity due to PCP in immunodeficient scid mice. This finding has clinical significance in the management of PCP, in that the identification and treatment of coinfecting pneumotropic pathogens may be as important as treatment targeted at Pc. A search for other synergistic (or antagonistic) microorganisms and determination of their mechanism(s) of action in altering the progression of PCP is indicated.

Animals↗