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C Holmberg

Publications and source records attributed to C Holmberg.

At least 73 records · Page 4Linked to original sources
PubMed1996

Health-related quality of life of adults surviving malignancies in childhood.

While sophisticated data on specific problems are available, very little is known about the overall quality of life of long-term survivors of malignancies in childhood. We used a previously validated 15-dimensional questionnaire to examine the perceived health-related quality of life of 168 survivors, currently aged 16-35 years, who had been treated for a malignancy at a single institution between 1961 and 1993. All had been off therapy for at least 1 year (median, 12 years). In statistical terms, the quality of life score of the survivors was significantly better than that of 129 normal controls [0.966 versus 0.941 (theoretical maximum 1), respectively; P < 0.001]; however, a difference of this magnitude is most likely not clinically significant. There were no associations between original diagnosis and present quality of life, but the numbers in each diagnostic group were small. The survivors reported significantly better levels of vitality, distress, depression, discomfort, elimination and sleeping dimensions than the controls. Although we are presently not able to identify all the contributing factors, we speculate that the high perceived quality of life of long-term survivors of childhood malignancies is at least in part a consequence of denial mechanisms which compensate or even overcompensate the objectively measurable late effects of childhood cancer.

Adolescent↗
PubMed1996

Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea.

A major transport function of the human intestine involves the absorption of chloride in exchange for bicarbonate. We have studied a recessively inherited defect of this exchange, congenital chloride diarrhoea (CLD; MIM 214700). The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea with a high chloride content. The CLD locus was previously mapped to 7q3 adjacent to the cystic fibrosis gene (CFTR). By refined genetic and physical mapping, a cloned gene having anion transport function, Down-regulated in adenoma (DRA), was implicated as a positional and functional candidate for CLD. In this study, we report segregation of two missense mutations, delta V317 and H124L, and one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD patients. The disease-causing nature of delta V317 is supported by genetic data in relation to the population history of Finland. By mRNA in situ hybridization, we demonstrate that the expression of DRA occurs preferentially in highly differentiated colonic epithelial cells, is unchanged in Finnish CLD patients with delta V317, and is low in undifferentiated (including neoplastic) cells. We conclude that DRA is an intestinal anion transport molecule that causes chloride diarrhoea when mutated.

Adenoma↗
PubMed1996

Positional candidate genes for congenital chloride diarrhea suggested by high-resolution physical mapping in chromosome region 7q31.

Congenital chloride diarrhea affects intestinal transportation of electrolytes, resulting in potentially fatal diarrhea. Linkage disequilibrium analyses have suggested the congenital chloride diarrhea gene (CLD) to lie within 0.37 cM from D7S496 in human chromosome 7q31. To clone the CLD gene, we have constructed and refined a physical map based on a 2.7-Mb YAC contig around D7S496 and identified two candidate genes. The physical positions of 4 known genes (DRA, PRKAR2B, LAMB1, DLD), 7 polymorphic repeat markers, and 13 CpG islands were established. DRA (down-regulated in adenoma) is expressed in the gut and encodes a protein with sequence homology to anion transporters, whereas PRKAR2B encodes a regulatory subunit for protein kinase A. Both genes map within 450 kb from D7S496, making them functionally and positionally relevant candidates for CLD.

Base Sequence↗
PubMed1996

Mechanisms of hyperuricemia in cyclosporine-treated renal transplanted children.

Mechanisms of hyperuricemia were investigated in 19 pediatric renal transplant recipients 6 months after transplantation. 51Cr-EDTA, PAH, lithium and sodium clearances, 24-hour urinary creatinine and urate excretions were measured. Ten patients had hyperuricemia. The hyperuricemic patients had lower EDTA, PAH, and urate clearances (mean 69.5 vs. 92.5, p < 0.05, 234 vs. 421, p < 0.05 and 4.3 vs. 10.6 ml/min/1.73 m2, p < 0.001, respectively). Serum urate concentration correlated with cyclosporine dose (r = 0.46, p < 0.05) and inversely with urate (r = -0.88, p < 0.001), and lithium (r = -0.55, p < 0.05) clearances. Urate clearance showed a significant positive correlation with lithium clearance (r = 0.66, p = 0.01) and an inverse correlation with fractional proximal tubular reabsorption (r = -0.63, p = 0.02). Results were not influenced by diuretic administration. Our data support increased proximal tubular urate reabsorption rather than decreased secretion as the mechanism in cyclosporine-induced hyperuricemia.

Azathioprine↗
PubMed1996

Mechanisms of proteinuria: vascular permeability factor in congenital nephrotic syndrome of the Finnish type.

Vascular permeability factor (VPF) is the most potent known mediator of vessel wall permeability. In the kidney, it is expressed preferentially in the glomerular visceral epithelial cells. The present study was designed to clarify the proposed role of VPF in diseases with increased glomerular permeability as here exemplified by the congenital nephrotic syndrome of the Finnish type (CNF). For this, we studied the expression levels and the sites of synthesis of VPF and its kinase-insert domain receptor (KDR) in kidneys of patients with CNF using Northern and in situ hybridization techniques and immunohistologic staining with anti-VPF antibody. In addition, we extended the study to include analysis of fetal kidney tissue and cultured glomerular cells of normal and CNF kidneys. In CNF and in normal kidneys VPF was localized in the visceral epithelial aspect of the glomeruli and in the collecting ducts, as also earlier described. A new finding was its localization also in the juxtaglomerular area. The VPF receptor KDR was found in glomeruli in the endothelial cells, but it was not detected in the peritubular capillaries. no consistent differences in the levels of VPF or KDR mRNAs or in their sites of production were seen in CNF and control samples. Also the distribution of VPF antigen in the CNF kidneys and normal kidneys was similar. Thus, we propose that VPF and KDR are not directly involved in the pathogenesis of the proteinuria in CNF.

Cells, Cultured↗
PubMed1996

Recombinant human growth hormone improves growth in children receiving glucocorticoid treatment after liver transplantation.

Linear growth is often impaired after successful liver transplantation. The cause is multifactorial; poor graft function and long term glucocorticoid treatment are the main factors responsible. The efficacy and safety of recombinant human GH (rhGH) treatment were assessed in eight growth-retarded children (five boys and three girls) with liver transplants. Immunosuppression comprised azathioprine, cyclosporin, and methylprednisolone. rhGH was administered in a dose of 1 IU/kg x week, given by daily sc injections. The median age at the start of treatment was 9.7 yr (range, 5.9-14.9 yr). All but one of the patients remained prepubertal during treatment. The median growth rate increased from 3.2 to 7.l cm/yr (P = 0.025) and height SD score increased from -3.9 to -3.1 (P = 0.036) during the first year of rhGH treatment. Serum insulin-like growth factor I and insulin-like growth factor-binding protein-3 levels increased significantly during treatment. Graft function was normal in all except one patient, and no rejections or other serious side-effects were documented. In conclusion, rhGH treatment is effective in short, non-GH-deficient, liver-transplanted children receiving long term glucocorticoid treatment. Due to potential risk of allograft rejection, close monitoring of liver function and immunosuppression is required.

Azathioprine↗
PubMed1996

Haplotype analysis of congenital nephrotic syndrome of the Finnish type in non-Finnish families.

Congenital nephrotic syndrome of the Finnish type (CNF) has an estimated incidence of 1 in 8000 newborns in the genetically isolated population of Finland. Although the disease is most common in Finland, it occurs throughout the world in families without known Finnish origin. In the past, these authors recently localized the CNF gene to the chromosome 19q13.1 region and observed strong linkage disequilibrium to the genetic markers D19S610, D19S608, D19S224, and D19S220 in Finnish families. In these Finnish families, four main CNF haplotype categories have been observed. In the study presented here, haplotype analysis was applied to several non-Finnish CNF families to determine whether the same genetic locus is involved in these families. The results of the haplotype analysis suggest linkage to the 19q13.1 chromosomal region. It was also observed that, in most cases, alleles typically found on CNF chromosomes of Finnish families are also found on CNF chromosomes of non-Finnish families from North America and Europe. In these families, the strongest association was found with marker D19S608. These findings suggest that Finnish and many non-Finnish CNF cases share the same disease locus.

Alleles↗
PubMed1996

Congenital nephrotic syndrome.

Congenital nephrotic syndrome (CNS) can be caused by neonatal infections, renal diseases which exceptionally occur in early infancy and syndromes with a renal histology of DMS. The most common CNS is the Finnish-type (CNF), an autosomal recessively inherited disease characterized by intrauterine onset of massive proteinuria. The CNF gene has been localized to the long arm of chromosome 19, but the pathogenesis remains unclear. Forty-six CNF patients have been treated at our institution. The diagnosis was based on family history, severe proteinuria of intrauterine onset (serum albumin < 10 g/liter at presentation and urinary protein > 20 g/liter when serum albumin was corrected to > 15 g/liter), a large placenta (> 25% of birth wt), exclusion of other CNS-types and normal glomerular filtration rate during the first six months. Treatment included i.v. albumin substitution, optimal nutrition, thyroxine and anticoagulation. Forty-one patients had been nephrectomized bilaterally at a mean age of 1.2 years and after 3 to 25 months on peritoneal dialysis renal transplantation (Tx) had been performed on 34 who were a mean age of 2.2 years. Growth and development has been normal. Patient survival after Tx was 97%, graft survival 94%, 81% and 81% one, three and five years after Tx was (50% cadaver grafts). Mean GFR was 75 ml/min/1.73 m2 after three years, mean height SDS -1.42, and the nine oldest patients attend school in a normal class.

Humans↗
PubMed1996

Provocative growth hormone testing is not required before initiation of rhGH treatment in children with renal and liver transplants.

GH provocative testing does not predict subsequent growth response, and is not therefore required before initiation of rhGH treatment in children with renal and liver transplants. However, therapeutic doses of glucocorticoids may potentially inhibit GH secretion in some patients, and determining GH secretory status by provocation tests and measuring spontaneous GH secretion is advisable at some point after organ Tx to exclude GH deficiency.

Adolescent↗
PubMed1995

Differences in linear growth and cortisol production between liver and renal transplant recipients on similar immunosuppression.

Linear growth is more often impaired after liver than after renal transplantation (Tx) in childhood. As similar triple immunosuppression was used in our liver and renal transplant recipients, we were able to compare growth and endocrine function between 19 prepubertal liver and 35 renal transplant recipients. There were no significant differences in median age, weight-for-height index, or height standard deviation score at Tx. Seventy-eight percent of the liver Tx patients, but only 7% of the renal Tx patients, were below the normal range for height 3 years after Tx. Graft function was good in both liver and renal transplant recipients 3 years after Tx. There was no significant difference in growth hormone secretion, serum insulin-like growth factor (IGF)-I, and IGF-binding protein-3 levels, or in methylprednisolone and cyclosporine doses. However, the blood cyclosporine levels were significantly higher in the liver transplant recipients (P = 0.001 1 year and P = 0.005 2 years after Tx). Cortisol production was significantly lower in the liver transplant recipients (P = 0.002 1 year and P = 0.049 2 years after Tx), which suggests greater steroid-mediated suppression of adrenal function. Growth inhibition is more often observed in liver than in renal transplant recipients on similar triple immunosuppression, and may not be related to deficient function of the growth hormone-IGF-I axis. Similar cyclosporine doses result in higher plasma levels of the drug and similar methylprednisolone doses result in more inhibited adrenal cortisol production in liver transplant recipients. In children with organ transplants, cyclosporine and methylprednisolone should be administered on an individual basis.

Adrenocorticotropic Hormone↗
PubMed1995

Rapid Ca2+ mobilization in single LGL cells upon interaction with K562 target cells--role of the CD18 and CD16 molecules.

Changes in the intracellular Ca2+ levels of human large granular lymphocytes (LGL), loaded with the fluorescent Ca2+ indicator fura-2, have been studied upon addition of human chronic myelogenous leukemia K562 cells. The measurements, analyzed at the single-cell level using image analysis, indicate a rapid Ca2+ mobilization in the effector cell upon interaction with its target cell. This mobilization appeared to be localized to an area within the effector cell that was in physical contact with target cells. The LGL responded with different kinetics in a transient manner and about 19% of them could undergo two or more responses. Data obtained from experiments performed with anti-CD16- and anti-CD18-pretreated LGL in the presence of target cells indicate that the CD16 and CD18 molecules are not likely to be the triggers of the Ca2+ response, although they might participate in the recognition of the target cell.

Antibodies, Monoclonal↗
PubMed1995

Management of congenital nephrotic syndrome of the Finnish type.

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessively inherited disease characterised by intrauterine onset of massive urinary loss of proteins, 90% of which is albumin. The CNF gene has been localised to the long arm of chromosome 19, but the pathogenesis remains unclear. Historically, all CNF patients died, usually within the first 6 months of life. Today, a normal life can be achieved for a child with CNF by correcting the protein deficiency and normalising nutrition. This is accomplished by early intravenous albumin supplementation, nutritional support, aggressive treatment of complications and early renal transplantation, after bilateral nephrectomy and peritoneal dialysis. In the present article current treatment strategies are reviewed, and our own experience with 43 CNF patients during the last 10 years is presented.

Child, Preschool↗
PubMed1995

Alphacalcidol oral pulses normalize uremic hyperparathyroidism prior to dialysis.

Alphacalcidol oral pulse therapy was given for secondary hyperparathyroidism to 22 children (mean age of 5.6 years) with renal insufficiency. At the beginning of the study, the glomerular filtration rate was < 50% of normal, serum intact parathyroid hormone (PTH) was > 100 ng/l and the serum phosphate and calcium concentrations were within the normal range. Alphacalcidol (0.5-3.0 micrograms) was given orally thrice weekly in the evening and adjusted according to PTH, ionized calcium and phosphate concentrations. Serum PTH (mean +/- SEM) decreased significantly from a pre-treatment level of 393 +/- 81 ng/l to 122 +/- 34 ng/l after 12 months, and stabilized at this level. Mean vitamin D metabolite concentrations were within the normal range. 1,25-Dihydroxyvitamin D did not increase during therapy, while PTH decreased. The estimated creatinine clearance remained almost unchanged (20 +/- 3 and 21 +/- 6 ml/min per 1.73 m2). Growth remained low normal (height standard deviation score -1.8 +/- 0.3 initially and -1.7 +/- 0.4 12 months later) and bone mineral density did not decrease. We concluded that feedback regulation of PTH with oral alphacalcidol pulse therapy is effective in the treatment of hyperparathyroidism in children with renal failure prior to dialysis.

Adolescent↗
PubMed1995

Alpha-actinin in nemaline bodies in congenital nemaline myopathy: immunological confirmation by light and electron microscopy.

To elucidate the protein composition of the nemaline bodies present in the muscle fibres of patients with congenital nemaline myopathy (CNM), we studied muscle biopsies with monoclonal antibodies against alpha-actinin and desmin in combination with a modified Gomori trichrome method. Electron microscopy of immunolabelled resin embedded sections was used for cytochemical localisation of alpha-actinin and desmin. Light microscopy of sections immunolabelled for alpha-actinin showed a cross-striation of the muscle fibres corresponding to the Z band pattern, focal thickening of the Z bands and additional reactivity with a granular pattern corresponding to the presence of nemaline bodies. Labelling of desmin did not show a similar pattern. Electron microscopy confirmed the presence of alpha-actinin in the nemaline bodies and Z bands, whereas desmin was only found in intermediate filaments around the Z bands. Western blots showed single, sharp alpha-actinin bands indistinguishable from normal. Our results provide direct evidence for the presence of alpha-actinin in nemaline bodies and a lack of quantitative or qualitative differences between the alpha-actinin of normal and CNM muscle.

Actinin↗
PubMed1995

Resistance to activated protein C as an underlying cause of recurrent venous thrombosis during relapsing nephrotic syndrome.

A 16-year-old patient with relapsing nephrotic syndrome had three episodes of deep vein thrombosis after the age of 15 years. An autosomal inherited genetic abnormality of clotting factor V, resistance to activated protein C, was found. The clinical course showed that this resistance and the nephrotic syndrome potentiated each other as risk factors for deep vein thrombosis, and long-term anticoagulation was indicated.

Adolescent↗
PubMed1995

Renal and adrenal mechanisms in cyclosporine-induced hyperkalaemia after renal transplantation.

CsA associated hyperkalaemia was investigated in 24 renal transplant recipients 6 months after transplantation. 51Cr-EDTA-, PAH-, lithium and sodium clearances, 24 h urinary creatinine and potassium excretions, plasma renin activity and aldosterone concentrations were measured. Transtubular potassium concentration gradient (TTKG) was calculated. An ACTH test was performed to document adrenal function. Eleven patients had hyperkalaemia. The TTKGs were low normal or reduced in both normo- and hyperkalaemic patients implying inhibition of K+ secretion. The hyperkalaemic patients received more CsA (mean dose 21.3 vs. 9.7 mg kg-1d-1, P = 0.01), and had lower lithium clearances (mean 9.9 vs. 17.0 mL min-1 1.73 m-2, P < 0.05). Adrenal function had no clear effect. Serum potassium concentration correlated with CsA dose (r = 0.773, P < 0.001) and inversely with lithium clearance (r = -0.568, P < 0.01) suggesting that CsA induced decrease in distal tubular flow rate reduced K+ excretion. Hyperkalaemia was not fully explained by renal mechanisms.

Adolescent↗