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Biomedical subjects

B D Johnson

Publications and source records attributed to B D Johnson.

At least 19 recordsLinked to original sources
PubMed1992

Analogues of platelet activating factor. 7. Bis-aryl amide and bis-aryl urea receptor antagonists of PAF.

A series of bis-aryl amide (13-57 and 66-81) and bis-aryl urea (58 and 85) antagonists of platelet-activating factor (PAF) was prepared that contain, separating the two aromatic rings, linear amide linkages of the form -(CH2)nCONH- (n = 0-2), -OCH2CONH-, and -(CH2)nNHCO- (n = 0-1), branched amide linkages of the form -(CH2)nN(COR)- (n = 1-3, R = CH3 or n-C3H7), and -N(COCH3)CH2-, and urea linkages of the form -NHCONH- and -CH2N(CONHCH3)-. These compounds were examined for their ability to inhibit PAF-induced platelet aggregation of rabbit platelets. These in vitro data were compared to similar data obtained for a number of known PAF antagonists. The compounds were evaluated in vivo, in the mouse, for their ability to prevent death induced by a lethal challenge of PAF. The relationships between the biological activity and the nature, lipophilicity, and position of substituents of the aromatic rings were studied. Best activity was observed for compounds having linkages of the type -CH2CONH-, -CH2N(COR)-, and -CH2NHCO-. Many of these compounds inhibit PAF-induced platelet aggregation with IC50's under 1 microM.

Amides↗
PubMed1992

A decrease in graft-vs.-host disease without loss of graft-vs.-leukemia reactivity after MHC-matched bone marrow transplantation by selective depletion of donor NK cells in vivo.

It is thought that natural killer cells may play a role in graft-vs.-host reactions after allogeneic bone marrow transplantation, but the use of NK cell-specific reagents has been limited. In this report, an NK allele-specific monoclonal antibody, anti-NK 1.1, was used to study the impact of in vivo donor NK cell depletion on GVH disease, graft-vs.-leukemia (GVL) reactivity and donor T cell chimerism after allogeneic murine BMT. AKR/J (H-2k) recipient mice were preconditioned with suboptimal irradiation (9 Gy = LD50) and transplanted with major histocompatibility complex-matched B10.BR (H-2k) BM cells with or without added spleen cells as a source of T cells. The addition of increasing numbers of spleen cells to the BM inoculum produced GVHD of varying intensities. The beneficial effect of NK depletion on GVHD was dependent on the intensity of the GVH reaction. Donor NK cell depletion had no effect on the survival of mice with severe GVHD after MHC-matched BMT (B10.BR into AKR) or after MHC-mismatched BMT (B10.BR into DBA/2; H-2k into H-2d). However, donor NK depletion increased survival of AKR hosts given sufficient B10.BR splenic T cells to induce mild-to-moderate GVHD. Ex vivo depletion of donor CD8+ T cells also reduced GVH-associated mortality, but the use of both CD8 and NK depletion offered no improvement over either alone, suggesting an interaction between CD8+ and NK 1.1+ cells. In contrast to CD8 depletion, donor NK depletion did not compromise the rapid and complete establishment of donor T cell chimerism nor the ability of chimeras to mount an effective GVL reaction. Thus, elimination of donor NK cells provides an alternate strategy for reducing GVHD without loss of GVL reactivity following MHC-matched allogeneic BMT.

Animals↗
PubMed1992

Vagal contributions to respiratory muscle activity during eupnea in the awake dog.

We examined the effects of reversible vagal cooling on respiratory muscle activities in awake chronically instrumented tracheotomized dogs. We specifically analyzed electromyographic (EMG) activity and its ventilatory correlates, end-expiratory lung volume (EELV) and diaphragmatic resting length via sonomicrometry. Elimination of phasic and tonic mechanoreceptor activity by vagal cooling doubled the EMG activity of the costal, crural, and parasternal muscles, with activation occurring sooner relative to the onset of inspiratory flow. Diaphragmatic postinspiration inspiratory activity in the intact dog coincided with a brief mechanical shortening of the diaphragm during early expiration; vagal blockade removed both the electrical activity and the mechanical shortening. Vagal blockade also doubled the EMG activity of a rib cage expiratory muscle, the triangularis sterni, but reduced that of an abdominal expiratory muscle, the transversus abdominis. Within-breath electrical activity of both muscles occurred sooner relative to the onset of expiratory flow during vagal blockade. Vagal cooling was also associated with a 12% increase in EELV and a 5% decrease in end-expiratory resting length of the diaphragm. We conclude that vagal input significantly modulates inspiratory and expiratory muscle activities, which help regulate EELV efficiently and optimize diaphragmatic length during eupneic breathing in the awake dog.

Afferent Pathways↗
PubMed1992

Vagal modulation of respiratory muscle activity in awake dogs during exercise and hypercapnia.

Using chronically instrumented awake tracheotomized dogs, we examined the contributions of vagal feedback to respiratory muscle activities, both electrical and mechanical, during normoxic hypercapnia (inspired CO2 fraction = 0.03, 0.04, 0.05, and 0.06) and during mild treadmill exercise (3, 4.3, and 6.4 km/h). Cooling exteriorized vagal loops eliminated both phasic and tonic mechanoreceptor input during either of these hyperpneas. At a given chemical or locomotor stimulus, vagal cooling caused a further increase in costal, crural, parasternal, and rib cage expiratory (triangularis sterni) muscles. No further change in abdominal expiratory muscle activity occurred secondary to vagal cooling during these hyperpneas. However, removal of mechanoreceptor input during hypercapnia was not associated with consistent changes in end-expiratory lung volume, as measured by the He-N2 rebreathe technique. We conclude that during these hyperpneas 1) vagal input is not essential for augmentation of expiratory muscle activity and 2) decrements in abdominal expiratory muscle activity may be offset by increments in rib cage expiratory muscle activity and contribute to the regulation of end-expiratory lung volume.

Afferent Pathways↗
PubMed1992

Oxygen cost of exercise hyperpnea: measurement.

To quantitate the O2 cost of maximal exercise hyperpnea, we required eight healthy adult subjects to mimic, at rest, the important mechanical components of submaximal and maximal exercise hyperpnea. Expired minute ventilation (VE), transpulmonary and transdiaphragmatic (Pdi) pressures, and end-expiratory lung volume (EELV) were measured during exercise at 70 and 100% of maximal O2 uptake. At rest, subjects were given visual feedback of their exercise transpulmonary pressure-tidal volume loop (WV), breathing frequency, and EELV, which they mimicked repeatedly for 5 min per trial over several trials, while hypocapnia was prevented. The change in total body O2 uptake (VO2) was measured and presumed to represent the O2 cost of the hyperpnea. In 61 mimicking trials with VE of 115-167 l/min and WV of 124-544 J/min, VE, WV, duty cycle of the breath, and expiratory gastric pressure (Pga) integrated with respect to time (integral of Pga.dt/min) were not different from those observed during maximum exercise. integral of Pdi.dt/min was 14% less and EELV was 6% greater during maximum exercise than during mimicking. The O2 cost measurements within a subject were reproducible over 3-12 trials (coefficient of variation +/- 10% range 5-16%). The O2 costs of hyperpnea correlated highly and positively with VE and WV and less, but significantly, with integral of Pdi.dt and integral of Pga.dt. The O2 cost of VE rose out of proportion to the increasing hyperpnea, so that between 70 and 100% of maximal VO2 delta VO2/delta VE increased 40-60% (1.8 +/- 0.2 to 2.9 +/- 0.1 ml O2/l VE) as VE doubled.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Oxygen cost of exercise hyperpnea: implications for performance.

We addressed two questions concerned with the metabolic cost and performance of respiratory muscles in healthy young subjects during exercise: 1) does exercise hyperpnea ever attain a "critical useful level"? and 2) is the work of breathing (WV) at maximum O2 uptake (VO2max) fatiguing to the respiratory muscles? During progressive exercise to maximum, we measured tidal expiratory flow-volume and transpulmonary pressure- (Ptp) volume loops. At rest, subjects mimicked their maximum and moderate exercise Ptp-volume loops, and we measured the O2 cost of the hyperpnea (VO2RM) and the length of time subjects could maintain reproduction of their maximum exercise loop. At maximum exercise, the O2 cost of ventilation (VE) averaged 10 +/- 0.7% of the VO2max. In subjects who used most of their maximum reserve for expiratory flow and for inspiratory muscle pressure development during maximum exercise, the VO2RM required 13-15% of VO2max. The O2 cost of increasing VE from one work rate to the next rose from 8% of the increase in total body VO2 (VO2T) during moderate exercise to 39 +/- 10% in the transition from heavy to maximum exercise; but in only one case of extreme hyperventilation, combined with a plateauing of the VO2T, did the increase in VO2RM equal the increase in VO2T. All subjects were able to voluntarily mimic maximum exercise WV for 3-10 times longer than the duration of the maximum exercise. We conclude that the O2 cost of exercise hyperpnea is a significant fraction of the total VO2max but is not sufficient to cause a critical level of "useful" hyperpnea to be achieved in healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise↗
PubMed1992

Mechanical constraints on exercise hyperpnea in endurance athletes.

We determined how close highly trained athletes [n = 8; maximal oxygen consumption (VO2max) = 73 +/- 1 ml.kg-1.min-1] came to their mechanical limits for generating expiratory airflow and inspiratory pleural pressure during maximal short-term exercise. Mechanical limits to expiratory flow were assessed at rest by measuring, over a range of lung volumes, the pleural pressures beyond which no further increases in flow rate are observed (Pmaxe). The capacity to generate inspiratory pressure (Pcapi) was also measured at rest over a range of lung volumes and flow rates. During progressive exercise, tidal pleural pressure-volume loops were measured and plotted relative to Pmaxe and Pcapi at the measured end-expiratory lung volume. During maximal exercise, expiratory flow limitation was reached over 27-76% of tidal volume, peak tidal inspiratory pressure reached an average of 89% of Pcapi, and end-inspiratory lung volume averaged 86% of total lung capacity. Mechanical limits to ventilation (VE) were generally reached coincident with the achievement of VO2max; the greater the ventilatory response, the greater was the degree of mechanical limitation. Mean arterial blood gases measured during maximal exercise showed a moderate hyperventilation (arterial PCO2 = 35.8 Torr, alveolar PO2 = 110 Torr), a widened alveolar-to-arterial gas pressure difference (32 Torr), and variable degrees of hypoxemia (arterial PO2 = 78 Torr, range 65-83 Torr). Increasing the stimulus to breathe during maximal exercise by inducing either hypercapnia (end-tidal PCO2 = 65 Torr) or hypoxemia (saturation = 75%) failed to increase VE, inspiratory pressure, or expiratory pressure. We conclude that during maximal exercise, highly trained individuals often reach the mechanical limits of the lung and respiratory muscle for producing alveolar ventilation. This level of ventilation is achieved at a considerable metabolic cost but with a mechanically optimal pattern of breathing and respiratory muscle recruitment and without sacrifice of a significant alveolar hyperventilation.

Adult↗
PubMed1992

Demand vs. capacity in the healthy pulmonary system.

This review examines the lung and chest wall adaptation to exercise in health in persons of widely varying degrees of fitness. First we examine the regulation of breathing and gas exchange in the sedentary young adult who shows a near perfect regulation of alveolar gases, ventilation to perfusion distribution, diffusion equilibrium in the lung during all levels of exercise. This individual's respiratory muscles are also ideally recruited both tonically and phasically so as to meet multi-faceted postural, locomotory and respiratory demands. The topic of plasticity in the pulmonary system is discussed with specific reference to the effects of physical training and athleticism. The key point made here is that both homeostasis of gas transport and mechanical efficiency, with which the pulmonary system meets the demands of muscular exercise will depend upon the ability to maintain a significant margin between demand vs. structural capacity. Pulmonary diffusion capacity and at least some aspects of respiratory muscle function seem to be "overbuilt" in the young untrained adult. This margin of safety no longer prevails as the athlete becomes fitter. The cause is to be found in the relative lack of adaptability of the lung and chest wall to the training stimulus. Examples of demand coming very close or exceeding the capacity of the pulmonary system include the highly trained young endurance athlete and the aged athlete. Examples of "failure" or near failure in the pulmonary system's response to exercise include: a) exercise induced arterial hypoxemia via diffusion limitation; b) diaphragmatic fatigue in endurance exercise; c) expiratory flow limitation at VO2max.; d) achieving the capacity of inspiratory muscles for pressure generation at VO2max. and e) oxygen cost of breathing which is in excess of 15% of VO2max. in those athletes who experience the most mechanical limitation.

Adaptation, Physiological↗
PubMed1991

Further characterization of PNK-E: a monoclonal antibody enhancing porcine natural killer cell activity.

Monoclonal antibody PNK-E binds to approximately 15% of porcine peripheral blood lymphocytes (PBL) which are PT4 negative and PT8 positive. When cells from tissues of adult pigs are treated with PNK-E, enhancement of natural killer (NK) cell activity is observed from PBL and spleen cells, and a dramatic induction of NK activity is observed from bone marrow cells. With cells derived from tissues of neonatal piglets, PNK-E induces NK activity from PBL and bone marrow cells. To investigate the mechanism of PNK-E-mediated enhancement of NK, proliferation assays, calcium-pulse assays, single-cell assays, and kinetic analyses were performed. PNK-E did not induce proliferation of PBL. PNK-E could be added as late as 30 min prior to termination of Ca(2+)-pulse assays and still enhance NK activity. Using kinetic analysis PNK-E was found to increase the rate of NK lysis (Vmax) and rate of lytic programming per NK cell (k2). In addition, results from single-cell assays indicate that PNK-E activates a population of normally inactive effector cells. These results indicate that PNK-E enhances the lytic capacity of mature NK cells and induces a population of nonlytic cells to become highly cytolytic cells. Furthermore, the enhancing effects are immediate and do not require an induction period. Thus, PNK-E recognizes and activates a unique triggering molecule that is present on NK cells.

Age Factors↗
PubMed1991

Flow limitation and regulation of functional residual capacity during exercise in a physically active aging population.

In 29 older (69 +/- 1 yr), physically active subjects (VO2max = 44 +/- 2 ml.kg-1.min-1), we determined the effect of an age-related decline in elastic lung recoil (i.e., Vmax50 = 65% of 30-yr-old adults) on the ventilatory response to progressive exercise. More specifically, we assessed if expiratory airflow limits were achieved and how this may modulate the regulation of end-expiratory lung volume (EELV). We found that with only mild to moderate (50 to 75% VO2max) exercise, the mean EELV was reduced 0.38 +/- 0.07 L, and that expiratory flow limitation was present over 25 +/- 4% of the VT. In 11 subjects during this intensity of exercise, EELV was within their closing capacity. As exercise intensity progressed, VT plateaued at 58 +/- 2% of the vital capacity, and increased expiratory air flow rates were achieved by significantly increasing the EELV back to near resting levels, thereby moving a portion of the expiratory tidal flow-volume envelope away from the constraints of the effort independent portion of the maximal flow-volume curve. During heavy exercise, end-inspiratory lung volume (EILV) approached 90% of TLC. To achieve greater expiratory flow with maximal exercise, EELV remained similar to the previous intensity, and a significantly greater portion of the tidal expiratory flow-volume envelope (greater than 40% of the VT) became flow-limited. Despite this significant expiratory limitation, a rise in EELV, and an EILV approaching TLC, TI/Ttot remained constant throughout exercise, and the ventilatory response for the metabolic demand (VA/VCO2) was appropriate.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Mechanical constraints on exercise hyperpnea in a fit aging population.

We studied 12 physically fit (VO2 max = 44 ml.kg-1.min-1) older subjects (age = 63 to 77 yr) who showed the usual age-related declines in lung function (i.e., reduced maximal expiratory flow rates, vital capacity and increased functional residual capacity, closing capacity, and residual volume). We measured the optimal transpulmonary pressures for maximal expiratory airflow and the capacity of the muscles of inspiration for developing pleural pressure (taking into account the effects of lung volume and flow rate). Within these mechanical constraints to ventilation we plotted tidal pleural pressure-volume loops for mild through maximal exercise according to a measured end-expiratory lung volume (EELV). We found EELV to decrease a mean of 0.26 +/- 0.09 L and maximal effective pleural pressures to be reached in nine subjects near EELV with only light to moderate exercise intensities, whereas peak inspiratory pressure was only 45% of the capacity for pressure generation. With progressive increases in exercise intensity, EELV increased, and pleural pressures encroached to a greater extent on the maximal effective pressures; however, they remained effective in the majority of subjects. During maximal exercise EELV was 0.13 +/- 0.10 L greater than resting values, 20% of the Vt reached maximal effective pressures, and 83% of the capacity for inspiratory pressure was achieved. Three subjects significantly surpassed their maximal effective expiratory pressures, and four subjects achieved 95 to 100% of the capacity for inspiratory pressure generation. These subjects also showed no further increase in ventilation while breathing 0.02 to 0.05 FICO2 at maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Humoral immune responses to Porphyromonas gingivalis before and following therapy in rapidly progressive periodontitis patients.

We have performed studies aimed at elucidating the nature of the humoral immune response in rapidly progressive periodontitis (RPP). We analyzed the sera of 36 periodontally normal subjects and 36 RPP patients for titers and avidities of IgG antibodies reactive with the antigens of Porphyromonas gingivalis using ELISA, prior to and following treatment. We used whole-cell sonicate, purified lipopolysaccharide (LPS), and total extractable protein as plate antigens. Twelve of the patients had antibody titers at least 2-fold greater than the median of the controls and were designated as seropositive. The remaining 24 patients had titers that did not exceed twice the median titer of the controls and were designated as seronegative. For both patient groups, antibody titers were highest when whole-cell antigen was used, intermediate for LPS, and lowest for the protein fraction. Following treatment, median titer for seropositive patients decreased from pretreatment values of 241.7 to 76.5, while median titer for seronegative patients increased from 39.5 to 80.1. Avidities of pretreatment sera from both patient groups for all 3 antigen preparations were lower than the median avidities of the control sera. Avidity significantly increased following treatment to levels greater than those for control sera in both patient groups. Thus, some young adults with severe periodontitis mount a humoral immune response and produce high levels of serum IgG antibodies reactive with antigens of P. gingivalis, while others do not. The antibodies produced are of relatively low avidity, and may therefore be relatively ineffective biologically. Therapy, which greatly reduces antigen load, appears to stimulate production of higher avidity IgG antibodies in both patient groups; in the seropositive group, low avidity antibodies appear to be replaced by antibodies of higher avidity. Both the purified LPS and protein fractions contain reactive antigen(s), although LPS binds more antibody. Our data are consistent with the idea that many RPP patients do not produce protective levels of biologically functional antibody during the course of their natural infection, but they may be stimulated to do so by treatment.

Adult↗
PubMed1990

Characterization of a monoclonal antibody enhancing porcine natural killer cell activity (PNK-E).

A monoclonal antibody, termed PNK-E, that functionally enhances porcine natural killer (NK) cell activity but not antibody-dependent cellular cytotoxicity (ADCC) is investigated in this report. When PNK-E and K562 target cells were simultaneously added to effector cells, killing of target cells could be detected as early as 30 min, and a dramatic enhancement of killing activity was observed in short term 51Cr-release assays. When a panel of five NK-sensitive targets were tested, PNK-E enhanced the killing of K562, MOLT-4, and U937 cells, but not the killing of CEM and YAC-1. F(ab)'2 fragments of PNK-E did not enhance NK activity, indicating a requirement for the Fc portion of PNK-E to elicit enhancement of NK. Immunofluorescence analysis shows that PNK-E antigen is expressed on approximately 15% of peripheral blood lymphocytes with a relatively dull fluorescence staining pattern. PNK-E-positive sorted cells were enriched for large granular lymphocytes (LGL) and contained all detectable NK activity as compared to the PNK-E-negative sorted cells. When analyzed by polyacrylamide gel electrophoresis, PNK-E antibody immunoprecipitated a protein from 125I-labeled peripheral blood lymphocyte (PBL) cell lysates that resolved as a single band of approximately 205 kDa under nonreducing conditions and as two bands of approximately 50 kDa and 47 kDa under reducing conditions. The present data demonstrate a functional association between PNK-E antigen and NK cell activation.

Animals↗
PubMed1990

Cranial electrostimulation (CES) use in the detoxification of opiate-dependent patients.

This paper reviews the scientific literature on cranial electrostimulation (CES) as a non-chemical means to alleviate opiate withdrawal symptoms. CES involves applying small amounts of electrical stimulation through electrodes applied to the skin surface over the cranium. The paper summarizes major theories (gate, endorphin, and Chinese acupuncture) which attempt to explain how CES may help alleviate drug withdrawal and craving. Two of the studies reviewed show that CES patients experienced more severe withdrawal during the early part of treatment than comparison groups of methadone patients. Other studies show that CES patients did better than methadone patients. The findings from all studies reviewed, however, were limited because of low participation rates, high dropout rates, difficulties in blinding subjects and evaluators, and the absence of standardized procedures and equipment. The evidence reviewed suggests that CES is a promising line of inquiry for continued efforts to develop nonchemical ways to detoxify opiate-dependent individuals. Improved research designs, larger sample sizes, more integrity in data collection, and improved data analysis are needed in the future.

Acupuncture Therapy↗
PubMed1990

Effect of cell donor age on the synthetic properties of fibroblasts obtained from phenytoin-induced gingival hyperplasia.

Diploid fibroblasts obtained from explants of human gingiva and maintained in vitro undergo a several-fold decrease in protein and collagen synthesis as a function of increasing donor age. Using drug-induced gingival hyperplasia as a model, we performed experiments to learn whether fibroblasts derived from hyperplastic tissue behave in a similar manner. Fibroblast strains were established from explants of hyperplastic gingiva obtained from 10 patients chronically ingesting phenytoin and ranging in age from 9 to 45 years. Protein production and degradation were compared to previously reported data similarly obtained from periodontally normal donors ranging in age from 12 to 68 yr. The total quantity of protein and collagen produced by the phenytoin cells was significantly greater than previously reported for cells from normal gingiva. No donor age-related decrease in protein and collagen production nor in the proportion of cell synthetic activity committed to collagen production was observed for cultures of phenytoin cells. The gross pattern of proteins produced, as assessed by 2-dimensional gel electrophoresis, was unrelated to donor age in both normal and phenytoin cells, but three polypeptides ranging in size from about 20 kD to 40 kD that were not found in the cultures of normal cells were produced by five of seven phenytoin cells strains. The observations demonstrate that the phenytoin cells do not undergo the donor age-dependent decrease in synthesis observed for normal cells. This abnormality may account in part for the phenytoin-induced hyperplasia. The phenytoin cells appear to be a unique phenotype.

Adolescent↗