Bone health in boys with Duchenne Muscular Dystrophy on long-term daily deflazacort therapy.

Quality of life in Duchenne Muscular Dystrophy (DMD) has improved significantly with corticosteroid treatment. However, corticosteroids decrease bone mass and increase vertebral fragility fracture risk. We report on bone health in 39 boys with DMD on long-term deflazacort (0.9 mg/kg/day) therapy. Bone health was defined by lumbar (L(1)-L(4)) bone mineral density (BMD), long-bone and/or symptomatic vertebral fractures. Lumbar BMD was reported as height-adjusted Z-scores at initiation of deflazacort (T(0)) and 1-2 year intervals thereafter. Subcapital body fat percentage and ambulatory status were recorded. At T(0), 39 boys, aged 6.6 ± 1.6 years had height-adjusted BMD Z-score -0.5 ± 0.8, and 23.5 ± 5.0% body fat. Height-adjusted Z-scores remained stable with years of deflazacort until loss of ambulation and accrual of body fat. Nine long-bone fractures occurred in eight ambulating boys, two before T(0). Seven vertebral fractures occurred in six non-ambulatory boys after ≥ 5 years of deflazacort with height-adjusted Z-score -1.8 ± 0.7, and 47.8 ± 12% body fat. Bone health in DMD is influenced by disease progression, corticosteroids, BMD Z-scores and fat mass accumulation. Adjustments for short stature must be considered during BMD interpretation. Percent body fat and ambulatory status are useful bone health indicators. Routine use of height adjusted Z-scores is advocated for use in routine clinical practice.

Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade.

We compare the clinical course of 74 boys 10-18 years of age with Duchenne muscular dystrophy (DMD) treated (40) and not treated (34) with deflazacort. Treated boys were able to rise from supine to standing, climb stairs and walk 10 m without aids, 3-5 years longer than boys not treated. After 10 years of age, treated boys had significantly better pulmonary function than boys not treated and after 15 years of age, 8 of 17 boys not treated required nocturnal ventilation compared with none of the 40 treated boys. For boys over 15 years of age, 11 of 17 boys not treated required assistance with feeding compared to none of the treated boys. By 18 years, 30 of 34 boys not treated had a spinal curve greater than 20 degrees compared to 4 of 40 treated boys. By 18 years, 7 of 34 boys not treated had lost 25% or more of their body weight (treated 0 of 40) and 4 of those 7 boys required a gastric feeding tube. By 18 years, 20 of 34 boys not treated had cardiac left ventricular ejection fractions less than 45% compared to 4 of 40 treated boys and 12 of 34 died in their second decade (mean 17.6 +/- 1.7 years) primarily of cardiorespiratory complications. Two of 40 boys treated with deflazacort died at 13 and 18 years of age from cardiac failure. The treated boys were significantly shorter, did not have excessive weight gain and 22 of 40 had asymptomatic cataracts. Long bone fractures occurred in 25% of boys in both the treated and not treated groups. This longer-term study demonstrates that deflazacort has a very significant impact on health, quality of life and health care costs for boys with DMD and their families, and is associated with few side effects.

Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols.

We compare the long-term benefits and side effects of deflazacort using two treatment protocols from Naples (N) and Toronto (T). Boys with Duchenne muscular dystrophy between the ages of 8 and 15 years and who had four or more years of deflazacort treatment were reviewed. Diagnostic criteria included males with proximal muscle weakness evident before 5 years, increased serum creatine kinase and genetic testing and/or a muscle biopsy consistent with Duchenne muscular dystrophy. Thirty-seven boys were treated with protocol-N using deflazacort at a dose of 0.6 mg/kg per day for the first 20 days of the month and no deflazacort for the remainder of the month. Boys with osteoporosis received daily vitamin D and calcium. Deflazacort treatment started between 4 and 8 years of age. Thirty-two were treated with protocol-T using deflazacort at a dose of 0.9 mg/kg per day, plus daily vitamin D and calcium. Treatment started between 6 and 8 years of age. All boys were monitored every 4-6 months. The results were compared with age-matched controls in the two groups (19 for protocol-N and 30 for protocol-T). For the boys treated with protocol-N, 97% were ambulatory at 9 years (control, 22%), 35% at 12 years (control, 0%), 25% at 15 years (control, 0%). For the 32 boys treated with protocol-T, 100% were ambulatory at 9 years (control, 48%), 83% at 12 years (control, 0%) and 77% at 15 years (control, 0%). No aids or leg braces were used for ambulation. In boys 13 years and older, a scoliosis of >20 degrees developed in 30% of the boys on protocol-N, 16% on protocol-T and 90% of controls. For protocol-N, no cataracts were observed while in protocol-T, 30% of boys had asymptomatic cataracts that required no treatment. Fractures occurred in 19% (control 16%) of boys on protocol-N and 16% (control, 20%) of boys on protocol-T. This report illustrates: (a) the importance of collaborative studies in developing treatment protocols in Duchenne muscular dystrophy and (b) the long-term beneficial effects of deflazacort treatment in both protocols. However, the protocol-T seems to be more effective and frequently is associated with asymptomatic cataracts.

Deflazacort treatment of Duchenne muscular dystrophy.

OBJECTIVE: We report the long-term effects on muscle strength and side effects with deflazacort in Duchenne muscular dystrophy (DMD). STUDY DESIGN: Boys with DMD between the ages of 7 and 15 years were reviewed retrospectively; 30 had been treated with deflazacort, and 24 had not. Muscle function, pulmonary function, and side effects were compared. RESULTS: The boys not treated with deflazacort stopped walking at 9.8 +/-1.8 years. Seven of 30 treated boys had stopped walking at 12.3+/-2.7 years (P<.05), and of the 23 boys who were still walking, 21 were older than 10 years. Pulmonary function (percent predicted functional vital capacity) was significantly greater in treated boys at 15 years (88% +/- 18%) than in boys not treated (39%+/-20%) (P<.001). Between 9 and 15 years, treated boys were shorter. Between 9 and 13 years, treated boys weighed less. After 13 years the treated boys maintained their weight, whereas boys not treated lost weight. Asymptomatic cataracts developed in 10 of 30 boys who received deflazacort. Other potential side effects of deflazacort such as hypertension, glucosuria, acne, infection, or bruising were not more common. CONCLUSIONS: We conclude that deflazacort can preserve gross motor and pulmonary function in boys with DMD with limited side effects.

Adolescents with physical disabilities: some psychosocial aspects of health.

PURPOSE: To examine the psychosocial issues related to growing up with a physical disability. METHODS: Adolescents with physical disabilities aged 11-16 years were compared with a Canadian national sample of adolescents using the Health Behaviours in School-Aged Children (HBSC), a World Health Organization Cross-National Study survey. RESULTS: Adolescents with physical disabilities reported good self-esteem, strong family relationships, and as many close friends as adolescents in the national sample. However, adolescents with physical disabilities participated in fewer social activities and had less intimate relationships with their friends. They had more positive attitudes toward school, teachers, and their fellow classmates than the national sample, but fewer had plans for postsecondary education. The majority of adolescents with physical disabilities reported that they had not received information on parenthood, birth control, and sexually transmitted diseases. CONCLUSIONS: There are a number of critical areas of risk for adolescents with physical disabilities to which health promotion efforts should be directed. These include lower levels of peer integration, heightened adult orientation, low educational aspirations, and poor knowledge of sexuality.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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)

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.

Clinical features and abnormal neutrophil function in disseminated staphylococcal disease.

Clinical features and immune status have been studied in seven previously healthy children with disseminated staphylococcal disease. Six of seven patients had a history of a viral-type illness before developing disseminated staphylococcal disease. Five patients had a petechial rash. Endocarditis occurred in three patients, two of whom had a cerebral embolism. All seven patients had an abnormal urinary sediment, and in two it was suggestive of glomerulonephritis. Two had transient renal failure. Three patients had evidence of pneumonia, one of the three developed pneumatoceles and one developed a pleural effusion. Four had osteomyelitis and/or septic arthritis. All patients had a transient abnormality of intracellular bacterial killing by neutrophils. One patient died. Three patients have residual valvular heart disease; one of the three patients has weakness of one arm and another has a seizure disorder. Cellular and humoral immunity in all six surviving patients is normal. We speculate that an antecedent viral infection temporarily suppressed neutrophil function and predisposed these children to secondary and severe staphylococcal disease.

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.