Lysinuric protein intolerance. Basolateral transport defect in renal tubuli.

In patients with an autosomal recessive diamino acid transport disorder, lysinuric protein intolerance (LPI), we measured plasma and urinary amino acids basally, and during intravenous infusion of citrulline at two rates. Compared with controls, the patients' plasma citrulline concentrations rose similarly, but urinary citrulline excretion increased excessively. Their plasma arginine and ornithine levels rose subnormally, but massive argininuria and moderate ornithinuria appeared. The excretion rates of the third diamino acid lysine and other amino acids remained practically unaltered, thus excluding mutual competition as the cause for the increases. The results suggest that (a) in the normal kidney reabsorption involves partial conversion of citrulline to arginine and ornithine (metabolic run-out), (b) in LPI, the diamino acid transport defect is located at the basolateral cell membrane of the renal tubules; this inhibits the efflux of arginine and ornithine, increasing their cellular concentration, which in turn inhibits the metabolic disposal of citrulline, and causes leakage of arginine, ornithine, and citrulline into the tubular lumen.

Skeletal changes in childhood acute lymphoblastic leukemia: correlation with the presence of the cALL antigen.

We studied the occurrence of the radiolucent metaphyseal bands in pretreatment skeletal X-rays and the phenotype of leukemic cell in 66 children with non-T, non-B ALL. A striking correlation was found between the expression of the CALLA on the leukemic cell and the occurrence of the early metaphyseal bands. We speculate that the bands might reflect an ongoing anti-leukemic reaction which may have been in progress before the disease became clinically manifest and which is associated with relatively favorable prognosis after even a modest chemotherapy.

Fibronectin concentration in cerebrospinal fluid reflects early central nervous system involvement in children with acute lymphoblastic leukemia.

We measured concentrations of fibronectin (FN) in the cerebrospinal fluid (CSF) in long-term follow-up patients with acute lymphoblastic leukemia (ALL). In 11 patients with neuroleukemia the CSF-FN level was elevated already at the time of diagnosis of ALL, 3.8 +/- 0.6 mg/l, increased during therapy to 4.7 +/- 0.5 mg/l, and at the time of concurrent blast cell finding it was 5.5 +/- 1.0 mg/l. In 11 patients with no subsequent CNS leukemia, the mean CSF-FN level was 2.4 +/- 0.6 mg/l at the time of diagnosis of ALL and 2.8 +/- 0.6 mg/l during therapy, and increased to 3.2 +/- 0.8 mg/l. The neuroleukemia rate was 43% in patients with initial CSF-FN levels greater than 2 mg/l, compared with 5% in patients with CSF-FN levels less than or equal to 2 mg/l (p less than 0.005) in a group of 45 long-term follow-up patients with ALL. Regression analysis on the 21 clinical or laboratory parameters studied showed that the only variable independently associated with CSF-FN was the total protein concentration in the CSF; this, however, explained only 14% of the observed variation in the CSF-FN concentration and did not show any correlation with CNS involvement. We conclude that the CSF-FN test at diagnosis of ALL showed significant differences between groups of patients with and without CNS leukemia, and may prove to be a new early marker for neuroleukemia.

Growth failure and growth hormone deficiency in children after bone marrow transplantation for leukemia.

Eleven patients between the ages of 6 and 18 years who had been treated for acute leukemia were investigated for growth and growth hormone (GH) secretion. All had undergone bone marrow transplantation (BMT) between 0.7 and 5.1 (median 2.0) years previously. Preparation of patients for BMT had included high-dose cyclophosphamide and total body irradiation. In the eight patients at risk of growth failure, the relative height decreased 0.5-2.5 SD units (median 1.0) during the follow-up period. Eight patients secreted subnormal amounts of GH as studied by measuring spontaneous pulsatile GH secretion overnight. The maximal nocturnal GH peak varied between 3.3 and 28.3 micrograms/l (median 9.3). The mean nocturnal GH concentration varied from 1.2 to 8.3 micrograms/l (median 2.3) and depended on the length of the follow-up period. We conclude that deficient GH secretion is one reason for poor growth after BMT. A good growth response to GH substitution would support the role of GH deficiency in the observed growth retardation after BMT.

Graft-versus-leukaemia activity associated with CMV-seropositive donor, post-transplant CMV infection, young donor age and chronic graft-versus-host disease in bone marrow allograft recipients. The Nordic Bone Marrow Transplantation Group.

Risk factors for post-transplant relapse were analysed retrospectively in 163 patients treated with allogenic bone marrow transplantation for acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma in first to fourth remission or during relapse. Multifactorial analysis was performed according to Cox with fixed pretransplant covariates and post-transplant cytomegalovirus (CMV) infection and graft-versus-host (GVHD) as time-dependent covariates. Advanced stage of leukemia at the time of transplantation was an important risk factor for subsequent relapse. Furthermore, the study confirmed a graft-versus-leukaemia (GVL) activity associated with chronic GVHD, including de novo chronic GVHD (intensity factor 0.08, p = 0.004). In a model excluding chronic GVHD, female donor-to-male recipient (a risk factor for GVHD), was associated with decreased post-transplant relapse risk (intensity factor 0.3, p = 0.008), suggesting that an allo-reaction against a minor transplantation antigen (Hy) may mediate antileukaemic activity. A decrease of the relapse risk by a factor 0.18 was observed in recipients with AML as well as ALL when the donor was CMV seropositive (p = 0.0002). This effect was restricted to patients who had laboratory evidence of post-transplant CMV infection. When CMV infection occurred and donor was seropositive the relapse risk was reduced by a factor 0.035. The effect was not mediated through an increased occurrence of grade 2-4 acute or chronic GVHD and could not be explained by a statistical bias due to censoring of patients who died in remission. Rather, donor CMV immunity was associated with GVHD independent GVL activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral administration of urea cycle intermediates in lysinuric protein intolerance: effect on plasma and urinary arginine and ornithine.

In lysinuric protein intolerance, an autosomal recessive disorder of amino acid transport, oral citrulline increases the plasma concentration of urea cycle intermediates more than does oral arginine or ornithine. The clinical improvement suggests that citrulline affords the best means of correcting the ornithinopenic malfunction of the urea cycle.

Ferritinemia with subnormal iron stores in lysinuric protein intolerance.

To study the mechanism of ferritinemia in patients with lysinuric protein intolerance (LPI), an autosomal recessive disorder of diamino acid transport, we made a histologic evaluation of intracellular iron and/or ferritin in bone marrow and liver aspirates of 21 patients. We found no stainable iron in bone marrow cells. This was also the case in the liver in 8/9 of the patients. The hepatocytes were negative for ferritin particles in electron microscopy. The ferritin half-time in plasma was computed from the decrease in serum ferritin concentration during partial exchange transfusion. In the two patients tested the values were prolonged (95 and 65 min). We give evidence that in LPI serum ferritin is increased disproportionately to the size of iron stores in bone marrow reticulum cells and in the hepatocytes. We speculate that this inappropriate ferritinemia is due to impaired uptake of ferritin from plasma.

t(11;19)(q23;p11) in a child with acute T-cell leukemia.

A translocation, t(11;19)(q23;p11), is reported in a child with T-cell leukemia. Our case indicates that the t(11;19) may not be restricted to the monocytic leukemias, as earlier reported, but may occur in other malignancies.

Nitrogen utilization during postoperative, low nitrogen, high caloric parenteral nutrition.

Twenty elderly patients having undergone colonic resection were randomized into two regimens of postoperative parenteral nutrition. Fructoglucose satisfied the basal caloric needs of the patients. Amino acids were given as a mixture that provided 0.11 (0.09-0.14; mean and range) g/kg/day of nitrogen only. In half of the patients the energy intake was doubled with fat emulsion. The mean nitrogen-energy ratios in grams of nitrogen/kcal/day were 1:201 and 1:336 in the two groups, respectively. Both regimens were given for three days, starting from the first postoperative day. On the first day, the mean nitrogen balance was negative in both groups. On the third day, the mean balance was slightly positive in the amino acid, fructoglucose plus fat emulsion group, but negative in amino acid plus fructoglucose group. Amino acid concentrations in plasma and urine were markedly elevated in both groups, but relative concentrations in plasma remained rather normal. Apparently, a positive postoperative nitrogen balance can be obtained with restricted amino acid supply, if energy is provided in abundance.

Perceptions of problematic events and quality of care among patients and parents after successful therapy of the child's malignant disease.

Fifty-three children (mean age 6.4 at diagnosis, 12.8 years at completion of questionnaires) identified as having acute lymphoblastic leukaemia (48) or non-Hodgkin lymphoma (5) during the 11-year period of 1976-1986 participated in the present study. Patients' and parents' perceptions of malignancy-related changes in significant relationships, of treatment-related problematic events, as well as of the quality of care provided during induction and maintenance-therapy were assessed using questionnaires. The results indicated mainly positive changes in significant relationships during the chemotherapy. However, concurrent stressful life events affected the relationships adversely. Alopecia (hair loss) was the most problematic disease-related event for the patient and the patient's anorexia for the parents. Patients' complaints were most often about the quality of care during induction, namely pain, fear and insufficient information. Parents' complaints were about the lack of continuity in the staff-patient relationship during maintenance-therapy.

Aggression: the dominant psychological response in children with malignant disease.

During the 11-yr. period of 1976 to 1986 leukemia or lymphoma treatment at the Children's Hospital, University of Helsinki was electively discontinued for the children in 90 different families. Of the 53 (59%) patients (mean age 6.4 yr. at diagnosis and 12.8 yr. at completion of questionnaires) who agreed to participate in the present study, 48 had acute lymphoblastic leukemia and five nonHodgkin lymphoma. Patients' and parents' impressions of the patients' psychological reactions during patients' prior chemotherapy were evaluated on parental and self-ratings. Also, knowledge of and presumed causes of the malignancy were studied. Patients' reactions of aggression, depression, eating disorders, hypersensitivity, phobic anxiety, death anxiety, and night terror were examined using factor analysis. Aggression, in the form of irritation and anger, was displayed more often by girls than by boys. Patients of families suffering from stress were prone to exhibit aggression in the form of mood changes, irritation, and anger. Patients with disease-related knowledge, as opposed to those less well informed, were less depressed. Discrepancies between parents' and patients' thoughts about the origin of the malignancy were noted.