W. Douglas Biggar

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.

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.

Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne muscular dystrophy: long-term follow-up.

BACKGROUND Duchenne muscular dystrophy, a progressive muscle disorder that occurs in males, causes a gradual decline in muscle strength. This progressive decline is associated with the development of scoliosis. Previous studies have shown that the use of glucocorticoids slows the progression of scoliosis, but it is unknown if the spine remains straight in the long term. We examined if glucocorticoid treatment has a long-term effect on the prevalence of scoliosis. METHODS Fifty-four boys who had been diagnosed with Duchenne muscular dystrophy while they were still walking were enrolled in a non-randomized comparative study of the glucocorticoid deflazacort. The families of thirty boys elected for them to use glucocorticoid treatment and the families of twenty-four boys elected for them not to have this treatment. The boys were matched for important baseline characteristics including age and pulmonary function. Every four to six months, they were examined for the development of scoliosis, and the duration of follow-up for surviving patients was fifteen years. Because surgery was recommended for spinal curves measuring >20° on sitting posteroanterior radiographs, a curve of this magnitude was used as the definition for a patient developing scoliosis. RESULTS Five boys (21%) in the non-treatment group and one boy (3%) in the glucocorticoid treatment group died. At the most recent follow-up, of the boys who survived, six (20%) in the glucocorticoid treatment group and twenty-two (92%) in the non-treatment group developed scoliosis and underwent spinal surgery. After fifteen years of follow-up, the survivorship analysis (avoiding surgery) was 78% (95% confidence interval, 57% to 89%) in the treatment group and 8.3% (95% confidence interval, 0.8% to 28%) in the non-treatment group. Significance (p = 5.8 × 10(-7)) was calculated with log-rank and chi-square tests. None of the patients in the glucocorticoid group developed scoliosis after ten years of deflazacort treatment. CONCLUSION The long-term use of the glucocorticoid results in a substantial decreased need for spinal surgery to treat scoliosis.

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.

A new form of nucleoside phosphorylase deficiency in two brothers with defective T-cell function

Two brothers, age 9 and 11, respectively, have marked deficiency of nucleoside phosphorylase associated with defective T-cell function and normal B-cell function. Unlike the previously described five patients with this syndrome, each of these children has sufficient NP catalytic activity in their red blood cells (below 1% of the normal level) to be visualized after electrophoresis and staining for the enzyme. Their healthy sibling has normal NP activity and a normal isozyme pattern. The nonconsanguineous parents have about half-normal NP activity, but their electrophoretic patterns differ from each others and from those of their affected children. These findings are consistent with genetic heterogeneity at the NP structural gene locus, resulting in compound heterozygosity for two different abnormal alleles.

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.

PHAGOCYTOSIS IN PATIENTS AND CARRIERS OF CHRONIC GRANULOMATOUS DISEASE

The phagocytic capacity of leucocytes from four patients and two carriers of chronic granulomatous disease (C.G.D.) was compared to that of normal leucocytes. Leucocytes from C.G.D. patients phagocytised more Staphylococcus aureus than did normal leucocytes after 5, 10, and 20 minutes of incubation. Phagocytosis by leucocytes from two carriers of C.G.D. was intermediate between that in the patients and in controls. In contrast, phagocytosis of Streptococcus faecalis, an organism readily killed by C.G.D. leucocytes, was similar for control and C.G.D. leucocytes. Enhanced phagocytosis may represent an attempt by leucocytes to compensate for a bactericidal abnormality. In addition, these observations may partly explain why carriers of C.G.D. are not more susceptible to infection despite abnormal leucocyte function. Detection of carriers using the described assay of phagocytosis appears relatively simple compared to previously described methods.

Chronic granulomatous disease in an adult male: A proposed X-linked defect

A 25-year old patient with chronic granulomatous disease of somewhat unusual history is described. The diagnosis of CGD was based on increased susceptibility to infection, granulomatous appearance of tissues, and diminished bactericidal and metabolic response of leukocytes during phagocytosis: the clinical and cellular features considered phenotypic of CGD. A 16-year-old female sibling had bactericidal and metabolic abnormalities of leukocyte function similar to those of the patients leukocytes. Leukocytes from another sister, 26 years of age, were intermediate in bactericidal capacity. Two populations of leukocytes were identified by a histochemical test of NBT reduction. Both normal and abnormal polymorphonuclear leukocytes were present in the leukocyte population of the two sisters. Leukocytes from the patients mother and maternal grandmother were normal by all methods tested. These findings are taken as evidence of a germ-line mutation in the chromosomal gene causing CGD, with transmission of the genetic defect from the mother to the son.

Long-Term Effects of Glucocorticoids on Function, Quality of Life, and Survival in Patients with Duchenne Muscular Dystrophy: A Prospective Cohort Study.

BACKGROUND Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

Immune Deficiency: Evaluation, Diagnosis, and Therapy

The striking advances made in the understanding, diagnosis, and treatment of immunodeficiency diseases have resulted in the dramatic cure of combined immunodeficiency disease by bone marrow transplantation as well as more effective prevention of recurrent infections in patients with antibody-deficiency syndromes through the judicious use of gammaglobulin.