Morphological and functional studies of fetal thymus transplants in mice.

The fetal thymus at 13 days of gestation withstands transplantation and develops normally under the renal capsule of a syngenic host. Distinct differences were observed between the fetal thymus grafts and grafts from neonatal or adult thymus donors. The fetal thymus graft did not undergo the rapid and severe necrosis observed when adult thymus was grafted. Furthermore, when thymuses were transplanted into allogenic recipients, rejection was delayed. The fetal thymus was as effective as the adult thymus in restoring syngenic neonatally thymectomized mice and far superior to adult thymus when grafted into allogenic recipients. These observations seem relevant to clinical efforts to restore immunocompetence in patients with congenital absence of the thymus.

B and T lymphocytes in primary immunodeficiency disease in man.

B- and T-cell populations in 32 patients with different forms of primary immunodeficiency disease were studied. The B-cells in peripheral blood were investigated with respect to surface immunoglobulins by means of immunofluorescence. The T-cell function was studied utilizing quantitation of proliferative response to phytochemagglutinin (PHA)(1) and delayed allergy to various antigens. In 10 patients lymph node lymphocytes were also evaluated 11 male children with infantile x-linked agammaglobulinemia were divided into two subgroups. One did not show immunoglobulin spots on peripheral blood lymphocytes at all, the other contained a very low percentage of IgM- and occasionally IgA bearing lymphocytes. Eight patients with common variable immunodeficiency had moderately decreased percentages of peripheral blood and lymph node lymphocytes with surface immunoglobulins, but these patients lacked immunoglobulin secreting cells. Four cases of isolated IgA deficiency had normal or high percentages, and two cases of ataxia-telangiectasia had high percentages of lymphocytes with IgA in so called receptor distribution in both peripheral blood and lymph nodes. In three patients with infantile combined immunodeficiency that had been corrected by marrow transplantation, the percentages of Ig-bearing lymphocytes increased to normal or high levels together with establishment of functional T-cell population and ultimate secretion of serum immunoglobulins. One case of Di George syndrome reconstituted by fetal thymus transplant showed gradual decrease of B lymphocytes in circulation parallel to restoration of T-cell population.

Partial purine nucleoside phosphorylase deficiency. Studies of lymphocyte function.

Immune function in two brothers with a deficiency of purine nucleoside phosphorylase was evaluated in vivo and in vitro. Both patients had a history of recurrent infections and profound lymphopenia. Studies of cell-mediated immunity revealed an absence of delayed cutaneous reactivity to a number of antigens, including dinitrochlorobenzene, and significantly reduced lymphocyte proliferative responses to nonspecific mitogens, specific antigen, and allogeneic cells. E-rosetting cells were present but reduced in number (20.0% and 31.5%). Serum immunoglobulin levels, percentages of circulating immunoglobulin-and C3-receptor-bearing B cells, as well as the ability to produce antibody in response to specific antigen in vivo were normal. Moreover, studies of the in vitro induction of specific IgM antibody delineated the presence of T-helper and T-regulator cells. The normal induction of bone marrow precursor T-cell maturation by human thymic epithelium-conditioned medium or thymosin suggested that the initial stages of T-cell generation were intact in these patients. Attempts to reconstitute the in vitro proliferative response with a variety of reagents, including purine nucleoside phosphorylase itself, were unsuccessful. Selective impairment of certain aspects of T-cell function in these patients and a less severe clinical picture than previously described may be explained by the presence of a partial deficiency of nucleoside phosphorylase activity and incomplete block of purine catabolism.

Purine nucleoside phosphorylase deficiency. Evidence for molecular heterogeneity in two families with enzyme-deficient members.

Purine-nucleoside phosphorylase (NP) deficiency is associated with severely defective thymus-derived (T)-cell and normally functioning bone marrow-derived (B)-cell immunity. In this study, two unrelated families with a total of three NP deficient members were investigated. High pressure liquid chromatography of the plasma of the three patients showed inosine levels greater than 66 muM. This nucleoside was absent from the plasma of their parents and control samples.NP was purified from normal human erythrocytes by affinity chromatography and an antiserum prepared in rabbits was used to study the NP variants in the two families. In family M the patient had no detectable erythrocyte NP activity and no detectable immunological-reacting material (irm) to the NP antibody. The parents, who are second cousins, had less than one-half of normal enzyme activity and approximately 14% irm attributable to a variant protein. Their electrophoretic patterns revealed a series of isozymes with slower than normal migration. In family B the patients had 0.5% residual enzyme activity and about one-half normal irm. Their electrophoretic pattern showed faintly staining bands which migrated faster than normal NP. The mother of the patients had one-half normal enzyme activity, 11% irm attributable to her variant protein, and a normal electrophoretic pattern. The father had less than one-half normal enzyme activity, equal amounts of normal and variant irm, and an electrophoretic pattern that showed increased activity of the more rapidly migrating isozyme bands.The combined use of immunological and electrophoretic techniques has shown the presence of three separate mutations; one in family M and two in family B associated with severely defective T-cell function.

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.

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.

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.

Malakoplakia: evidence for an acquired disease secondary to immunosuppression.

A 44-year-old man was maintained on prednisone and azathioprine after renal transplantation. One and a half years after transplantation, he developed multiple perianal Escherichia coli abscesses. These became chronic and resisted antibiotic therapy. Histologically, the lesions were typical of malakoplakia. Peripheral blood neutrophils and monocytes had impaired killing of Staphylococcus aureus and E. coli in vitro. No abnormality of hexose monophosphate pathway activity, tetrazolium dye reduction, lysosomal degranulation, or cyclic nucleotides could be demonstrated in either neutrophils or monocytes. Cholinergic agonists in vitro and in vivo did not improve bacterial killing by these cells. The infection resolved rapidly and bacterial killing returned to normal when the dose of azathioprine was reduced. Our findings, when considered with previous reports, suggest that there are different causes of malakoplakia and malakoplakia may be more common than previously thought. The etiology of malakoplakia should be identified for each patient if appropriate treatment is to be given.

Congenital asplenia: immunologic assessment and a clinical review of eight surviving patients.

Eight children with congenital asplenia syndrome have been studied for their cardiac and immunologic status. All patients were greater than 2 years of age and had severe complex cyanotic heart disease. All eight patients had abnormalities of cardiac and/or visceral situs. All patients had evidence of pulmonary stenosis or atresia and a common atrium or large atrial septal defect. Five patients required palliative cardiac surgery. All patients were given prophylactic antibiotics; there were no documented episodes of sepsis. One patient had an isolated deficiency of IgM; two patients had an isolated deficiency of IgE. Seven of eight patients were immunized with a dodecavalent pneumococcal vaccine. Four of the seven patients failed to have a twofold or greater antibody response. Our findings suggest that prophylactic antibiotics may reduce the incidence of sepsis in the asplenia syndrome. Because the prognosis for these patients must be optimistic, we recommend early documentation of splenic function in children suspected of having the asplenia syndrome, prophylactic antibiotics, and parent education. Children immunized with bacterial vaccines should have their antibody responses monitored.

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.

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.

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.

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.