Glucocorticoids and growth problems.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
C Holmberg
Publications and source records attributed to C Holmberg.
Glomerular antigens in severe hereditary nephrosis.
In search of the basic defect and cell type responsible for the massive treatment-resistant proteinuria of congenital nephrotic syndrome of the Finnish type (CNF), we examined tissue samples of CNF kidneys using established antibody and lectin markers of various glomerular cell types. Markers of vascular endothelium (antibodies to factor VIII and a human homologue of podocalyxin (anti-PHM5) and UEA I lectin) showed no qualitative changes in the endothelial cells of glomeruli or peritubular areas in CNF as compared with controls. Markers of glomerular mesangial cells (antibodies to desmin, smooth muscle actin, RCA I lectin) revealed a secondary increase in mesangial reactivity reflecting the sclerosis and expansion of the mesangial areas in CNF. Markers of visceral epithelial cells (antibodies to a human homologue of podocalyxin, C3b receptor, vimentin, common lymphocytic leukemia antigen, gp44, and the WGA, LFA and, after neuraminidase treatment, PNA lectin) failed to show appreciable qualitative changes in CNF kidney samples. Interestingly, the alpha 2 beta 1 integrins appeared greatly reduced in all CNF samples studied, possibly explaining the mechanisms of CNF-associated proteinuria.
Autoantigens↗
The nephropathy of type I tyrosinemia after liver transplantation.
Type I tyrosinemia (HTI) is an autosomally recessively inherited disease caused by deficiency of fumarylacetoacetate hydrolase. The disease manifests with liver failure, renal tubular defects, and neurologic crises. Currently orthotopic liver transplantation (OLT) enables patients to survive. However, renal fumarylacetoacetate hydrolase deficiency is not corrected by OLT, and the long-term prognosis of the nephropathy is not known. We investigated tyrosine metabolism, GFR, renal tubular function, and histopathology before and 18-36 mo after OLT in eight patients with HTI. Progressive renal dysfunction was not documented despite continuing, although diminished, urinary succinylacetone excretion in all patients. The mean GFR was 82 mL/min/1.73 m2 before and 102 mL at 18 mo and 93 mL at 36 mo after OLT. All patients showed tubular dysfunction before OLT. At 18 mo, glucosuria occurred in one, amino aciduria and phosphaturia in three, and hypercalciuria in six patients. Only hypercalciuria was seen at 36 mo. Renal biopsies showed mild nonspecific changes caused either by minimal progression of the renal disease or by mild cyclosporine nephrotoxicity. In conclusion, patients with HTI had normal GFR, but showed signs of tubular dysfunction 18-36 mo after OLT. Renal function and histopathology should be monitored after OLT for HTI.
Amino Acid Metabolism, Inborn Errors↗
Growth delay after liver transplantation in childhood: studies of underlying mechanisms.
After liver transplantation in children, growth is often impaired, but the underlying mechanisms are unknown. Glucocorticoids used for immunosuppression are believed to be partly responsible. After renal transplantation in children, reduced growth hormone (GH) secretion and increased serum insulin-like growth factor-binding protein-3 (IGFBP-3) levels have been reported. We attempted to find endocrine factors predicting growth in 18 prepubertal children followed for more than 1 y (mean 2.4 y) after liver transplantation. Spontaneous and stimulated GH secretion, serum IGF-I, IGFBP-3 concentrations, and endogenous cortisol production were measured. GH secretion was reduced in only two patients. Serum IGF-I concentration was normal, but serum IGFBP-3 was elevated or 1 SD above the mean for age in 62% of the patients. Endogenous cortisol production was reduced in most patients during the first year and improved later in only a few. Growth velocity after transplantation did not correlate with GH secretion, serum IGF-I or IGFBP-3 concentration, or with methylprednisolone dose, but correlated positively with serum basal (rs = 0.44, p < 0.05) and stimulated (rs = 0.53, p < 0.005) cortisol concentration. In conclusion, after liver transplantation 1) the normal pulsatile character of nocturnal GH secretion is sustained, and the GH response to stimulation is reduced in only a few patients; 2) serum IGF-I concentrations are normal; 3) serum IGFBP-3 concentrations are elevated or in the upper part of the normal range in most patients; and 4) endogenous cortisol production is reduced in most patients and correlates positively with growth velocity.
Child↗
Antimicrobial susceptibility of microorganisms isolated from the mammary glands of dairy heifers.
Minimum inhibitory concentrations were determined with 1494 microorganisms isolated from the mammary glands of dairy heifers. The antimicrobial agents tested were penicillin, cloxacillin, cephapirin, ceftiofur, novobiocin, enrofloxacin, erythromycin, and pirlimycin. All minimum inhibitory concentrations were expressed as micrograms per milliliter. The isolates tested included 135 Staphylococcus aureus, 1222 Staphylococcus sp., 42 Streptococcus sp., 15 Enterococcus sp., 60 enteric species, and 20 miscellaneous organisms. The minimum inhibitory concentrations for 90% of isolates for the various antimicrobial agents with Staph. aureus were as follows: penicillin, .13; cloxacillin, .5; cephapirin, .5; ceftiofur, 1; novobiocin, .5; enrofloxacin, .5; erythromycin, .5, and pirlimycin, .5. In comparison, the minimum inhibitory concentrations for 90% of isolates for the Staphylococcus sp. were 1, 1, .5, 1, .5, .5, 1, and .5 for penicillin, cloxacillin, cephapirin, ceftiofur, novobiocin, enrofloxacin, erythromycin, and pirlimycin, respectively. The minimum inhibitory concentrations for 90% of isolates for the Streptococcus sp. were 2, 32, 2, 2, 8, 1, 64, and 32 for the respective antimicrobial agents; the minimum inhibitory concentrations for 90% of isolates were 4, 64, 32, 64, 4, 1, 4, and 4 for the enterococci. Against the Gram-negative enteric bacilli, only ceftiofur and enrofloxacin were active; minimum inhibitory concentrations for 90% of isolates were 1 microgram/ml for ceftiofur and .25 microgram/ml for enrofloxacin. Results indicated that the majority of staphylococcal strains were susceptible to the antimicrobial agents tested but that antimicrobial susceptibility varied for Streptococcus sp. Compounds currently available in intramammary infusion products demonstrated poor activity against the enteric organisms.
Animals↗
Glomerular anionic charge in congenital nephrotic syndrome of the Finnish type.
Decrease of the anionic charge of the glomerular basement membrane and especially the reduced amount of heparan sulphate proteoglycan in the lamina rara externa has been suggested to be the basic pathogenetic defect in congenital nephrotic syndrome. In the present study the anionic charge of glomeruli was examined in the congenital nephrotic syndrome of the Finnish type and in controls using cationic stains (polyethyleneimine, Ruthenium Red) in electron microscopy. Chondroitinase and heparinase treatments were used to characterize further the anionic elements detected. Scanning electron microscopy (SEM) was used in addition to transmission electron microscopy (TEM) to examine the tridimensional structure and secondary changes of podocytes in this syndrome. The number (mean +/- SD) of polyethyleneimine granules per 1 micron length of lamina rara externa of the glomerular basement membrane was 24.9 +/- 4.5 in control and 23.2 +/- 4.3 [corrected] in congenital nephrotic syndrome subjects. The Ruthenium Red staining pattern was closely similar in syndrome and control kidneys. The granules evident after staining with either cationic stain were seen after chondroitinase but not after heparinase treatment in control as well as in syndrome patient kidney samples. No denuded areas of basement membrane in 42 glomeruli from four syndrome patients were found in SEM. In conclusion, the amount of anionic sites in the lamina rara externa as detected by either cationic stain was comparable to controls. These results do not support the hypothesis of decreased anionic sites in the lamina rara externa of the glomerular basement membrane in congenital nephrotic syndrome of the Finnish type.
Anions↗
Fine mapping of the congenital chloride diarrhea gene by linkage disequilibrium.
Congenital chloride diarrhea is a recessively inherited intestinal disorder affecting electrolyte transportation. The clinical presentation is a life-threatening watery diarrhea with a high chloride content. Recently, the congenital chloride diarrhea gene (CLD) was assigned to chromosome 7 by linkage in eight Finnish families. In the present study, refined mapping of CLD was performed by studying linkage and linkage disequilibrium in 24 Finnish and 4 Swedish families. Recombination mapping assigned CLD to an approximately 10-cM region flanked by D7S515 and D7S799. Linkage disequilibrium was detected over this large genetic region, with the strongest allelic association at D7S496. Application of the Luria and Delbrück-derived analysis allowed for a further narrowing of the CLD region to approximately 0.37 cM from the marker D7S496. Haplotype analysis placed CLD unequivocally between D7S501 and D7S692, very close to D7S496 and most likely on the distal side of D7S496. This combined analytical approach allowed highly accurate mapping of CLD, each component adding complementary and consistent mapping information.
Child↗
Renal allograft histology and correlation with function in children on triple therapy.
Histopathological findings of 13 LRD and 17 CAD renal allografts of paediatric recipients were prospectively semiquantitatively scored and correlated with clinical and functional parameters 18 and 36 months after transplantation. The most common findings at 18 months were diffuse interstitial fibrosis (incidence 57%), glomerular mesangial matrix increase (91%), arteriolar intimal proliferation (70%), and tubular atrophy (83%). Most changes were mild and most biopsies were scored normal or borderline (Banff classification). At 18 and at 36 months 30% of grafts showed mild chronic rejection (CR). Only two grafts showed grade II CR at 18 months and one graft grade III CR at 36 months. Progressive CR was not seen. Donor source or recipient age had no effect on graft histology. Vascular-interstitial cyclosporin (CsA) nephrotoxicity was not found. On the contrary, cumulative CsA dose (mg/kg/day) showed an inverse correlation with arteriolar intimal proliferation (P < 0.001). 51Cr-EDTA and lithium clearances showed inverse correlations with diffuse interstitial fibrosis and lymphocytosis. PAH clearance did not correlate with interstitial or vascular changes. The results indicate good prognosis in children on triple immunosuppression (with CsA administered in three doses/day to pre school children) regardless of donor source.
Adolescent↗
Functional and histopathological cyclosporine A nephrotoxicity in children after organ transplantation.
Explore the source record for details and available documents.
Adolescent↗
Fine mapping and haplotype analysis of the locus for congenital nephrotic syndrome on chromosome 19q13.1.
We have recently localized the gene for congenital nephrotic syndrome of the Finnish type (CNF) to chromosome 19q12-13.1. On the basis of observed recombination events, the gene was localized between markers D19S416/D19S425/D19S213/D19S208/D19S191 and D19S224. Here we have extended the mapping efforts, on the basis of a detailed physical map of the region. By means of three new polymorphic markers--D19S608, D19S609, and D19S610--developed in this study, the critical candidate region could be further restricted. Significant linkage disequilibrium was observed with markers D19S610, D19S608, D19S224, and D19S220, the strongest allelic association being 84% with marker D19S610 at 19q13.1. This suggests that the CNF gene locus lies in close proximity to marker D19S610. Combination of the informative markers revealed four main haplotype categories. Different geographic distribution was observed between these haplotype groups when they were placed on the map of finland according to the birthplaces of grandparents.
Base Sequence↗
Present situation and future R&D at Nobelpharma AB.
Nobelpharma's long-term objectives are to reach many patients with implant treatment, to strengthen our position as the world's leading implant company and to become one of the world's leading companies in the dental field. We have defined a number of strategies and identified obstacles which need to be overcome in order to achieve these objectives. Research and development is of course one of the most important strategic fields for our company. For a leading research company, it is essential to be able to protect its innovations, so patents are very important. Our patent situation today is very strong and we now have more than 100 original patents or patent applications. We are continuously working on the development of new techniques and products. Our research areas include studying interface geometries, soft tissue integration, defining guidelines for treatment planning and increasing our knowledge about precision requirements in support of future product development.
Clinical Trials as Topic↗
[Organ transplantation in children is a rational therapy].
Explore the source record for details and available documents.
Age Factors↗
Congenital nephrotic syndrome of the Finnish type is not associated with the Pax-2 gene despite the promising transgenic animal model.
Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disease with an incidence of 1 in 8000 in Finland. CNF is characterized by massive proteinuria and nephrotic syndrome at birth. In a recent report, deregulation of expression of the gene coding for the Pax-2 DNA-binding protein was shown to generate severe kidney abnormalities in transgenic mice resembling the clinical and pathological findings in congenital nephrotic syndrome, making it a candidate gene for CNF. However, in this study, we have unequivocally excluded the Pax-2 gene locus as a causative for congenital nephrotic syndrome of the Finnish type.
Animals↗
Renal transplantation in children with emphasis on young patients.
We report the results of 41 consecutive renal transplantations performed on 39 children (median age 2.7 years). Twenty-six recipients were less than 5 years old. Twenty-one recipients (13 under the age of 5 years) received cadaver (CAD) grafts. All grafts except 2 were from adult donors and were placed extraperitoneally. Patients were on triple immunosuppression (cyclosporine plus azathioprine plus methylprednisolone). Mean follow-up time was 2.3 years. No vascular and only one ureteral complication was seen. Acute tubular necrosis occurred in 3 patients (7.3%). No grafts were lost due to acute rejection. Three-year patient survival and 1-year graft survival were 100%. The overall 3-year actuarial graft survival was 86%. Three-year survival of grafts from living-related donors (LRD) was 92% and that of CAD grafts 75%. In recipients younger than 5 years, 3-year LRD graft survival was '89% and CAD graft survival 73%. No significant differences in graft survival between recipients of different age groups or between LRD and CAD grafts were found. We conclude that results of renal transplantation in children under 5 years of age are comparable to those of older children, even using CAD grafts, when adult donors and triple immunosuppression are used.
Adolescent↗
Renal function and histopathologic changes in children after liver transplantation.
Up to 60% reduction of renal function has been reported after orthotopic liver transplantation (OLT) in patients receiving cyclosporine. We prospectively investigated renal function and histopathology in 16 children on triple immunosuppression therapy during 3 years after OLT. Cyclosporine was administered in 3 doses/day to preschool children. The median age at OLT was 5.4 years. Determinations of chromium 51-labeled ethylenediaminetetraacetic acid, p = aminohippuric acid, lithium, and sodium clearances, measurements of serum and urinary electrolytes, and urinary concentration tests were performed. Renal biopsy specimens were taken 18 and 36 months after transplantation. The mean glomerular filtration rate was 121.5 ml/min per 1.73 m2 before transplantation, 86.3 at discharge, and 119.4 36 months after OLT. Hyperuricemia, hyperkalemia, and reduced urinary concentrating capacity were common. Hyperkalemia occurred in 13% to 19% of the patients, only during the first 6 months. Hyperuricemia and reduced concentrating capacity occurred with incidences of 17% to 44% and 40% to 63%, respectively. Histopathologic changes were mild, and severe nephrotoxic effects of cyclosporine was not seen. However, tubular atrophy, mesangial matrix increase, and mesangial cell proliferation were common. We conclude that triple immunosuppression with cyclosporine administration, in three doses per day, to small children and careful renal follow-up ensure good renal function after OLT.
Adolescent↗
Exclusion of eight genes as mutated loci in congenital nephrotic syndrome of the Finnish type.
The congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disease characterized by massive proteinuria already at birth. The gene locus defective in CNF was searched for using polymorphic markers of candidate genes coding for components of the basement membrane (BM). The linkage analyses in 17 Finnish CNF families demonstrated exclusion of obligatory recombination events between the disease and eight genes coding for BM components. The genes coding for the alpha 1(IV), alpha 2(IV), alpha 3(IV) and alpha 4(IV) chain of type IV collagen, the B1e, B2e and B2t chains of laminin, as well as the BM heparan sulfate proteoglycan core protein were all excluded in this Finnish family material. Since the defect is not in any of the genes coding for major components of BM, the identification of the gene defect will most probably reveal a new gene important for the development and function of the glomerular basement membrane.
Cell Line↗
Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I.
Hereditary tyrosinemia type I is a metabolic disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2), the last enzyme in the catabolic pathway of tyrosine. The molecular basis of FAH deficiency was examined in five Finnish patients suffering from this severe metabolic disease. No immunoreactive FAH nor enzymatic activity were found in their liver. Direct sequencing of the 14 exons of the FAH gene showed a G to A transition, which predicts a change from tryptophan to a stop codon (TGG-->TGA) at position 262 (W262X). Four of the five patients examined were homozygous for the mutation. Allele specific oligonucleotide hybridization showed a predominance of the W262X mutation in Finland (9 of 10 alleles) and the absence of this mutant allele in patients from other parts of the world. The loss of a BsaJI restriction site in those patients may be used for diagnosis.
Amino Acid Metabolism, Inborn Errors↗
Pathology of renal arteries of dyslipidemic children with congenital nephrosis.
Congenital nephrotic syndrome of the Finnish type (CNF) is well characterized in infants and associated with major lipid risk factors for atherosclerosis. This study was undertaken to investigate if any arterial pathology is present in children with CNF and, if so, to describe its nature in renal arteries collected at nephrectomy at a mean age of 12.5 +/- 4.4 months. Denuded endothelial injury and intimal thickening were seen in 9 out of 10 patient specimens of renal arteries. Intimal thickening contained loose abundant extracellular matrix with a few smooth muscle or myofibroblastoid cells. Only a few Sudan black- or oil red O-positive lipid droplets were found in six and seven samples, respectively. Areas immunoreactive with antibodies against apoprotein B were seen in only two specimens. Immunohistochemistry did not reveal any activated T or B cells, or any expression of IL-1 or IL-2 receptors. Macrophages were present in only two specimens. No foam cells were seen. We conclude that the vascular pathology together with altered lipoprotein metabolism indicates that children with CNF might be at risk for early atherosclerotic arterial disease, particularly if their hyperlipidemia persists.
Apolipoproteins B↗