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Biomedical subjects

W D Biggar

Publications and source records attributed to W D Biggar.

At least 19 recordsLinked to original sources
PubMed1988

Metabolism of dapsone to a hydroxylamine by human neutrophils and mononuclear cells.

Dapsone is an effective anti-inflammatory agent in conditions in which inflammation is mediated by neutrophils. Dapsone also has been associated with agranulocytosis. We found that neutrophils, which had been activated by a phorbol ester or opsonized zymosan, oxidized dapsone to its nitroderivative. It appears as if this is due to oxidation of dapsone by myeloperoxidase to the hydroxylamine, followed by nonenzymatic oxidation of the hydroxylamine to the nitroderivative. The hydroxylamine can be isolated if ascorbic acid is added to the incubations. Monocytes also contain myeloperoxidase and activated mononuclear leukocytes also metabolize dapsone to the hydroxylamine. Dapsone also causes a mononucleosis-like syndrome. The reactive hydroxylamine could be responsible for both the pharmacologic and toxic properties of dapsone.

Anti-Inflammatory Agents↗
PubMed1987

The influence of hypothermia on the disposition of fentanyl--human and animal studies.

The effect of hypothermia on the disposition of fentanyl was evaluated in 18 children undergoing corrective cardiac surgery. They received a bolus of fentanyl followed by a continuous infusion which was stopped when cardiopulmonary bypass was established and profound hypothermia was achieved (18 degrees C-25 degrees C). Fentanyl plasma concentration remained essentially unchanged during hypothermia (6.45 ng/ml 5 min into hypothermia and 5.26 ng/ml 100-140 min later; p greater than 0.1). In subsequent experiments, the effect of hypothermia on the pharmacokinetics of fentanyl was studied in 4 piglets serving as their own controls. Both distribution volume (Vz) and total body clearance (CL) were significantly smaller during hypothermia. Our studies indicate that being a drug with a large distribution volume and a high hepatic extraction ratio, both CL and Vz are significantly reduced by hypothermia-induced hypoperfusion. In addition, TBC is influenced by the temperature-dependent hepatic metabolism of fentanyl.

Adolescent↗
PubMed1986

Cytoplasmic pH regulation in normal and abnormal neutrophils. Role of superoxide generation and Na+/H+ exchange.

The cytoplasmic pH of human neutrophils was determined fluorometrically using carboxylated fluorescein derivatives. When normal neutrophils were activated by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) in Na+-containing medium, the cytoplasmic pH initially decreased but then returned to near normal values. In Na+-free media or in Na+ medium containing amiloride, TPA induced a marked monophasic intracellular acidification. The cytoplasmic acidification is associated with net H+ equivalent efflux, suggesting metabolic acid generation. The metabolic pathways responsible for the acidification were investigated by comparing normal to chronic granulomatous disease neutrophils. These cells are unable to oxidize NADPH and generate superoxide. When treated with TPA in Na+-free or amiloride-containing media, chronic granulomatous disease cells did not display a cytoplasmic acidification. This suggests that in normal cells NADPH oxidation and/or the accompanying activation of the hexose monophosphate shunt are linked to the acidification. Unlike normal neutrophils, chronic granulomatous disease cells treated with TPA in Na+-containing medium displayed a significant cytoplasmic alkalinization. The alkalinization was Na+-dependent and amiloride-sensitive, indicating activation of Na+/H+ exchange. Thus, the Na+/H+ antiport, which can be indirectly stimulated by the metabolic cytoplasmic acidification, is also directly activated by the phorbol ester.

Amiloride↗
PubMed1986

Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning.

We retrospectively evaluated the clinical and pathologic effects of hypothermia and high-dose barbiturate therapy on hypoxic/ischemic cerebral injury after near-drowning in children. Of 40 near-drowned patients admitted to the ICU, 13 died, seven had permanent cerebral damage, and 20 survived. Twenty-four patients (group 1) were treated with a regime of hyperventilation, hypothermia, and high-dose phenobarbitone while intracranial pressure (ICP) was continuously monitored. Of ten who died in this group, three were diagnosed as having cerebral death shortly after admission; autopsy revealed severe cerebral edema with herniation. The remaining seven nonsurvivors had severe cerebral hypoxia without raised ICP and had the features of severe adult respiratory distress syndrome and hypoxic/ischemic damage to other organs. Six of these seven patients developed septicemia which was invariably associated with a profound neutropenia. Sixteen patients (group 2) were treated with a similar protocol but without hypothermia. Three of these patients died but only one developed septicemia. Neutropenia after resuscitation from near-drowning seemed to indicate a poor prognosis; the mean polymorphonuclear leukocyte count in nonsurvivors (1.9 +/- 0.5 X 10(9) cell/L) was significantly (p less than .01) lower than that in survivors (6.4 +/- 1.1 X 10(9) cell/L). Hypothermia was associated with a decreased number of circulating PMNs but did not increase the number of neurologically intact survivors. Similarly, although barbiturates may control ICP, their use did not improve outcome. Because severe cerebral edema and herniation after near-drowning is usually associated with irreversible brain damage, measures to control brain swelling such as hypothermia and barbiturates will be of little benefit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Partial recovery of neutrophil functions during prolonged hypothermia in pigs.

The changes in circulation and migration of mature and immature neutrophils during 12 h of hypothermia have been studied using an experimental pig model. At 29 degrees C the number of circulating neutrophils fell from 5 +/- 1.1 at 37 degrees C to 3.5 +/- 0.6 X 10(9)/l and then remained unchanged while hypothermia was maintained. The number of circulating immature neutrophils did not fall during hypothermia. During hypothermia, hydrocortisone failed to stimulate the release of mature and immature neutrophils from the bone marrow. In contrast, endotoxin caused a profound neutropenia followed by a gradual increase in the number of circulating mature neutrophils, which by 6 h, was similar to the number circulating before endotoxin administration. At 29 degrees C the number of circulating immature neutrophils also fell following endotoxin but then increased over the number circulating before endotoxin administration by approximately 10-fold. Compared with neutrophil migration at 37 degrees C, very few mature or immature neutrophils migrated to an inflammatory site during the 12 h of hypothermia (29 degrees C). Unlike hypothermia in vitro, where neutrophil function may improve with time in vivo, neutrophil function remains compromised.

Animals↗
PubMed1986

Migration in vitro by blood and exudate neutrophils assessed serially during an inflammatory response.

Migration in vitro by blood and inflammatory neutrophils has been compared serially during an inflammatory response. Using an experimental pig model, neutrophils are isolated from the peripheral blood and from the pleural space at hourly intervals after an intrapleural challenge with zymosan activated pig serum (ZAS). Following acepromazine sedation and halothane anesthesia, blood neutrophil migration was transiently reduced. By 1 hour random and directed migration of blood neutrophils returned to normal. Directed and random migration of exudate neutrophils was markedly decreased to both a stimulus-specific (ZAS) and an unrelated (LTB4) chemoattractant. After 3 hours, migration by exudate neutrophils was similar to migration by blood neutrophils examined in parallel. These findings emphasize the importance of performing serial evaluations of cell function during an inflammatory response.

Animals↗
PubMed1986

Sequelae of acute bacterial meningitis in children treated for seven days.

The sequelae of acute bacterial meningitis in children who were treated with ampicillin or chloramphenicol for seven days during the period January 1979 to June 1983 were assessed prospectively. The 235 patients (117 boys and 118 girls) ranged in age from four days to 18 years (mean 26.4 months). Haemophilus influenzae type b was isolated in 70% of patients, Streptococcus pneumoniae in 20%, and Neisseria meningitidis in 10%. The mortality rate was 6.4%. No relapses occurred. Of the 220 survivors, 171 had neurologic psychometric, audiologic, and ophthalmologic assessments performed for a minimum of 1 year following their illness. One hundred thirty-six (80%) children had no detectable sequelae; 20% had mild to severe handicaps. The frequency of sequelae was greatest among children with S pneumoniae meningitis (57%) and least among children with N meningitidis (0%). The sequelae observed included: sensorineural hearing loss (12.9%), developmental delay (5.3%), speech defect (4.7%), motor defect (3.0%), hydrocephalus (1.7%), and seizure disorder (1%). The frequency of observed sequelae among these patients is similar to that previously reported in children treated for ten to 14 days. Our findings indicate that seven days of intravenous antibiotic therapy is adequate for the treatment of bacterial meningitis in children.

Adolescent↗
PubMed1985

The effects of hypothermia on neutrophil function in vitro.

Hypothermia may be associated with compromised host defenses and serious bacterial infections in man. We have examined the effects of moderate hypothermia (29 degrees C) on neutrophil function in vitro. At 29 degrees C, neutrophil phagocytosis of Staphylococcus aureus was impaired. In contrast, neutrophil killing of Streptococcus faecalis was most affected by hypothermia. Phagocytosis, as measured by neutrophil ingestion of opsonized oil-red-O-particles, was reduced at 29 degrees C over the 15 min of observation. Neutrophil metabolism linked to bactericidal pathways dependent on oxidative metabolism was reduced at 29 degrees C. Hexose monophosphate pathway (HMP) activity in neutrophils early after stimulation with latex particles was reduced. After 2 hr HMP activity was similar at 29 degrees C and 37 degrees C. Neotetrazolium dye reduction was reduced early after latex stimulation of neutrophils and after 30 min it was similar to cells at 37 degrees C. Leukocyte migration under agarose to bacterial-derived and formyl-methionyl-phenylalanine chemotactic factors was reduced by 50% and 70%, respectively. Migration to serum-derived chemotactic factor was reduced by only 20%. When cells were cooled to 29 degrees C for 30 to 90 min and rewarmed, neutrophil function was normal. These effects of hypothermia on neutrophil function may explain, in part, the increased incidence of serious and frequently fatal bacterial infections in man.

Chemotaxis, Leukocyte↗
PubMed1985

Influence of hypothermia on the pharmacokinetics of gentamicin and theophylline in piglets.

The influence of hypothermia on gentamicin and theophylline pharmacokinetics was studied in anesthetized pigs given an iv bolus of gentamicin and theophylline during normothermia (37 degrees C) and again 1 wk later after the induction of controlled hypothermia (29 degrees C). During hypothermia, the elimination half-time for gentamicin was significantly prolonged (135 +/- 19 min at 37 degrees C vs. 187 +/- 7 min at 29 degrees C), and there were significant decreases in the volume of the central compartment (Vc) of gentamicin, the gentamicin volume of distribution (Vd), and the gentamicin total body clearance (TBC). Hypothermia was associated with a small but significant decrease in theophylline Vd and Vc, but no change in TBC. In separate experiments, cardiac output decreased during the induction of hypothermia in a temperature-dependent fashion. The changes in gentamicin Vd and TBC may be explained by the decrease in cardiac output and the associated decrease in glomerular filtration rate. This study suggests that the elimination of theophylline, which has a relatively low hepatic extraction ratio, is not influenced by the hypothermia-induced decrease in liver blood flow.

Animals↗
PubMed1985

Susceptibility of human and porcine neutrophils to hypothermia in vitro.

Hypothermia may contribute to serious life-threatening infections. An experimental model has been established in pigs in order to study the effects of hypothermia on host bacterial defenses. The function of blood neutrophils from pigs and humans was examined in vitro at 37 and 29 degrees C. Bacterial killing of Staphylococcus aureus 502A by human neutrophils after 90 and 180 min incubation at 29 degrees C was reduced to 76 +/- 6% and 83 +/- 7% of killing at 37 degrees C. Porcine neutrophil killing was similarly reduced at 90 min (72 +/- 9%) and remained significantly impaired after 180 min (52 +/- 11%). Phagocytosis of ORO-DP-LPS particles by human neutrophils after 5 min at 29 degrees C was 40 +/- 5% of that at 37 degrees C and only 55 +/- 7% after 15 min by which time maximum phagocytosis had occurred at 37 degrees C. Porcine neutrophils ingested significantly less ORO (68 +/- 8%) after 5 min at 29 degrees C and reached normal values by 15 min. Stimulation of hexose monophosphate pathway in human neutrophils for 20 min at 29 degrees C was only 13 +/- 5% of that at 37 degrees C and required 2 h of stimulation to reach normal values. Porcine cells were reduced to 74 +/- 9% after 20 min incubation and reached normal values by 30 min. Directed neutrophil migration as assessed under agarose was impaired for both human (39 +/- 6%) and porcine (20 +/- 4%) neutrophils at 29 degrees C compared to 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

An experimental model to study blood and inflammatory neutrophils.

We sought to develop an experimental animal model in order to study the effects of hypothermia on host defences under conditions which were similar to those used for humans. We required a large animal which could tolerate arterial and venous catheters and serial blood sampling without significantly altering its blood volume and blood pressure. The animal should be intubated and ventilated to control blood gases and fluid and electrolyte balance. Finally the model should have anatomic, metabolic and physiologic similarities to humans. We describe an experimental pig model which appears to fulfill these criteria and provide important information relevant to man.

Animals↗
PubMed1985

Malakoplakia and immunosuppressive therapy. Reversal of clinical and leukocyte abnormalities after withdrawal of prednisone and azathioprine.

Malakoplakia is a chronic granulomatous inflammatory disorder. It is suspected clinically by the presence of chronic infection and diagnosed by histologic examination of affected tissues. Studies of 4 patients with malakoplakia--2 renal transplant recipients, 1 patient with systemic lupus erythematosus, and 1 patient with polymyositis--are reported. All patients were receiving prednisone and azathioprine at the time of diagnosis and had an infection caused by Escherichia coli. Leukocytes from all patients failed to kill Staphylococcus aureus and E coli normally in vitro. Cholinergic agonists had no apparent effect on bacterial killing in vitro or in vivo in the 2 patients examined. Clinically, malakoplakia improved significantly when immunosuppressive therapy was tapered or discontinued, and leukocyte function returned to normal in all 4 patients. The cases reported here and those documented previously suggest that the pathogenesis of malakoplakia and its treatment may not be the same for all patients. Malakoplakia may be more common than previously thought, particularly with the increased use of immunosuppressive therapy.

Abscess↗
PubMed1984

Neutrophil migration in vitro and in vivo during hypothermia.

The effect of hypothermia on pig leukocyte migration in vitro and in vivo was studied. Neutrophil chemotaxis in vitro under agarose was significantly impaired at 29 degrees C (2.7 +/- 0.6 [mean +/- standard error]; 37 degrees C, 7.1 +/- 1.1). Leukocytes isolated from hypothermic pigs and tested at 37 degrees C migrated normally (7.8 +/- 0.6). Neutrophil and monocyte migration in vivo was markedly reduced at 29 degrees C. Reduced inflammatory responses may contribute to increased infections during hypothermia.

Animals↗
PubMed1983

Chronic granulomatous disease of childhood: a changing pattern?

We have followed nine male patients with Chronic Granulomatous Disease at The Hospital for Sick Children, Toronto, since 1972. The diagnosis was established in each case by the failure of neutrophils to reduce nitroblue tetrazolium dye and to kill Staphylococcus aureus normally in vitro. Bacterial infections began between 6 months and 14 years of age. In five of the nine patients, infections began after 4 years of age. The first significant infection in five patients was a liver abscess(es), and one patient each had lymphadenitis, pulmonary aspergillosis, a parapharyngeal abscess, and a draining inguinal incision following surgery. Following diagnosis, all patients were started on Trimethoprim-Sulfamethoxazole at a dose of 2 mg/kg/day of Trimethoprim. The patients have been followed for 50 patient-years. Five of nine patients have been free of infection during 16 years of observation. For the remaining four patients, there have been six infections during 34 years of observation. A possible infection-related death occurred in one patient. The patients reported here appear to differ from those in previous reports. They present later in life, often with a liver abscess. They have a low incidence of subsequent bacterial infections which may, in part, be due to Trimethoprim-Sulfamethoxazole prophylaxis. The patients with chronic granulomatous disease reported here appear to have a better prognosis than previously thought.

Adolescent↗
PubMed1983

Neutrophil circulation and release from bone marrow during hypothermia.

The effect of hypothermia on neutrophil circulation and release from bone marrow has been studied. Pigs were anesthetized and maintained at 37 degrees C or surface cooled to 29 degrees C over 60 min. As the core temperature was reduced to 29 degrees C, the number of circulating neutrophils (X 10(9) per liter) fell from 6.0 +/- 0.6 to 2.3 +/- 0.3 by 60 min. No significant change in the number of circulating mature or immature neutrophils was observed over the 4 h of observation at 29 degrees C. Neutrophil demargination after administration of intravenous catecholamines was similar at 37 and 29 degrees C. Steroid stimulation of bone marrow to release neutrophils was markedly impaired at 29 degrees C. Circulating mature neutrophils in normothermic pigs increased from 5.6 +/- 1.2 to 10.4 +/- 1.2 by 120 min after administration of intravenous hydrocortisone sodium succinate. Circulating immature neutrophils increased from 1.7 +/- 0.3 to 5.3 +/- 0.4. At 29 degrees C, no significant changes in the number of circulating mature or immature neutrophils occurred. Endotoxin also failed to stimulate neutrophil release from the bone marrow. Furthermore, a marked neutropenia occurred in hypothermic pigs after intravenous endotoxin, which persisted for the 3 h of observation. Neutrophil circulation and release from bone marrow are compromised by hypothermia, which may increase the risk for bacterial infection.

Animals↗
PubMed1982

Neutrophil function in the immotile cilia syndrome.

Patients with ICS have a microtubular abnormality of cilia, which is thought to contribute to frequency respiratory tract infections. Neutrophils have a cytoplasmic microtubular system that, if abnormal and malfunctioning, could also contribute to recurrent infections. Neutrophil function has been assessed in 14 patients with ICS and compared with that of controls. The ICS patients included those with the dynein defect, the radial spoke defect, and microtubular transposition. Cell migration in each patient has been examined under agarose and by Boyden chamber techniques. No significant abnormality was detected in random or directed migration of neutrophils. Six patients representing the three different types of abnormal cilia had more extensive studies of neutrophil function performed. These included assessments of bacterial phagocytosis and killing, lysosomal degranulation, and oxidative pathway activity. Phagocytosis and killing of Staphylococcus aureus 502A in vitro was normal. Hexose monophosphate pathway activity, tetrazolium dye reduction, and lysosomal degranulation by neutrophils at rest and during phagocytosis were similar to those of control neutrophils. Our findings suggest that an abnormality of neutrophil function does not play an important role in the respiratory infections of patients with ICS.

Adolescent↗