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Biomedical subjects

C Holmberg

Publications and source records attributed to C Holmberg.

At least 109 records · Page 6Linked to original sources
PubMed1994

Serum levels of oncofetal markers CA 125, CA 19-9, and alpha-fetoprotein in children with hereditary tyrosinemia type I.

Hereditary tyrosinemia type I (HTT-I) is an inherited metabolic disorder with severe liver disease and a high risk for hepatic malignancy. Patients with HTT-I are monitored with repeated analyses of serum amino acids, urine succinylacetone, and serum alpha-fetoprotein (AFP). Oncofetal markers CA 125 and CA 19-9 are elevated in serum of patients with various gastrointestinal diseases and malignancy. To study the biology of oncofetal antigens in tyrosinemia and to assess the possible usefulness of these markers in HTT-I, we studied serum concentrations of CA 125 (n = 160) and CA 19-9 (n = 188), together with AFP (n = 337), in serial samples from 10 patients. At early stages of the disease, most children with an acute type of disease had a remarkably elevated serum CA 125 concentration (153-1560 IU/L) that normalized gradually after the institution of therapy. Serum CA 125 levels may thus reflect acute metabolic imbalance in fulminant HTT-I. The patients with a chronic type of disease showed CA 125 levels within the normal range at diagnosis that slowly increased as the liver condition worsened. These concentrations, however, never reached values seen in acute HTT-I. Serum concentration CA 19-9 in HTT-I was mostly normal. Serum AFP levels fluctuated in all patients and positively correlated with tests for metabolic state and biliary function. A distinct increase in the serum AFP level was recorded in association with the detection of massive hepatocellular carcinoma and also preceded metabolic imbalance leading to porphyria crises.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Thirty years of renal transplantation in Helsinki.

During triple-drug immunosuppression, consisting of azathioprine, steroids, and cyclosporine, the number of acute rejections was low. Close monitoring of the patient and the graft during the early posttransplant weeks with regular cytological and histological analyses was the cornerstone of early diagnosis and a favorable outcome of acute rejection. Genetic homogeneity of our patient population, third-party transfusion program, and use of well HLA-matched kidney grafts may have been additional factors behind the low rate of acute rejection. Acute rejection within the first three postoperative months did not predispose the renal graft to chronic rejection in the long term. The histologically determined allograft damage index was a reliable predictor of future graft survival. Recipients with systemic diseases such as diabetes and amyloidosis, as well as elderly patients, could be transplanted safely with results only slightly inferior to those achieved with primary kidney disease. Results in diabetic recipients have steadily improved, encouraging the continuation of critical evaluation of the patients' pretransplant status and the preference for cadaveric transplants. Renal transplantation in small children yielded superior patient and graft survival rates. We consider the use of living donors justifiable in these cases. The five million population of Finland offers an ideal size for a transplant center. Continuous education of medical personnel and the general public is crucial for the cadaver transplant program.

Adolescent↗
PubMed1994

Effect of donor source on renal allograft function in children on triple immunosuppression.

Results of renal transplantation using cadaver donors (CAD) are usually inferior to those using living related donors (LRD). We have previously reported 100% 1-year CAD and LRD graft survival using adult cadaver donors and triple immunosuppression. In the present study glomerular and tubular function of 23 LRD and 22 CAD grafts (median ages 3.5 and 2.6 years) were compared during 3 years after transplantation. Glomerular filtration rate (GFR) and renal plasma flow were lower in CAD grafts but remained stable in both groups. The mean GFRs were 87.3 and 63.2 ml/min/1.73 m2 at discharge and 82.8 and 72.5 ml/min/1.73 m2 at 36 months in LRD and CAD grafts respectively. No significant differences were found after 6 months. Tubular function was good in both groups. The only significant difference was in urate handling at 36 months (mean serum urate 396 mumol/l in CAD, 301 in LRD grafts, P < 0.05). Cyclosporin nephrotoxicity manifested as hyperkalaemia due to reduced distal potassium secretion and/or adrenal suppression. In conclusion, donor source had little effect on the development of progressive allograft dysfunction using adult CAD grafts and triple immunosuppression with CsA administered in three daily doses to preschool children.

Adolescent↗
PubMed1994

Paternal isodisomy for chromosome 7 is compatible with normal growth and development in a patient with congenital chloride diarrhea.

Uniparental disomy for maternal chromosome 7 has been described in three patients with recessive disorders. Short stature in each of these patients has been explained by the effect of imprinting of growth-related genes on maternal chromosome 7. Alternatively, although less likely, all these patients may be homozygous for a rare recessive mutation. Here we report both paternal isodisomy for chromosome 7 and normal growth in a patient with a recessive disorder, congenital chloride diarrhea. She had inherited only paternal alleles at 10 loci and was homozygous for another 10 chromosome 7 loci studied. Her physical status and laboratory tests were normal except for a mild high-frequency sensorineural hearing loss. As the patient has normal stature, it is likely that the paternal chromosome 7 lacks the suggested maternal imprinting effect on growth. Paternal isodisomy for human chromosome 7 may have no phenotypic effect on growth.

Adult↗
PubMed1994

Short-term effects of renal transplantation on plasma lipids and lipoprotein lipase in children with congenital nephrosis.

Plasma lipoprotein and apoprotein (apo) A-I, A-II and B concentrations and post-heparin plasma lipoprotein lipase (LPL) activity and mass were measured in 13 children with congenital nephrotic syndrome of the Finnish type (CNF) six months after renal transplantation to determine whether the severe lipid abnormalities documented prior to and during peritoneal dialysis would normalize. Plasma total triglyceride decreased by 52% (p < 0.001), VLDL triglyceride by 55% (p < 0.01) and total cholesterol by 17% (p < 0.01). HDL cholesterol increased by 51% (p < 0.001), whereas no significant change was observed in LDL cholesterol. Despite these improvements, plasma lipoprotein concentrations were still abnormal after transplantation. Total (p < 0.01) and VLDL triglyceride (p < 0.05) as well as total (p < 0.01), VLDL (p < 0.01) and LDL cholesterol (p < 0.01) were higher than in control children. HDL cholesterol normalized. Plasma apo A-I and A-II concentrations were normal, but the apo B concentration remained high (p < 0.01). Post-heparin LPL activity and mass were normal (25.0 +/- 9.1 mumol FFA/ml/h and 227.2 +/- 88.4 ng/ml). The mean cyclosporine dose correlated positively with the serum creatinine concentration (r = +0.72, p < 0.01). Positive correlations were also observed between total (r = +0.68, p < 0.05) and VLDL triglyceride (r = +0.62, p < 0.05) and the serum creatinine concentrations. We conclude that renal transplantation substantially improves the triglyceride and cholesterol abnormalities in CNF but significant abnormalities still persist.

Apolipoprotein A-I↗
PubMed1994

Congenital nephrotic syndrome of the Finnish type maps to the long arm of chromosome 19.

Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disease that is characterized by massive proteinuria and nephrotic syndrome at birth. CNF represents a unique, apparently specific dysfunction of the renal basement membranes, and the estimated incidence of CNF in the isolated population of Finland is 1 in 8,000 newborns. The basic defect is unknown, and no specific biochemical defect or chromosomal aberrations have been described. Here we report the assignment of the CNF locus to 19q12-q13.1 on the basis of linkage analyses in 17 Finnish families. Multipoint analyses and observed recombination events place the CNF locus between multiallelic markers D19S416 and D19S224, and the significant linkage disequilibrium observed suggests that the CNF gene lies in the immediate vicinity of the markers D19S224 and D19S220.

Cell Line↗
PubMed1993

The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

Congenital chloride diarrhea (CLD) is characterized by watery stools with high chloride content beginning prenatally and is inherited as an autosomal recessive trait. Perfusion studies have established a basic defect in ileal and colonic Cl-/HCO3- transport, resulting in defective chloride absorption. The protein and its gene defects have, however, remained uncharacterized. We attempted to exclude candidate genes by considering linkage disequilibrium as well as genetic linkage in a small number of Finnish families. Initial results were suggestive of linkage between CLD and the cystic fibrosis transmembrane regulator gene (CFTR). Extended analysis in eight families confirmed close linkage to chromosome 7 markers proximal of CFTR, with maximum logarithm of odds scores of 5.11 and 5.06 for D7S501 and D7S496, respectively, at zero recombination. Allelic associations were observed that were striking between CLD and D7S496 and weaker between CLD and D7S501. Multipoint analyses mapped CLD unequivocally at D7S496 with a maximum logarithm of odds score of 9.33. We conclude that the CLD gene maps close to, but is distinct from, CFTR.

Chlorides↗
PubMed1993

Congenital nephrosis of the Finnish type (CNF): matrix components of the glomerular basement membranes and of cultured mesangial cells.

Congenital nephrosis of the Finnish type (CNF) is a hereditary renal disease of unknown aetiology manifested by massive proteinuria of the newborn and unresponsive to any treatment. In this study kidney samples and cultured glomerular mesangial cells from five patients with CNF were studied by indirect immunofluorescence microscopy for the presence and location of major basement membrane matrix (GBM) components. Histological changes of glomeruli ranging from mild thickening of basement membranes to total obliteration and sclerosis were seen. Notably, thickening of the subepithelial layer of Bowman's capsules was regularly seen along with hypercellularity at the juxtaglomerular areas. The matrix components studied (laminin, plasma- and cellular fibronectin, type IV collagen, including the NC-1, alpha-1 and alpha-3 chains, heparan sulphate proteoglycan (HSPG) core protein, thrombospondin) were characteristically seen within the glomeruli. Local thickenings alternating with total loss of epitopes along the GBM were seen, especially with anti-type IV collagen and anti-HSPG antibodies. Sera from CNF patients after transplantation failed to show antibodies against GBM structures in immunofluorescence microscopy, suggesting that no missing epitopes of GBM are introduced with the transplant kidney. Cultured mesangial cells of CNF glomeruli also showed continued in vitro production of the matrix components and their incorporation into the matrix underneath the cell layer.

Adult↗
PubMed1993

Post-transplantation nephrosis in congenital nephrotic syndrome of the Finnish type.

Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessively inherited disease manifesting as massive proteinuria, edema and ascites in the neonatal period. The disease is believed to be limited to the kidneys and recurrences after renal transplantation have not been reported. At our center 29 transplantations have been performed on 28 CNF patients. One to 33 months after transplantation, seven grafts (24%) of six patients have developed a steroid-resistant nephrotic syndrome. The clinical data and renal histology of these patients were analyzed in order to elucidate the cause of the proteinuria. At the onset of six of the seven episodes of nephrosis, the patient had evidence of a preceding CMV- or EBV-infection and the remaining patient had sinusitis. Upon light and electron microscopy examination, endothelial swelling of the glomerular capillaries resembling transplant glomerulopathy (TG) was seen, but unlike TG, the glomerular basement membranes were normal. The response of proteinuria to steroid or cyclophosphamide therapy was poor, with total remission in only two patients and partial remission in one patient, all treated with methylprednisolone and cyclophosphamide immediately after the diagnosis. Four grafts have been lost. Our data show that CNF patients have an increased tendency for post-transplantation nephrosis.

Biopsy↗
PubMed1993

Impaired renal function after pregnancy in renal transplant recipients.

Twenty-two renal transplant recipients had 29 posttransplant pregnancies and 39 male transplant recipients became fathers to 65 children between 1971 and 1991. Of the deliveries of the female patients, 62% took place between the third and sixth year after transplantation. Seven patients had 2 pregnancies. Mean follow-up time after the first posttransplant pregnancy was 7.5 years. The patients survived the pregnancy well, but the increase in serum creatinine concentration from the prepregnancy level, registered 3 months and 1 year after delivery, was higher than in matched control patients without pregnancy at corresponding times after transplantation (the increase in serum creatinine was 47.7 and 61.2 mumol/L in the pregnant patients versus -2.7 and 5.4 mumol/L in the control patients, P < 0.0001 and P < 0.02, respectively). All pregnant and control patients were alive at the end of follow-up, but the long-term graft survival of those with a pregnancy was significantly (P < 0.005) worse than in the control patients. Ten-year graft survival was 69% in the pregnant versus 100% in the control patients. Although 80% of the neonates born to a mother with a transplanted kidney were below the mean for gestational age, the weight and length at birth were within normal limits and no severe intrauterine growth retardation was documented.

Adult↗
PubMed1993

The glpP and glpF genes of the glycerol regulon in Bacillus subtilis.

The Bacillus subtilis glpPFKD region contains genes essential for growth on glycerol or glycerol 3-phosphate (G3P). The nucleotide sequence of glpP encoding a regulatory protein and the previously unidentified glpF encoding the glycerol uptake facilitator was determined. glpF is located immediately upstream of glpK and the two genes were shown to constitute one operon which is transcribed separately from glpP. A sigma A-type promoter and the transcriptional start point for glpFK were identified. In the 5' untranslated leader sequence (UTL) of glpFK mRNA a conserved inverted repeat is found. The repeat is believed to be involved in the control of expression of glpFK by termination/antitermination of transcription, a control mechanism previously suggested for the regulation of glpD encoding G3P dehydrogenase. Expression of glpFK and glpD requires the inducer G3P and the glpP gene product. A 2.9 kb B. subtilis chromosomal DNA fragment containing the glpP open reading frame was cloned to give plasmid pLUM7. pLUM7 contains a functional glpP gene as shown by its ability to complement various glpP mutants. Immediately upstream of glpP an open reading frame is found (ORF1). Disrupting ORF1 by plasmid integration in the B. subtilis chromosome does not affect the ability to grow on glycerol as sole carbon and energy source. With the present report all B. subtilis glp genes located at 75 degrees on the chromosomal map have been identified.

Amino Acid Sequence↗
PubMed1993

Changes in biological activity and immunoreactive mass of lipoprotein lipase in congenital nephrosis: relationship to hypertriglyceridaemia.

The major lipid disturbance in children with congenital nephrosis of the Finnish type (CNF) is hypertriglyceridaemia. To determine whether or not hypertriglyceridaemia is caused by defective triglyceride catabolism, we measured lipoprotein lipase (LPL) activities and masses at various stages of the disease. At age 3 months in CNF both LPL activity and mass were decreased, but a close positive correlation between these parameters similar to that in controls was observed. At age 9 months both LPL activity and mass were even lower. At that time a significant positive correlation (r = 0.72, P < 0.05) between LPL activities and albumin concentrations and significant negative correlations between plasma free fatty acid (FFA) concentrations and LPL activities (r = -0.72, P < 0.05) and between plasma FFA concentrations and serum albumin concentrations (r = -0.73, P < 0.05) were observed, suggesting that low albumin concentrations result in increase of FFA levels, which could interfere with a normal LPL function at the endothelial surface. On dialysis after nephrectomy, LPL activities and masses increased. At age 3 and 9 months apoprotein C-II (apo C-II) and apoprotein C-III (apo C-III) levels were not decreased although apoproteins were being lost into the urine. On dialysis the mean ratio of apo C-II/C-III was significantly lower than the mean in controls (P < 0.001). We conclude that impaired function of LPL seems to be the major cause of hypertriglyceridaemia and disintegrity of the VLDL-IDL-LDL delipidation cascade in children with CNF.

Apolipoprotein C-II↗
PubMed1993

An update on developments at Nobelpharma.

At Nobelpharma there is a strong belief in clinical trials; the way products function should always be documented before those products are introduced to the market. The safety of the patient must not be jeopardised. Now, Nobelpharma introduces a new system on documentation of new products, similar to the one used in the pharmaceutical industry. In its clinical studies, Nobelpharma collaborates with some 175 clinics all over the world. At present, some 40 scientific studies are in progress, involving around 1500 patients and 40,000 fixtures. The current R&D plan of Nobelpharma consists of, among others, the following four areas: 1. Improved technique and function including research on improved fit and methods for measuring fit. 2. Simplified surgery, where the self-tapping fixture and a new surgical kit are important products. 3. Reduced contra-indications, mainly concentrating on the upper jaw, with contra-indications caused by resorbed bone or poor bone quality. 4. Obtaining increased understanding of biomechanical aspects. Further research to increase biomechanical understanding and, in the longer term, to adapt components and forms of treatment to produce the optimum biomechanical system.

Clinical Trials as Topic↗
PubMed1992

The glycosaminoglycan content of renal basement membranes in the congenital nephrotic syndrome of the Finnish type.

A decrease in the concentration of heparan sulphate proteoglycan (HSPG) in the glomerular basement membrane (GBM) is supposed to cause the increased GBM permeability in the congenital nephrotic syndrome (CNS). Therefore, we analysed the glycosaminoglycan (GAG) content and composition of the GBM and tubular basement membrane (TBM) from 3 patients with CNS of the Finnish type (FCNS) and 16 control infants. The GAG content, determined by spectrophotometric assay after papain digestion, was not significantly different in FCNS patients compared with controls. In addition, the GAG composition was comparable in the two groups, with heparan sulphate (HS) constituting at least 75% of the total GAG content. The urinary GAG content (expressed as mg GAG/mmol creatinine) was age dependent, but similar in both groups. Indirect immunofluorescence studies on kidney tissue from normal human infants, using monoclonal or polyclonal antibodies against the core protein of human GBM HSPG, showed linear staining of almost all renal basement membranes. A monoclonal antibody directed against the HS chain of HSPG showed strong GBM and a weak TBM staining. Kidney tissue from three patients with FCNS displayed no discernible differences in the distribution or quality of staining with the same antibodies. These biochemical and immunohistochemical results are in contrast to the decrease in anionic sites (by polyethyleneimine staining) and the replacement of GBM HS by chondroitin sulphate, observed by others in CNS of the diffuse mesangial sclerosis type.

Basement Membrane↗