References and cutoffs for triceps and subscapular skinfolds in Norwegian children 4-16 years of age.

BACKGROUND/OBJECTIVES: To establish new reference values for triceps (TSF) and subscapular (SSF) skinfolds of Norwegian children 4-16 years of age, and to define cutoff values for overweight and obesity using the criteria of the International Obesity Task Force (IOTF). SUBJECTS/METHODS: A cross-sectional sample of 4606 children 4-16 years of age, part of a larger growth study, was used to estimate reference curves with the LMS method; suggested cutoffs were selected using receiver operating characteristic analyses. RESULTS: Reference values for TSF and SSF are presented as percentiles. Mean skinfold size increased with age. Girls had higher values than boys over the entire age range. There was a strong positive correlation between both skinfolds and body mass index (BMI). For all ages together, a cutoff of 1.0 standard deviation score (SDS) gave a sensitivity of 76% for SSF, and 70% for TSF to detect overweight, with a corresponding specificity of 92% for both. To detect obesity, a cutoff value of 1.3 SDS gave a sensitivity of 91% and specificity of 90% for SSF. Corresponding values for TSF were 86% for the sensitivity, and 91% for the specificity. CONCLUSIONS: This study presents new reference values for TSF and SSF skinfolds in Norwegian children 4-16 years of age. Both skinfolds had a high-discriminating power to detect overweight and obesity as defined by the IOTF BMI criteria.

Waist circumference and waist-to-height ratio in Norwegian children 4-18 years of age: reference values and cut-off levels.

AIM: To establish reference values for waist circumference and waist-to-height ratio of Norwegian children. MATERIAL: Data were collected in 2003-2006 as part of a cross-sectional study, including 5725 children 4-18 years of age. Reference curves were fitted with the LMS method; appropriate cut-offs were selected using receiver operating characteristic analysis. RESULTS: Reference values for waist circumference and waist-to-height ratio are presented. Mean waist circumference increased with age for both genders. Boys had a higher waist circumference at almost all ages. Mean waist-to-height ratio decreased until early adolescence and thereafter increased slightly towards adult age. There was a strong positive correlation between waist circumference and BMI (r = 0.907, p < 0.01) and a moderate positive correlation between waist-to-height ratio and BMI (r = 0.397 p < 0.01). A waist circumference cut-off value of 1.0 SDS (85th percentile) gave a sensitivity of 79% and a specificity of 94% to detect overweight. A cut-off value of 1.6 SDS (95th percentile) gave a sensitivity of 94% and a specificity of 96% to detect obesity. CONCLUSION: This study presents the first reference values of waist circumference and waist-to-height ratio for Norwegian children 4-18 years, which also represent the first reference in Scandinavian schoolchildren. The 85th and 95th percentiles of waist circumference are proposed as appropriate cut-offs for central overweight and obesity.

A comparison of different definitions of growth response in short prepubertal children treated with growth hormone.

BACKGROUND: How to define poor growth response in the management of short growth hormone (GH)-treated children is controversial. AIM: Assess various criteria of poor response. SUBJECTS AND METHODS: Short GH-treated prepubertal children [n = 456; height (Ht) SD score (SDS) ≤-2] with idiopathic GH deficiency (IGHD, n = 173), idiopathic short stature (ISS, n = 37), small for gestational age (SGA, n = 54), organic GHD (OGHD, n = 40), Turner syndrome (TS, n = 43), skeletal dysplasia (n = 15), other diseases (n = 46) or syndromes (n = 48) were evaluated in this retrospective multicenter study. Median age at GH start was 6.3 years and Ht SDS -3.2. RESULTS: Median [25-75 percentile] first-year gain in Ht SDS was 0.65 (0.40-0.90) and height velocity (HtV) 8.67 (7.51-9.90) cm/year. Almost 50% of IGHD children fulfilled at least one criterion for poor responders. In 28% of IGHD children, Ht SDS gain was <0.5 and they had lower increases in median IGF-I SDS than those with Ht SDS >0.5. Only IGHD patients with peak stimulated growth hormone level <3 µg/l responded better than those with ISS. A higher proportion of children with TS, skeletal dysplasia or born SGA had Ht SDS gain <0.5. CONCLUSION: Many children respond poorly to GH therapy. Recommendations defining a criterion may help in managing short stature patients.

Growth of Belgian and Norwegian children compared to the WHO growth standards: prevalence below -2 and above +2 SD and the effect of breastfeeding.

BACKGROUND: New national growth references have been published in Belgium and Norway. The WHO recommends universal use of their 2006 Child Growth Standards based on data from breastfed children. OBJECTIVE: To compare the growth of Belgian and Norwegian children with the WHO standards. PARTICIPANTS: 6985 children 0-5 years of age from Belgium and Norway. DESIGN: Proportion of children below -2 SD and above +2 SD of the WHO standards was calculated for length/height, weight, body mass index and head circumference. Average SD scores of exclusively breastfed children of non-smoking mothers were compared with national reference data and with the WHO standards. RESULTS: Generally, the number of Belgian and Norwegian children below -2 SD lines of the WHO standards was lower and above +2 SD higher than expected. The largest differences were for head circumference (0.97% Belgian and 0.18% Norwegian children below -2 SD, 6.55% Belgian and 6.40% Norwegian children above +2 SD) and the smallest for length/height (1.25% Belgian and 1.43% Norwegian children below -2 SD, 3.47% Belgian and 2.81% Norwegian children above +2 SD). The growth pattern of breastfed children of non-smoking mothers was in both countries more alike the local national growth references than the WHO standards. CONCLUSIONS: There are significant deviations in the proportion of children outside normal limits (±2 SD) of the WHO standards. This was true for all children, including those who were exclusively breastfed. Hence, adoption of the WHO growth charts could have consequences for clinical decision-making. These findings advocate the use of national references in Belgium and Norway, also for breastfed children.

Overweight and obesity in Norwegian children: secular trends in weight-for-height and skinfolds.

AIM: The prevalence of overweight and obesity in paediatric populations has been rapidly increasing in many countries over the past decades. The aims of the present study were to provide new data on weight-for-height and skinfolds, and to compare these to growth references for children between 3 and 17 years, collected in the same city between 1971 and 1974. MATERIAL: The present study is based on cross-sectional data of 4115 children (2086 boys and 2029 girls) aged 4-15 years measured in 2003-6. RESULTS: Overall, 18.0% of the boys and 20.1% of the girls were above the 90th weight-for-height percentile of the 1971-1974 references, 8.0% and 7.2% were above the 97.5th percentile, indicating an upward shift in weight-for-height. An even more prominent increase was observed for skinfold thicknesses; for triceps skinfolds about 30% of the boys and 28% of the girls were above the 90th percentile of the 1971-1974 references, and corresponding values for subscapular skinfolds were 26.5% and 25.9%. Using international cut-off values for body mass index, the overall prevalence of overweight and obesity was 12.5% and 2.1% in boys, and 14.8% and 2.9% in girls. CONCLUSIONS: Our study has demonstrated a significant increase in weight-for-height in Norwegian children over the last 30 years, and that these changes are caused by an increase in fat tissue, as shown by skinfold measurements. The current prevalence of overweight and obesity is comparable to recent estimates from most Western and Northern European countries.

Nordic consensus on treatment of undescended testes.

AIM: To reach consensus among specialists from the Nordic countries on the present state-of-the-art in treatment of undescended testicles. METHODS: A group of specialists in testicular physiology, paediatric surgery/urology, endocrinology, andrology, pathology and anaesthesiology from all the Nordic countries met for two days. Before the meeting, reviews of the literature had been prepared by the participants. RECOMMENDATIONS: The group came to the following unanimous conclusions: (1) In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long term adverse effects on spermatogenesis. Thus, surgery is to be preferred. (2) Orchiopexy should be done between 6 and 12 months of age, or upon diagnosis, if that occurs later. (3) Orchiopexy before age one year should only be done at centres with both paediatric surgeons/urologists and paediatric anaesthesiologists. (4) If a testis is found to be undescended at any age after 6 months, the patient should be referred for surgery--to paediatric rather than general surgeons/urologists if the boy is less than one year old or if he has bilateral or non-palpable testes, or if he has got relapse of cryptorchidism.

The association between nutritional conditions during World War II and childhood anthropometric variables in the Nordic countries.

BACKGROUND: The purpose of the study was to examine the height and weight in Nordic children during the years around World War II (WWII), and compare them with the nutritional situation during the same period. METHODS: Information on food consumption and energy intake were obtained from the literature. Anthropometric data were collected from the Nordic capitals and cover the period from 1930 to 1960 for ages 7-13 years. RESULTS: The greatest energy restriction took place in Norway (20%), followed by Finland (17%), while Sweden and Denmark had a restriction of 4-7% compared to pre-war levels. The most pronounced effect of WWII on height and weight is seen in Norwegian children, while some effect is observed for the youngest children in Finland. Little or no effect is seen in Sweden and Denmark. CONCLUSION: The Nordic children were affected by WWII in terms of a transient reduction in temporal trends in height and weight, and the magnitude of this decrease was associated with the severity of the energy restriction prevailing in the respective country during the war. These findings warrant further studies of the chronic diseases associated with height and weight for cohorts being in their growth periods during WWII.

Eosinophil counts and urinary eosinophil protein X in children hospitalized for wheezing during the first year of life: prediction of recurrent wheezing.

UNLABELLED: Early identification of wheezing children with an increased risk of recurrent wheezing or subsequent asthma is important. The aim of the study was to determine the role of markers of eosinophil activation, along with other parameters, in the prediction of recurrent wheezing and allergic sensitization in children with early and severe wheezing. We examined 105 children without atopic dermatitis, hospitalized for wheezing during the first year of life. At a 20-mo follow-up, 101 of the children were assessed for the occurrence of recurrent wheezing (at least 3 episodes, including 1 in the previous 6 mo) and allergic sensitization (positive skin-prick test). By univariate analysis, levels of eosinophil counts at the time of hospitalization (p = 0.005, OR = 18.9), age in months (p < 0.0001, OR = 1.5), respiratory syncytial virus (RSV)-negative disease (p < 0.0001, OR = 8.8), parental atopy (p = 0.006, OR = 3.3) and male sex (0.02, OR = 2.7) were all predictive factors for recurrent wheezing at follow-up. With all parameters included in a multiple regression analysis, RSV-negative disease was not a predictive factor for recurrent wheezing. A simple model including eosinophil counts > or = 0.1 x 10(9)/L and age had a predictive accuracy of 79%, with only a 6% chance of a child being wrongly predicted as symptomatic. Urinary protein X (U-EPX) was not a predictive factor for recurrent wheezing. When included in a multiple logistic regression analysis, a level of U-EPX > or = 100 microg/mmol creatinine was the only parameter with a positive predictive value for allergic sensitization (p = 0.007, OR = 18.9), whereas age, parental allergy or parental asthma were not. CONCLUSION: Children with severe wheezing during the first year of life and subsequent recurrent wheezing are characterized by a normal or high eosinophil count in response to viral infections.

A previous abrasion in the contralateral eye influences the cell kinetics during healing of a central corneal abrasion.

PURPOSE: To study the influence of a previous erosion in the fellow eye on the proliferative response during healing of a central corneal erosion. METHODS: A corneal abrasion was made on the right eye of 20 rats. After 1 week a corneal erosion was made in the left eye of the pre-treated animals and in 20 previously untreated animals. Cell kinetic methods were used to estimate the labelling index (LI) and the mitotic rate (MR) after 1, 2, 4, 6 and 12 days. RESULTS: After 24 hours the corneal erosions were covered by epithelial cells in 3 of 4 animals in both groups. The LI and the MR were significantly higher in the pre-treated group on the 2nd day after erosion. CONCLUSIONS: The proliferation measured by LI and MR was increased when an abrasion was made in the contralateral eye 1 week earlier. This might explain the faster healing rate of the second eye reported by other authors (Rask et al. 1996). The healing process in the cornea is modulated by systemic influence.

[Generalized edema following insulin treatment of newly diagnosed diabetes mellitus]. / Generaliserte ødemer ved insulinbehandling av nyoppdaget diabetes mellitus.

BACKGROUND: Generalised oedema after introducing insulin therapy is an infrequent complication, usually appearing when large doses are used in underweight patients. The pathophysiology is unclear. MATERIALS AND METHODS: Two patients from two different hospitals are presented by case histories. A limited literature search was performed. RESULTS: Patient 1. A 13-year-old girl was admitted with polyuria and polydipsia and a weight loss of 15 kg over six months. She had ankle oedema, dry scaling skin, weight 31.6 kg (2 kg below 2.5th centile), marked hyperglycaemia (60 mmol/l), and ketonuria without acidosis. After one day with insulin infusion she was treated with subcutaneous injections, reaching after a few days a dose of 2 U/kg/day. She gradually developed generalised oedema and gained 20 kg over two weeks. From day 8 after admission she was treated with furosemide and from day 16 also with ephedrine. S-albumin reached a nadir of 25 g/l. The oedema gradually disappeared. The patient was discharged after one month, weighing 42 kg, and with a daily insulin dose of 88 U. Patient 2. A 14-year-old girl presented with decreased vision over a period of six months. She felt otherwise healthy and had no weight loss. Bilateral cataract and hyperglycaemia (20.7 mmol/l) were detected. There were normal serum electrolytes and no acidosis. After administration of insulin (increased up to 1.5 U/kg/day) she gradually developed generalised oedema, gaining 8.5 kg over nine days. S-albumin fell from 36 g/l to 28 g/l. She was treated with furosemide and the oedema gradually disappeared in the course of one month. None of the patients had proteinuria, liver failure or hyperaldosteronism, but both experienced transient and unexplained muscle pain and neuralgic pain in the legs. INTERPRETATIONS: One of the cases with newly diagnosed diabetes and generalised oedema presented here, supports suggestions in the literature of an association between marked weight loss and large insulin doses. However, as shown by the other case presented, this association is not obligate.

Urinary eosinophil protein X in children with asthma: influence of atopy and airway infections.

It has been suggested that urinary eosinophil protein X (U-EPX) can be used to monitor bronchial inflammation in childhood asthma. However, the influence of atopy and airway infections is not well elucidated. To determine the clinical value of measuring U-EPX in children with asthma and to evaluate the influence of atopy and airway infections, U-EPX was measured in 170 children with asthma (mean age 69 months, range 12-179 months), in 79 children with lower or upper respiratory tract infections (mean age 41 months, range 1-165 months), and in 64 controls. U-EPX was elevated in children with acute asthma (median 132 microg/mmol of creatinine, quartiles 77-195 microg/mmol of creatinine, n = 51, p <0.001) and chronic asthma (median 93 microg/mmol of creatinine; quartiles 46-149 microg/mmol of creatinine, n = 119, p <0.01) compared with controls (median 54 microg/mmol of creatinine, quartiles 40-89 microg/mmol of creatinine, n = 39). Atopic children had higher levels of U-EPX than non-atopics with acute asthma (median 155 microg/mmol of creatinine, quartiles 113-253 microg/mmol of creatinine, n = 27, vs. median 102 microg/mmol of creatinine, quartiles 56-168 microg/mmol of creatinine, n = 24, p <0.05), as well as with chronic asthma (median 110 microg/mmol of creatinine, quartiles 65-162 microg/mmol of creatinine, n = 63, vs. median 60 microg/mmol of creatinine, quartiles 39-123 microg/mmol of creatinine, n = 56, p <0.01). In chronic asthma, children without atopy had levels of U-EPX similar to values of controls; levels were similar in symptomatic and asymptomatic patients, and not influenced by treatment with inhaled corticosteroids. Moreover, U-EPX levels were higher in children with pneumonia (median 207 microg/mmol of creatinine, quartiles 111-280 microg/mmol of creatinine, n = 35, p <0.001), laryngitis (median 109 microg/mmol of creatinine, quartiles 65-161 microg/mmol of creatinine, n = 24, p <0.01), and rhinitis (median 172 microg/mmol of creatinine, quartiles 123-254 microg/mmol of creatinine, n = 19, p <0.001) than in controls (median 62 microg/mmol of creatinine, quartiles 41-93 microg/mmol of creatinine, n = 64). There was significant overlap among all groups of children with disease, as well as between children with disease and controls. Hence, U-EPX may reflect differences in eosinophil involvement and activation between children with atopic and non-atopic asthma, but the individual spread within groups and the influence of airway infections limits the clinical value of U-EPX in childhood asthma.

Soluble CD30 and CD23 in cord blood are not related to atopy in early childhood.

Atopic disease, including atopic dermatitis (AD), is associated with a T-helper 2 (Th2)-dependent immune response. The cytokine receptor CD30 appears to be preferentially expressed on, and its soluble form (sCD30) released by, Th2 cells. Therefore, sCD30 may be a potential marker for atopic disorders. The aim of this study was to test the hypothesis that the sCD30 level in cord blood could be used to predict the development of atopy or AD in early childhood. In a case-control study, levels of sCD30, as well as soluble low-affinity immunoglobulin E (IgE) receptor (sCD23), interleukin-4 (IL-4) and IgE, were measured in cord blood in 35 children who subsequently developed allergic sensitization and AD before the age of three, and the results were compared to those of 35 matched children without a history of atopy. There was no difference in cord blood levels of sCD30 between controls (32.5 U/ml; 19.7-80.1) and children with subsequent atopy and AD (32.2 U/ml; 22-75.9) (median; quartiles). The concentration of sCD30 showed no relation to the levels of total IgE, sCD23 or IL-4. Levels of sCD23 were similar in children with subsequent atopy (60.2 U/ml; 44.5-76.8) and controls (55.2 U/ml; 38.3-72.5), whereas IL-4 was detectable in 10 of the atopic children and in only two of the controls (p <0.05). In conclusion, cord blood levels of sCD30 or sCD23 do not seem to be related to the subsequent development of atopy or AD at the age of three.

Urinary eosinophil protein X in children with atopic dermatitis: relation to atopy and disease activity.

BACKGROUND: Parameters of eosinophil inflammation have been suggested as markers of disease activity in atopic dermatitis (AD), but the value of urinary eosinophil protein X (U-EPX) in children with AD, as well as the influence of allergic sensitization, is not known. METHODS: We measured U-EPX in 59 atopic and 29 nonatopic children with mild (n = 32), moderate (n = 34), and severe (n = 22) AD, as well as in 64 controls. RESULTS: U-EPX was increased in children with AD (110; 67-164 microg/mmol creatinine, median; quartiles) compared to controls (62; 41-95, P<0.001). Children with mild (97; 63-164, P < 0.01), moderate (108; 67-157, P < 0.01), and severe disease (152; 99-202, P < 0.001) had levels of U-EPX higher than controls. U-EPX was significantly higher in children with severe AD than in mild and moderate disease (P < 0.05 for both). Children with AD and a positive skin prick test (120; 81-176) had higher levels of U-EPX than children with a negative skin prick test (87; 56-155, P<0.05). CONCLUSIONS: U-EPX is significantly increased in children with AD and may reflect disease activity. U-EPX may also reflect differences in eosinophil activation between those sensitized and those not sensitized to common allergens.

Studies of Atlantic salmon (Salmo salar L.) blood, spleen and head kidney leucocytes using specific monoclonal antibodies, immunohistochemistry and flow cytometry.

Monoclonal antibodies (mabs) raised against Atlantic salmon serum IgM (C7G7 and G2H3) and isolated peripheral blood leucocytes (PBL) (E3D9, C4B6 and D8B3) were applied in this study. Using immunoenzymehistochemistry, immunofluorescence and flow cytometry, the distribution of mab+ cells in blood, spleen and head kidney from Atlantic salmon were studied. Immunostaining on cytospin preparations and flow cytometry of isolated PBL showed that the Ig+ cells recognised by C7G7 and G2H3 were mononuclear leucocytes (MNL). The cytospin preparations showed some Ig+ cells with strong cytoplasmic staining, most likely plasma cells. The salmon blood neutrophils were the only E3D9+ cells in cytospin preparations of PBL, and E3D9 recognised about 94% of the defined neutrophil fraction in flow cytometry. The reactivities of C4B6 and D8B3 were to a large degree similar in both immunoenzymehistochemistry and flow cytometry, recognising both MNL and blood neutrophils. Immunofluorescence double staining of PBL with C4B6 and D8B3 showed double staining of all mab+ cells and D8B3 was apparently not able to block the binding of C4B6 to PBL. Immunofluorescence double staining of PBL also revealed more E3D9+ than C4B6+ neutrophils. In immunostaining on cryostat sections of spleen and head kidney, staining of cells was observed with all the mabs, the head kidney generally containing more positive cells than the spleen. Some potential applications for immunological studies using these mabs are suggested.

Insulin-like Growth Factor-1 (IGF-1) is a Costimulator of the Expansion of Lineage Committed Cells Derived from Peripheral Blood Mobilized CD34(+) Cells in Multiple Myeloma Patients.

The effect of insulin-like growth factor-1 (IGF-1) on highly enriched human apheresis CD34(+) progenitor cells was investigated in vitro. The progenitor cells were mobilized by treatment with cyclophosphamide + granulocyte-colony stimulating factor (G-CSF) in patients with multiple myeloma. CD34(+) cells were cultured for 7 days in serumfree medium containing stem cell factor (SCF), granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-3 (IL-3), and this is referred to as cytokine-dependent proliferation. After 7 days of cytokine-dependent proliferation the total number of viable cells increased 1.6-8.2 times, and subsets of cells expressing the granulocyte marker CD15, the myelomonocytic marker CD64 and the erythrocyte phenotype CD71(high)/CD64(-) were detected among the in vitro cultured cells. Addition of G-CSF together with SCF + IL-3 + GM-CSF increased the number of CD15(+) and CD64(+) cells, but without altering the number of erythroid cells. IGF-1 caused a dose-dependent increase in the number of CD15(+), CD64(+) and CD71(high)/CD64(-) cells, and this increase was detected when cells were cultured in both SCF + IL-3 + GM-CSF alone and G-CSF + SCF + IL-3 + GM-CSF. A minor subset of CD34(+) cells could still be detected among in vitro cultured cells and the number of CD34(+) cells was not altered by adding G-CSF and/or IGF-1. Morphologically recognizable mature granulocytes or erythroid cells could not be detected for any of the combinations investigated. We conclude that IGF-1 can enhance the in vitro proliferation of committed progenitor cells derived from apheresis CD34(+) cells.

Correlates of apoptosis of CD4+ and CD8+ T cells in tonsillar tissue in HIV type 1 infection.

The immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection has been associated with increased death by apoptosis of T cell subsets. In the present study, we have examined correlates of apoptosis of CD4+, CD8S+CD28+, and CD8+CD28- T cells in tonsillar lymphoid tissue in persons with HIV-1. Single-cell suspensions of tonsillar lymphocytes were analyzed by flow cytometry to determine the fraction of cells showing typical characteristics of apoptosis as well as the expression of activation markers within the live and the apoptotic cell populations. The proportion of cells carrying infectious provirus was quantified by limiting dilution analysis. Compared with uninfected controls, apoptosis of both CD4+ and CD8+ T cells was enhanced in HIV-1 infection and was higher among CD8+ than among CD4+ T cells. Apoptosis of CD28-cells was more prevalent than apoptosis of CD28+ cells for both CD4+ and CD8+ T cells. Occurrence of apoptosis of CD4+ T cells correlated with provirus levels and proportional expression of the activation marker HLA-DR. Apoptosis of CD8+CD28+ cells correlated with expression of the activation markers CD69 and HLA-DR while apoptosis within CD8+CD28- cells did not correlate with any of the studied parameters. Although apoptosis was much more prevalent among CD8+ than CD4+ T cells, CD8+ T cells still accumulated in tonsillar lymphoid tissue in persons with HIV-1. Our data may be interpreted to suggest that apoptosis of CD4+, CD8+CD28+, and CD8+CD28- cells in tonsillar tissue is regulated by different mechanisms and the results are of importance to our understanding of the immunopathogenesis of HIV-1 infection.

Familial disseminated infection due to atypical mycobacteria with childhood onset.

We describe two brothers of consanguineous Pakistani parents who lived in Norway and had disseminated infections due to nontuberculous mycobacteria. The first boy developed clinical signs of disseminated BCG infection after vaccination. He was successfully treated with antimycobacterial agents. Two and one-half years later, he developed disseminated Mycobacterium avium complex infection and died at 6 years of age. The second boy, born 5 years after the death of his brother, did not receive BCG vaccine. At 2 years of age, he developed disseminated M. avium complex infection. Because he responded only partly to specific chemotherapy, empirical interferon gamma treatment was added to the antimycobacterial regimen. After 2 years of combined therapy, his condition is stable. Studies of peripheral blood mononuclear cells from the second boy demonstrated reduced surface expression of the ligand binding chain of interferon gamma receptor 1. This defect explains the increased susceptibility to mycobacterial disease in the two brothers.