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Biomedical subjects

B J Nelson

Publications and source records attributed to B J Nelson.

At least 37 records · Page 2Linked to original sources
PubMed1996

A phase I safety and pharmacokinetic study of a recombinant amino terminal fragment of bactericidal/permeability-increasing protein in healthy male volunteers.

A phase I pharmacokinetic and safety clinical trial of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein, was conducted in healthy male volunteers. rBPI23 was administered as a 5 or 30 min infusion at doses of .1 to 1 mg/kg. The pharmacokinetics of rBPI23 in human subjects were described by a bi-exponential disposition function with evidence of concentration-dependent kinetics. The alpha half-life increased significantly with increasing dose, from 4-5 min at .1 mg/kg to 7-8 min at 1 mg/kg. The beta half-life varied between 18 and 29 min regardless of dose and the clearance varied from 5 to 10 mL/min/kg. Very little, if any, of the administered rBPI23 was excreted intact in the urine. Electrocardiograms, ionized calcium concentration, prothrombin and partial prothrombin times, hematologic parameters, and blood chemistries remained normal. Furthermore, no antibody response to rBPI23 was observed in any of the subjects.

Adolescent↗
PubMed1996

Improving drug use in rheumatic disorders.

A recent study concluded that approximately 50 elderly people are admitted to the major teaching hospital in Tasmania, Australia each year suffering from gastrointestinal bleeding related to the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to examine whether academic detailing, designed to encourage a rational approach to the prescribing of NSAIDs and performed by a pharmacist; could modify prescribing practices in the community. The intervention was conducted in Southern Tasmania, using the north of the state as a control area. The target group of all general practitioners (approximately 250) working in Southern Tasmania was sent educational material designed to assist in the appropriate prescribing of NSAIDs. A pharmacist then visited each general practitioner and discussed the rational use of NSAIDs directly with them. The outcome of the programme was measured using evaluation feedback from the general practitioners and pharmacoepidemiological data provided by (i) a state-wide pharmacoepidemiology database derived from community pharmacy records, and (ii) dispensing under the Pharmaceutical Benefits and Repatriation Pharmaceutical Benefits Schemes. The key variable examined was the defined daily dose (DDD) dispensed for the NSAIDs compared with paracetamol. The educational programme was very well received by the general practitioners. Changes in the prescribing of NSAIDs were evident in both study regions, but were more marked in the intervention area. For instance, the state-wide pharmacoepidemiological database indicated that the ratio of dispensed DDDs of NSAIDs: paracetamol declined from 3.00 to 2.59 in the intervention region and remained steadier (3.16 to 2.92) in the north of the state. The improvement was significantly greater in the intervention region. This study has revealed that an educational programme utilizing academic detailing by pharmacists can modify prescribing practices within the community setting.

Acetaminophen↗
PubMed1995

Inhibition of endotoxin-induced activation of the coagulation and fibrinolytic pathways using a recombinant endotoxin-binding protein (rBPI23).

A recombinant endotoxin-neutralizing protein, rBPI23, was shown to partially prevent endotoxin-induced activation of the fibrinolytic and coagulation systems in experimental endotoxemia in humans. In a placebo-controlled, blinded crossover study, eight volunteers were challenged twice with an intravenous bolus injection of endotoxin (40 EU/kg of body weight) and concurrently received either rBPI23 (1 mg/kg) or placebo (human serum albumin, 0.2 mg/kg). rBPI23 treatment significantly lowered the endotoxin-induced fibrinolytic response, ie, reduced the release of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor antigen, and complex formation of plasmin alpha 2-antiplasmin (P = .0078 for each). Plasminogen activator inhibitor activity was also reduced, but not significantly according to the Hochberg method (P = .0304). The endotoxin-induced activation of the procoagulant state as reflected by increase in F1 + 2 fragments and TAT complexes was blunted by rBPI23 infusion (P = .0391 [not significant according to the Hochberg method] and .0078, respectively). These results indicate that rBPI23 is capable of reducing both the activation of the fibrinolytic and the coagulation systems after low-dose endotoxin infusion in humans.

Anticoagulants↗
PubMed1995

Inhibition of endotoxin-induced cytokine release and neutrophil activation in humans by use of recombinant bactericidal/permeability-increasing protein.

To investigate the effects of a recombinant endotoxin-binding protein, bactericidal/permeability-increasing protein (rBPI23), on cytokine release and neutrophil activation in endotoxemia in humans, 8 volunteers were challenged twice with endotoxin and concurrently received either rBPI23 or placebo in a randomized, placebo controlled, double-blind crossover study, rBPI23 treatment significantly lowered circulating endotoxin levels (P = .02) and resulted in a significant reduction in the release of tumor necrosis factor (TNF), soluble TNF receptors p55 and p75, interleukin (IL)-6, IL-8 (P < .01 for each), and IL-10 levels (P = .02) but did not prevent the endotoxin-induced rise in body temperature. The early endotoxin-induced leukopenia was blunted (P = .08), and neutrophil degranulation, as measured by circulating levels of elastase/alpha 1-antitrypsin complexes (P = .03) and lactoferrin (P < .01), was largely prevented by rBPI23. The results of this study indicate that rBPI23 is capable of neutralizing many of the biologic effects of endotoxin in humans.

Antimicrobial Cationic Peptides↗
PubMed1995

Plasma bactericidal/permeability-increasing protein concentrations in critically ill children with the sepsis syndrome.

Bactericidal/permeability-increasing protein (BPI) is a neutrophil azurophilic granule component that is bactericidal towards Gram-negative bacteria and inhibits lipopolysaccharide-mediated inflammatory responses. We conducted a prospective study to measure plasma BPI concentrations in 36 critically ill children with and without the sepsis syndrome. Plasma BPI concentrations ranged from 0.5 to 452 ng/ml. Patients with the sepsis syndrome had higher median plasma BPI concentrations than critically ill controls (5.1 vs. 1.8 ng/ml, P = 0.006). Patients with organ system failure had higher median plasma BPI concentrations than those with no organ system failure (4.5 vs. 1.3 ng/ml, P = 0.001). Plasma BPI concentrations were positively associated with pediatric risk of mortality score (P = 0.03, rs = 0.4). These data provide the first clinical insights regarding the role of endogenous BPI production in critically ill children and suggest that BPI may play an important role in host defenses.

Anti-Bacterial Agents↗
PubMed1994

Interleukin-2 suppresses activated macrophage intracellular killing activity by inducing macrophages to secrete TGF-beta.

Phorbol myristate acetate (PMA) treatment of an EL-4 thymoma cell line (EL-4FARRAR) induced secretion of a factor that inhibited intracellular killing of Leishmania major amastigotes by activated macrophages. Analysis of the cytokines produced by EL-4 cells after PMA stimulation identified interleukin-2 (IL-2, 2500 U/ml), IL-4 (1280 U/ml), interferon-gamma (IFN-gamma; 100 U/ml), and granulocyte-macrophage colony-stimulating factor (GM-CSF; 50 U/ml). Neither tumor necrosis factor nor transforming growth factor beta (TGF-beta) was detected. Each of the cytokines present in EL-4 fluids was assessed for capacity to activate macrophages for destruction of parasites or to suppress intracellular killing. IFN-gamma and GM-CSF both activated macrophages to kill Leishmania; IL-2 and IL-4 had no activity for induction of this antimicrobial effector function. IL-2 and IL-4 were tested for their capacity to inhibit lymphokine- or IFN-gamma-induced destruction of L. major by macrophages: IL-4 was ineffective, but IL-2 markedly suppressed the activation of macrophages for intracellular killing. Addition of > or = 10 U/ml of IL-2 at the time of infection, or up to 4 h before, blocked up to 100% of the capacity of activated macrophages to kill intracellular amastigotes. Immunoaffinity treatment of EL-4 fluids with anti-IL-2 antibody resulted in > 80% reduction in suppression of intracellular killing. The suppressive effects of IL-2 were not direct, but mediated by TGF-beta. IL-2 induced resident peritoneal macrophages to secrete > 5000 pg/ml TGF-beta 1, a quantity that is > 500-fold higher than constitutive background levels (20-40 pg/ml) and is sufficient to block intracellular killing activities. This increase in secretion of TGF-beta was not dependent increases in TGF-beta 1 mRNA. Treatment of cultures with EL-4 fluids or recombinant IL-2 in the presence of antibody to TGF-beta 1 blocked the suppressive activity of both. Thus, IL-2 was the major suppressor factor in EL-4 fluids, and it acted indirectly through the induction and autocrine action of TGF-beta.

Animals↗
PubMed1994

Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens.

To discover how nitric oxide (NO) synthesis is controlled in different tissues as cells within these tissues combat intracellular pathogens, we examined three distinctively different experimental murine models designed for studying parasite-host interactions: macrophage killing of Leishmania major; nonspecific protection against tularemia (Francisella tularensis) by Mycobacterium bovis (BCG); and specific vaccine-induced protection against hepatic malaria with Plasmodium berghei. Each model parasite and host system provides information on the source and role of NO during infection and the factors that induce or inhibit its production. The in vitro assay for macrophage antimicrobial activity against L. major identified cytokines involved in regulating NO-mediated killing of this intracellular protozoan. L. major induced the production of two competing cytokines in infected macrophages: (1) the parasite activated the gene for tumor necrosis factor (TNF), and production of TNF protein was enhanced by the presence of interferon-gamma (IFN-gamma). TNF then acted as a autocrine signal to amplify IFN-gamma-induced production of NO; and (2) the parasite upregulated production of transforming growth factor-beta (TGF-beta), which blocked IFN-gamma-induced production of NO. Whether parasite-induced TNF (parasite destruction) or TGF-beta (parasite survival) prevailed depended upon the presence and quantity of IFN-gamma at the time of infection. The relationship between NO production in vivo and host resistance to infection was demonstrated with M. bovis (BCG).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1993

Comparison of two dentifrices in the control of chlorhexidine-induced stain.

An eight-week, double-blind, parallel and unsupervised clinical study was conducted to compare the ability of two dentifrices, Arm & Hammer Dental Care toothpaste and Crest toothpaste, to prevent the formation of stain induced by the twice daily use of 0.12% chlorhexidine gluconate (Peridex). Stain formation was evaluated through the use of a new index (Modified Stain Index) designed to selectively detect stain of the proximal and facial surfaces of the anterior teeth. Examinations of stain formation were conducted at two-week intervals for a total of eight weeks. The results indicated equivalent stain prevention benefits for Arm & Hammer Dental Care and Crest when evaluated during eight weeks of chlorhexidine therapy. The modified stain index was shown to be valuable for discriminating location and intensity of early stain formation.

Adult↗
PubMed1992

The motivational benefits of a dentifrice containing baking soda and hydrogen peroxide.

Twenty-two family practice dentists, in a large metropolitan area, were recruited to act as independent examiners in a study to evaluate the compliance of their patients to accept a good oral hygiene regimen with the use of a fluoride dentifrice, containing hydrogen peroxide and baking soda, dispensed from a dual dispensing package. To evaluate compliance, the dentists attended an orientation seminar and were trained to assess gingival health using the CPITN periodontal probe. Each dentist evaluated the gingival health status of five to seven of his own patients, initially and after one and three months of product use following hygiene instruction and product assignment. One-hundred and thirty-one patients successfully completed the study. After one month of using the hydrogen peroxide/baking soda toothpaste, the mean reduction in bleeding sites was 53%; at three months the reduction was 62%. The hydrogen peroxide/baking soda dentifrice was well accepted by dentist and patient, and a discernible improvement in oral health of the patients was achieved when the product was used in a conscientious oral hygiene program.

Adult↗
PubMed1991

Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1.

We examined the effects of TGF-beta 1 on induction of several activated macrophage antimicrobial activities against the protozoan parasite Leishmania, and on induction of tumoricidal activity against the fibrosarcoma tumor target 1023. TGF-beta by itself did not affect the viability of either the intracellular or extracellular target in concentrations up to 200 ng/ml. As little as 1 ng/ml TGF-beta, however, suppressed more than 70% of the intracellular killing activity of macrophages treated with lymphokines. In contrast, more than 100 ng/ml TGF-beta was required to suppress intracellular killing by cells activated with an equivalent amount of recombinant IFN-gamma. Addition of TGF-beta for up to 30 min after exposure to activation factors significantly reduced macrophage killing of intracellular parasites. Pretreatment of macrophages with TGF-beta was even more effective: treatment of cells with TGF-beta for 4 h before addition of activation factors abolished all macrophage intracellular killing activity. Regardless of treatment sequence, however, TGF-beta had absolutely no effect, at any concentration tested, on activated macrophage resistance to infection induced by lymphokines or by the cooperative interaction of IFN-gamma and IL-4. Effects of TGF-beta on tumoricidal activity of activated macrophages was intermediate to that of its effects on intracellular killing or resistance to infection. Lymphokine-induced tumor cytotoxicity was marginally (25%) affected by TGF-beta; 200 ng/ml was able to suppress IFN-gamma-induced tumoricidal activity by 40%. Thus, TGF-beta dramatically suppressed certain activated macrophage cytotoxic effector reactions, but was only partially or not at all effective against others, even when the same activation agent (IFN-gamma) was used. The biochemical target for TGF-beta suppressive activity in these reactions may be the pathway for nitric oxide production from L-arginine, because TGF-beta also inhibited the generation of nitric oxide by cytokine-activated macrophages.

Animals↗
PubMed1991

Heterogeneity of changes in lymphoproliferative ability with increasing age.

Although mean mitogen-induced lymphoproliferation decreases with increased age, the response of individual subjects demonstrates great heterogeneity. Results of this study clearly illustrate that individual variation is apparent not only in the level of proliferation, but also in the amount of interleukin-2 (IL-2) detectable after mitogen stimulation. Further, addition of exogenous IL-2 significantly increases proliferation in only about one third of elderly subjects. Data from inbred strains of rats housed under identical environmental conditions indicate that although genetic factors greatly influence both the level of proliferation and the rate of decline with age, variation occurs even within one inbred strain of rat.

Adult↗
PubMed1989

Comparative study of glutamate decarboxylase immunoreactive boutons in the mammalian inferior olive.

An antiserum raised against rat glutamate decarboxylase was used to map GABAergic boutons in the inferior olive of rabbit, cat, rhesus monkey, and human. A description of the human periolivary region is also included. The inferior olive of each species contained a dense GABAergic innervation, but immunostaining intensities varied among regions. These intensities were evaluated visually and photometrically, and the sizes and frequencies of occurrence of boutons in various olivary subnuclei were measured. The beta nucleus in all species was intensely immunostained and contained the largest boutons. The caudal subdivision of the dorsal accessory olive stained with a lower intensity than the beta nucleus, but contained similarly large GABAergic boutons. By visual analysis, the rostral subdivision and the subnucleus a of the medial accessory olive and the principal olive were stained with an intermediate intensity, and these regions contained small GABAergic boutons. Photometric analysis of focal regions of the neuropil, however, revealed species differences in teh staining intensity of the principal olive, which was lowest in rabbits and highest in primates. In all species, the lowest immunostaining intensity was observed in the subnucleus b of the medial accessory olive. Species variations in bouton sizes and regional staining intensities were observed in the dorsal cap and the dorsomedial cell column. The heterogeneous staining pattern and regional variation of bouton size argue for the existence of separate GABAergic projections to discrete regions of the inferior olive. Since glutamate decarboxylase immunostaining patterns in the olive are largely similar across species, the afferent projections producing these patterns may also be similar.

Adolescent↗
PubMed1988

The rat inferior olive as seen with immunostaining for glutamate decarboxylase.

Boutons presumed to use gamma-aminobutyric acid as neurotransmitter (GABAergic boutons) were detected by glutamate decarboxylase (GAD) immunocytochemistry in all regions of the rat inferior olive. The remarkably high concentration of these boutons allowed a clear visualization of olivary subnuclei boundaries. Regional variations in GAD immunostaining intensity were observed within the nuclear complex and were graded both visually and photometrically. The regional staining variations, for the most part, followed subnuclei boundaries and olivary zonal compartments that have been delineated by the topography of climbing fibre projections. Some subnuclei were grouped by similar staining intensities. The beta nucleus and a medial region in the ventral fold of the dorsal accessory olive were most intensely immunostained, followed by the subnucleus c of the medial accessory olive. Lower staining intensities were observed in the dorsomedial cell column, the dorsal fold of the dorsal accessory olive and the dorsal cap. The lowest intensities were observed in the subnuclei a and b of the medial accessory olive, the ventrolateral outgrowth, the rostral lamella of the medial accessory olive, the principal olive, and the lateral part of the ventral fold of the dorsal accessory olive. The factors contributing to the variations in immunostaining intensity (bouton size and frequency of occurrence) were investigated. The largest boutons were observed in the beta nucleus. Intermediate sized boutons were observed in the dorsomedial cell column, dorsal cap and the dorsal fold of the dorsal accessory olive. The smallest boutons were present in the remaining regions of the inferior olive, including the principal olive, the rostral lamella of the medial accessory olive, and the ventral fold of the dorsal accessory olive. The medial region of the dorsal accessory olive ventral fold contained a higher density of GABAergic boutons than other regions. GABAergic bouton size and innervation density therefore largely accounted for the variations in GAD immunostaining intensity. This study provides a map of the rat inferior olive based on the distribution of GABAergic nerve terminals, and may serve as a basis for characterizing different GABAergic afferent systems in the inferior olive.

Animals↗
PubMed1987

Influence of long-term optokinetic stimulation on eye movements of the rabbit.

Two kinds of optokinetic afternystagmus (OKAN) have been studied in rabbits; positive and negative OKAN. Positive OKAN is the persistence of eye movements evoked by optokinetic stimulation following the termination of the stimulus, with the slow phase of the eye movements in the same direction as the inducing stimulus. Negative OKAN is evoked by long duration optokinetic stimulation, and has a slow phase of opposite direction to the inducing stimulus. The stimulus conditions which are optimal for inducing and maintaining negative OKAN were characterized. Rabbits were placed in an optokinetic drum for periods of 12-96 h (with appropriate intervening periods for food and water). Eye movements were recorded during and after the termination of optokinetic stimulation. The optimum optokinetic stimulus velocity for the induction of negative OKAN was 5 degrees/s. The minimum duration of stimulation for the induction of negative OKAN of maximum velocity was 48 h. Once induced, the slow phase of negative OKAN attained velocities of 50-100 degrees/s. Three conditions of restraint of the rabbits were studied after negative OKAN was induced during the intervening periods when eye movements were not being recorded. These conditions were: (1) unrestrained (full freedom of movement) without visual stimulation (in a dark enclosure); (2) restrained (horizontal head and body movement prevented) without visual stimulation; and (3) restrained with visual stimulation (in the stationary optokinetic drum). Conditions 1 and 2 caused negative OKAN to dissipate within 24 h. Condition 3 caused negative OKAN to be maintained for more than 70 h. The velocity imbalance of the horizontal vestibuloocular reflex (HVOR) was measured at different times following the induction of negative OKAN. It provided a more sensitive index of the central imbalance which caused negative OKAN, than did spontaneous nystagmus. One of the consequences of optokinetic stimulation measured over a 16 h period was a decrease in the gain of the optokinetic reflex. This reduction in gain could represent a central adaptation to maintained stimulation which in the absence of continued optokinetic stimulation is expressed as a nystagmus.

Adaptation, Physiological↗