Long-term renal function following bone marrow transplantation.

Renal function, evaluated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), was investigated in 187 pediatric patients who underwent allogeneic (n=169) or autologous bone marrow transplantation (BMT). Allogeneic BMT patients were divided into three groups: hematological malignancies, aplastic anemia and non-malignant diseases, whereas autologous patients constituted a fourth group. A total of 64% received total body irradiation (TBI) as conditioning therapy, and 50 healthy children served as controls. GFR and ERPF were normal before transplantation. After 1 year, both GFR and ERPF were significantly reduced. GFR had recovered slightly after 3 years and remained stable thereafter. Recovery in ERPF was not apparent. Renal impairment was found in 41% of patients at 1 year, in 31% at 3 years and in 11% 7 years after BMT. Patients with hematological malignancies had lower GFRs than patients with non-malignant diseases at all time points. The most important risk factor as regards chronic renal impairment was TBI. Type of donor, cyclophosphamide (CY), or acute graft-versus-host disease (GVHD) did not seem to contribute to the development of chronic renal impairment. We suggest that tests of renal function should be included in long-term followup after BMT.

Effects of perinatal asphyxia on the mesostriatal/mesolimbic dopamine system of neonatal and 4-week-old male rats.

The present study was undertaken in order to study the effects of perinatal asphyxia on tyrosine hydroxylase (TH) activity, dopamine levels and turnover, and dopamine metabolites (3,4-dihydroxyphenylacetic acid, DOPAC, homovanillic acid, HVA, and 3-methoxytyramine, 3-MT, analyzed by high-performance liquid chromatography, HPLC) measured in the basal ganglia of the 20- to 40-min-old newborn and 4-week-old male rat. Asphyxia was induced in pups by placing the fetuses, still in their uterus horns removed by hysterectomy from pregnant rats at full term, in a 37 degrees C water bath for 15-16 min or 19-20 min. Following asphyxia, the uterus horns were opened, and the pups were removed and stimulated to breathe. A 100% and 50-80% pup survival was obtained following 15-16 min and 19-20 min of asphyxia, respectively. Acute changes were studied in brains from newborn pups 20-40 min after delivery, and long-term changes were studied in brains from 4-week-old rats. No changes in TH-activity could be observed in the substantia nigra/ventral tegmental area (SN/VTA), the striatum, or the accumbens nucleus/olfactory tubercle (ACC/TUB), in the newborn or the 4-week-old rat. In the newborn rat, 19-20 min of asphyxia increased (as compared to controls) dopamine levels in the SN/VTA to 136 +/- 14% and in the ACC/TUB to 160 +/- 10%, indicating an increased synthesis and/or release of dopamine. DO-PAC levels were increased in the SN/VTA to 150 +/- 14% and in the ACC/TUB to 151 +/- 10%, and HVA levels were increased to 152 +/- 16% in the striatum and to 117 +/- 4% in the ACC/TUB. Following 15-16 min of asphyxia, dopamine levels were increased to 130 +/- 12% in the ACC/TUB, and DOPAC levels were increased to 135 +/- 6% and 130 +/- 12% in the SN/VTA and the ACC/TUB, respectively. This suggests that the increased dopamine levels may preferably reflect an increased release of dopamine following perinatal asphyxia. In the 4-week-old rat, dopamine levels were decreased in the SN/VTA to 71 +/- 4%, in the striatum to 52 +/- 8%, and in the ACC/TUB to 53 +/- 7%, following 19-20 min of perinatal asphyxia as compared to controls. No changes were observed in DOPAC, HVA, or 3-MT levels, indicating that the reduced dopamine levels reflect a reduced dopamine synthesis following perinatal asphyxia. A decrease in dopamine utilization was observed in the striatum to 15 +/- 8% and in the ACC/TUB to 9 +/- 13% following 19-20 min of perinatal asphyxia as compared to controls. This indicates that perinatal asphyxia produced long-lasting reductions in activity in the mesostriatal/mesolimbic dopamine systems in the 4-week-old rat.

Specific T and B cell immunity to measles after allogeneic and autologous bone marrow transplantation.

Lymphocyte stimulation with measles virus antigen (MLY) and ELISA for measles IgG antibodies were performed on 60 patients after allogeneic bone marrow transplantation (BMT), and on 59 patients after autologous bone marrow transplantation (ABMT). The T cell response was significantly higher in the 75 measles seropositive patients than in the 29 seronegative patients (P < 0.001), but not significantly different from the MLY in the 15 patients with uncertain serologic reactivity. When the patient group was divided according to type of transplant, the T cell response to measles was also significantly higher in seropositive patients than in seronegative patients after both ABMT (P < 0.001) and after BMT (P < 0.05). Twenty-three seronegative children who were measles vaccinated after BMT had a significantly higher T cell response to measles (7100 c.p.m.) than 17 seronegative non-vaccinated children (100 c.p.m.; P < 0.01). No significant difference was seen in the T cell response in 12 seronegative children vaccinated after ABMT (2500 c.p.m.) compared to seven children not vaccinated (2800 c.p.m.; NS). Seroconversion after vaccination was more frequent in children after BMT (20/23; 87%) compared to ABMT (5/12; 42%; P < 0.05) but no significant difference was found in the T cell response. Therefore, most patients who lost IgG antibodies to measles after bone marrow transplantation also lost their T cell response to measles. A T cell response to measles developed in most patients who seroconverted after vaccination. Failure to develop antibodies to measles in ABMT patients after revaccination may depend on a persisting T cell immunity.

Nicotine treatment counteracts perinatal asphyxia-induced changes in the mesostriatal/limbic dopamine systems and in motor behaviour in the four-week-old male rat.

In the present study, the effects of nicotine treatment on the changes induced by perinatal asphyxia in exploratory and D-amphetamine-induced behaviour, and in the number of brain tyrosine hydroxylase-immunoreactive nerve cell bodies were investigated in four-week-old male rats. Asphyxia was induced in pups by placing the fetuses, still in their uterus horns removed by hysterectomy from full-term pregnant rats, in a 37 degrees C water bath for 15-16 min or 19-20 min. Surviving male pups were treated with nicotine via suckling from surrogate mothers implanted subcutaneously with Alzet minipumps containing nicotine (0.2 mumol/kg per h) for four weeks. The minipumps implanted in the mothers of sham-treated animals contained saline only. After treatment, exploratory behaviour and D-amphetamine-induced behaviour was analysed in a computerized "activity" box. After the behavioural experiments, the rats were taken for tyrosine hydroxylase immunohistochemistry, and the total number of tyrosine hydroxylase immunoreactive cell bodies were counted in the A9 and A10 regions of the substantia nigra and the ventral tegmental area, respectively. Nicotine serum levels were measured using gas chromatography in selected asphyctic and control pups at different periods after delivery. During the exploratory phase, in saline-nurtured rats, 15-16 min of asphyxia slightly increased (approximately 25%) locomotion, motility and rearing. In contrast, 19-20 min of asphyxia reduced the locomotion and rearing by approximately 50%, as compared to controls. An increase in amphetamine-induced behaviours was observed after 15-16 min, but not after 19-20 min of asphyxia, as compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of stimulatory and inhibitory thyrotropin receptor antibodies on lipolysis in infant adipocytes.

TSH is a potent lipolytic hormone for isolated human adipocytes from neonatal subjects. Crude immunoglobulin fractions from sera of patients with Graves' disease, containing stimulatory TSH receptor (TSHR) autoantibodies, significantly increased lipolysis in fat cells from infants, whereas immunoglobulin fraction from a patient with inhibitory TSHR autoantibodies (TBab) blocked TSH-induced lipolysis in a dose-dependent manner. Although TBab totally blocked the maximum lipolysis induced by TSH (10(5) mU/L), no effect was seen on isoprenaline-induced lipolysis. The maximum lipolytic response to TSH was similar to that seen with the beta-adrenoceptor agonist isoprenaline, and there was a similar cAMP increase in response to both stimulators. From these results, it is concluded that the TSHR in infant adipocytes is likely to be coupled to the adenylate cyclase system, and the lipolytic effect of TSH can be simulated by stimulatory TSHR autoantibodies or inhibited by TBab.

Malnutrition and pharmacokinetics of penicillin in Ethiopian children.

Penicillin was given to 104 children with different nutritional status, normal, underweight, marasmus and kwashiorkor. Penicillin was given either intravenously, intramuscularly or orally and the plasma concentration was followed at regular times after administration. There was a significantly decreased plasma clearance of penicillin in all malnourished groups compared to the normal weight-for-age group. The half-lives of penicillin were, however, not significantly different between the nutritional groups. This was explained by the fact that also the volume of distribution was decreased in the malnourished group with a net result that the half-life was unchanged. The bioavailability was decreased if penicillin was given to non-fasting individuals. The greatest difference between fasting and non-fasting was seen in the severely malnourished children with marasmus and kwashiorkor. Therefore, it is advised that, if penicillin is given orally to very sick and undernourished children, the dose should be increased and preferably be given in the fasting state.

Neuropsychological deficits in very young bone marrow transplant recipients.

Bone marrow transplantation (BMT) involves conditioning with cyclophosphamide and, for patients with malignant disease, total body irradiation (TBI). This study describes the neuropsychological development of 10 children treated for leukemia (n = 7), neuroblastoma (n = 1) or severe aplastic anemia (SAA; n = 2) at 3 years of age or younger. A moderate general developmental delay, with pronounced motor deficits and varying degrees of perceptual and cognitive problems, was observed in all children treated for malignant disease. Children treated for SAA had normal development. We conclude that BMT, including TBI, can be directly associated with long-term neuropsychological impairment in children treated at a very young age. Continued medical and psychological follow-up procedures are needed.

Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings.

Among 42 consecutive recipients of unrelated marrow were 39 HLA-A, -B, -DR identical, matched unrelated donors (MUD) and three with one HLA antigen mismatch. The majority were genomically typed for DRB, DQA, DQB and DPB. The recipients of MUD marrow were compared with 39 recipients of marrow from HLA-identical siblings with similar diagnoses, disease status and age. Each group included 24 patients with hematological malignancies, 6 with severe aplastic anemia and 9 inherited disorders. Immunosuppression consisted of anti-thymocyte globulin (ATG; pre-BMT mainly to recipients of unrelated marrow), CsA and four doses of MTX. Grade I acute GVHD was treated with prednisolone 2 mg/kg. In a comparison of MUD marrow recipients and HLA-identical siblings 34 of 39 and 36 of 39 of the patients engrafted, respectively. Recipients of MUD marrow and HLA-identical siblings achieved 0.2 x 10(9) WBC/l on day 16 (median) and 14, respectively (P = 0.03). Furthermore, the recipients of MUD marrow needed more platelet transfusions (P = 0.04). The incidence of acute GVHD grade II-III was 15% in the MUD marrow recipients compared with 11% among the HLA-identical siblings. The 2-4 year cumulative incidence of chronic GVHD was 29% and 22% in the two groups, respectively. The overall 2-year survival was 59 and 78%, respectively. Among patients with CML in chronic phase or accelerated phase (n = 26), 2-year relapse-free survival was 79% in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Total body irradiation: a neuropsychological risk factor in pediatric bone marrow transplant recipients.

Bone marrow transplantation (BMT) involves conditioning with cyclophosphamide and, for leukemic patients, total body irradiation (TBI). Based on the concern that this may lead to later neuropsychologic impairment in children, a longitudinal study was conducted. Thirty pediatric bone marrow transplant recipients, treated for leukemia or severe aplastic anemia (SAA), and their sibling donors, were given a neuropsychological examination in 1986 and 1988. A third follow-up study of patients treated before 12 years of age was undertaken in 1990-91. We present longitudinal data on patients treated with BMT when 3-11 (n = 15) and 12-17 (n = 11) years old. No neuropsychological deficits were found in the older group, or among non-irradiated SAA patients. In the first follow-up, children treated with BMT, including TBI at 3-11 years of age, performed less well than donors on tasks involving perceptual and fine-motor speed. In the second follow-up, this group of patients also demonstrated a slight deficit in non-verbal problem solving. An additional relative decline in verbal reasoning was noted in the third follow-up, 5.5-10 years after treatment. Alertness to signs of developmental difficulties in children treated with BMT, including TBI, is recommended.

Allogeneic bone marrow transplantation for hemophagocytic lymphohistiocytosis in Sweden.

Six children (aged 9 months to 10 and 5/12 years) with hemophagocytic lymphohistiocytosis (HLH) have undergone allogeneic BMT in Sweden. In two of the children unrelated donors were used. Parents were available as donors in two of the cases and siblings in the other two. Conditioning before BMT consisted of etoposide, busulfan and cyclophosphamide with the addition of ATG in two cases and OKT 3 in one case. For post-transplant immunosuppression, i.v. methotrexate and cyclosporin A (CsA) were used in five cases, and in one child CsA was combined with methylprednisolone. Of the six children, four are alive and well 2 and 3/12 to 3 and 1/12 years after BMT. One child, who had an unrelated donor with one DR-antigen mismatch, died 30 days after BMT of fulminant grade IV GVHD. Another patients, seropositive for CMV, received marrow from an unrelated HLA-A, -B, -DR and -DP identical donor. After an initially uneventful course, CMV was isolated from her leukocytes. Seven months after BMT she developed a progressive obstructive chronic bronchiolitis and succumbed to respiratory insufficiency 14 months after the transplant. This study supports the view that BMT is the treatment of choice in HLH, particularly if an HLA-identical related donor is available.

Perinatal asphyxia increases bFGF mRNA levels and DA cell body number in the mesencephalon of rats.

The present investigation was undertaken in order to study the long-term effects of perinatal asphyxia on basic fibroblast growth factor (bFGF) gene expression and the number of dopamine nerve cell bodies in the mesencephalon of the rat. Asphyxia was induced during birth for 19-20 min. A 30% increase in the number of tyrosine-hydroxylase immunoreactive (TH-IR) nerve cell bodies (i.e. dopamine-containing neurones) as well as a 50% increase in bFGF gene expression following asphyxia was found in the substantia nigra/ventral tegmental area 4 weeks after birth. The increase in bFGF mRNA levels may underlie the increase found in the number of dopamine cell bodies. The present results indicate that asphyxia during birth can prime the long-term development of the central nervous system.

Longitudinal study of adrenocortical function following allogeneic bone marrow transplantation in children.

Basal serum concentrations of cortisol, dehydroepiandrosterone (DHA) and its sulfate (DHAS), 4-androstene-3,17-dione (A4) and 17 alpha-hydroxyprogesterone (17OHP) were measured yearly in children treated with bone marrow transplantation (BMT) with or without preceding total body irradiation (TBI). Age-matched controls were used for comparison. ACTH stimulation tests were performed in the patients before and after treatment. However, in the samples taken before BMT only cortisol was measured. Basal posttreatment cortisol levels were subnormal in TBI-treated boys (n = 14, aged 5-17 years at BMT) during the adrenarcheal period (7-14 years) but became normal afterwards. All other groups had normal cortisol values. Treatment neither affected basal levels nor the ACTH-induced increment (delta-value) of cortisol. In the boys treated with TBI, normal basal levels of 17OHP and adrenal androgens were found with the exception of decreased DHA levels in the postadrenarcheal boys. However, the delta-17OHP values and had an abnormal age relation and were significantly higher than in the patients not treated with TBI. In the patients not treated with TBI (6 boys aged 2-17 years) normal responses were found for 5 years or more after treatment. In female patients treated with TBI (n = 12, aged 1-16 years) circulating levels of DHA, DHAS and A4 were significantly decreased up to 5 years or more following treatment. It is concluded that after TBI, the cortisol homeostasis is maintained at the cost of reduced adrenal androgen secretion.

Busulfan bioavailability.

Busulfan is widely used as a component of the myeloablative therapy in bone marrow transplantation. Recent studies have shown that the drug disposition is altered in children and is associated with less therapeutic effectiveness, lower toxicities, and higher rates of engraftment failure. We have evaluated the bioavailability of the drug in two groups of patients: eight children between 1.5 and 6 years of age and eight older children and adults between 13 and 60 years. Oral bioavailability showed a large interindividual variation. In children, the bioavailability ranged from 0.22 to 1.20, and for adults, it was within the range 0.47 to 1.03. The elimination half-life after intravenous administration in children (2.46 +/- 0.27 hours; mean +/- SD) did not differ from that obtained for adults (2.61 +/- 0.62 hours). However, busulfan clearance normalized to body weight was significantly higher in children (3.62 +/- 0.78 mL.min-1.kg-1) than that in adults (2.49 +/- 0.52 mL.min-1.kg-1). Also, the distribution volume normalized for body weight was significantly higher in children (0.74 +/- 0.10 L.kg-1) compared with 0.56 +/- 0.10 L. kg-1 in adults. The difference in clearance between children and adults was not statistically significant when normalized to body surface area, which most probably shows that busulfan dosage should be calculated on the basis of surface area rather than body weight. However, to avoid drug-related toxicities, drug monitoring and an individual dose adjustment should be considered because of the variability in busulfan bioavailability.

Long-term immunity to measles, mumps, and rubella after allogeneic bone marrow transplantation.

A total of 124 patients who had survived at least 2 years after allogeneic bone marrow transplantation (BMT) were studied. Serum was collected at least once yearly. IgG antibodies were determined by enzyme-linked immunosorbent assay for measles and mumps. Rubella antibodies were analyzed by radial hemolysis. Antibody levels were interpreted as representing immunity, seronegativity, or seropositivity, but with uncertain immunity. The median follow-up of the patients was 6.5 years (range, 2 to 13.5 years). The calculated probabilities of being immune to measles at 3, 5, and 7 years from BMT were 47%, 27%, and 20%, respectively. The corresponding probabilities for mumps were 37%, 12%, and 6%, respectively; and for rubella, 47%, 33%, and 28%, respectively. The probabilities for being seronegative for measles, mumps, and rubella at 5 years after BMT were 60%, 73%, and 52%, respectively. When compared with those patients who had experienced previous natural measles disease (P < .05), the only factor that was important for immunity to measles after BMT was whether the patient had been immunized before BMT. There was no influence of donor seropositivity on the probability of becoming seronegative to mumps during follow-up. We conclude that most allogeneic patients will become seronegative to measles, mumps, and rubella during follow-up. Therefore, long-term B-cell memory function is not maintained, regardless of the immune status of the donor.

Thyroid function in children after allogeneic bone marrow transplantation.

Thyroid function was investigated in 35 children after allogeneic BMT. The study was longitudinal and all patients were followed for at least 5 years. Once a year TSH, T4, T3 and the TRH test were performed. Patients with severe aplastic anemia (n = 6) were transplanted without total body irradiation (TBI) and they had no detectable alterations in thyroid function. Patients with leukemia (n = 27) were conditioned with 10 Gy TBI in one fraction. The accumulated frequencies of thyroid dysfunction were 3 of 27 (11%) with high TSH and low T3 or T4 levels, and 10 of 27 (37%) with high basal TSH and normal T3 and T4 levels. An additional 11 of 27 (41%) had an exaggerated TSH response in the TRH test and normal basal TSH and T3/T4 levels. Only 3 of 27 (11%) continued to have normal values. Treatment with levo-thyroxine (L-T4) was given to the patients with a high basal TSH level. As 24 of 27 (89%) children had signs of disturbance in the thyroid axis, prophylactic L-T4 treatment for a few years after BMT with TBI may be of value. The main cause of a change in thyroid function after BMT seems to be conditioning with TBI.

Growth hormone increases the lipolytic sensitivity for catecholamines in adipocytes from healthy adults.

The lipolytic effect of growth hormone (GH) was investigated in adipocytes obtained during elective surgery from otherwise healthy adults, 18-40 years old. No lipolytic or antilipolytic effect of GH was found when the cells were incubated with GH alone during 30min-6h. When the cells were preincubated with GH during 3h, the lipolytic sensitivity for isoprenaline increased markedly without any change in maximal lipolysis. However, a full effect was only obtained if GH was also present during the incubation with isoprenaline. GH did not alter DB-CAMP, enprophylline, or forskolin-induced lipolysis in human fat cells. In conclusion, GH had no direct lipolytic effect on human fat cells but GH markedly increased the catecholamine sensitivity. The site of the GH effect seems to be in the beta-adrenoceptors or in the Gs coupling protein.

Disposition of salicylic acid in malnourished Ethiopian children after single oral dose.

The disposition of salicylic acid and salicyluric acid was studied in 57 Ethiopian children of varying nutritional status after oral administration of sodium salicylate in single doses of either 12.5 or 25 mg/kg. There was no apparent influence of nutritional status on oral salicylate disposition when related to total plasma concentrations. Unbound concentrations were predicted from total plasma concentrations on the basis of a single time point determination of protein binding in each individual, according to a Scatchard model. Areas under the unbound plasma concentration-time curve were larger and the fractional excretion of salicyluric acid was lower in children with kwashiorkor compared with control individuals. This was interpreted as lower hepatocellular metabolic activity in patients with kwashiorkor. Children with marasmus retained an unimpaired capacity for salicylate metabolism. The influence of saturable distribution and elimination are discussed.

Expression of beta 1- and beta 2-receptor genes and correlation to lipolysis in human adipose tissue during childhood.

beta 1- and beta 2-adrenoceptor (bar1 and bar2) mRNA levels were measured in adipose tissue obtained from children (between 1 month and 10 yr of age) and adults during inguinal hernia operations. Bar1 mRNA levels were constant in all age groups studied. In infants and children less than 7 yr old, bar2 levels were twice as high (P < 0.01) as those in adults, and in infants 1-4 months old, bar2 mRNA levels were higher than bar1 levels (P < 0.01). The bar2/bar1 ratio gradually decreased, and in adults, there was 2.3-fold higher bar1 mRNA expression (P < 0.01). In infants 1-5 months old, the lipolytic sensitivity to noradrenaline was 5 times lower (P < 0.05) than that in adults, whereas the sensitivity to adrenaline and isoprenaline was unchanged. The maximal lipolytic response to adrenaline was higher than that to noradrenaline in infants (P < 0.01), whereas the opposite was found in adults (P < 0.01). The lipolytic sensitivity to the bar1-selective agonist dobutamine was not influenced by age, whereas the sensitivity to the bar2-selective agonist terbutaline was 10,000 times higher in infants than in adults. In conclusion, these data indicate subtype-specific developmental changes in bar expression, with higher bar2 mRNA levels accompanied by increased bar2-induced lipolysis during infancy.