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Biomedical subjects

J Partanen

Publications and source records attributed to J Partanen.

At least 127 records · Page 7Linked to original sources
PubMed1997

THA disrupts mismatch negativity in Alzheimer disease.

The present study investigates the effects of 25 or 50 mg tetrahydroaminoacridine (THA), a cholinesterase inhibitor, on auditory mismatch negativity (MMN) event-related response in 19 patients with Alzheimer disease (AD). MMN is produced by the deviant tones representing passive attention and automatic detection of stimulus change. In an inattentive task condition, standard (85%) and deviant (15%) tones were represented in a random order with interstimulus interval of 1 s in separate blocks. THA 25 mg had no effect on MMN in AD patients. In contrast, THA 50 mg diminished MMN in AD subjects. The results suggests that acute treatment of AD subjects with a cholinesterase inhibitor disrupts the passive detection of change in an auditory input.

Aged↗
PubMed1997

Mutation-haplotype analysis of steroid 21-hydroxylase (CYP21) deficiency in Finland. Implications for the population history of defective alleles.

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common inherited defect of adrenal steroid hormone biosynthesis. Unusually for genetic disorders, the majority of mutations causing CAH apparently result from recombinations between the CYP21 gene encoding the 21-hydroxylase enzyme and the closely linked, highly homologous pseudogene CYP21P. The CYP21 and CYP21P genes are located in the major histocompatibility complex class III region on chromosome 6p21.3. We analyzed the mutations and recombination breakpoints in the CYP21 gene and determined the associated haplotypes in 51 unrelated Finnish families with CAH. They represent no less than half of all CYP21 deficiency patients in Finland. The results indicate the existence of multiple founder mutation-haplotype combinations in the population of Finnish CAH patients. The three most common haplotypes constituted half of all affected chromosomes; only one-sixth of the haplotypes represented single cases. Each of the common haplotypes was shown consistently to carry a typical CYP21 mutation and only in some cases was additional variation observed. Surprisingly, comparisons with previous published data revealed that several of the frequent mutation-haplotype combinations in Finland are in fact also found in many other populations of patients of European origin, thus suggesting that these haplotypes are of ancient origin. This is in clear contrast to many reports, including the present one, where a high frequency of de novo mutations in the CYP21 gene has been reported. In addition, two unique sequence aberrations in CYP21 (W302X and R356Q), not known to exist in the CYP21P pseudogene, were detected.

Adrenal Hyperplasia, Congenital↗
PubMed1997

A cluster of missense mutations at Arg356 of human steroid 21-hydroxylase may impair redox partner interaction.

Lesions in the gene encoding steroid 21-hydroxylase result in congenital adrenal hyperplasia, with impaired secretion of cortisol and aldosterone from the adrenal cortex and overproduction of androgens. A limited number of mutations account for the majority of mutated alleles, but additional rare mutations are responsible for the symptoms in some patients. A total of 11 missense mutations has previously been implicated in this enzyme deficiency. We describe two novel missense mutations, both affecting the same amino acid residue, Arg356. The two mutations, R356P and R356Q, were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells, and enzyme activity towards the two natural substrates, 17-hydroxyprogesterone and progesterone, was determined. The R356P mutant reduced enzyme activity to 0.15% towards both substrates, whereas the R356Q mutant exhibited 0.65% of normal activity towards 17-hydroxyprogesterone, and 1.1% of normal activity towards progesterone. These activities correspond to the degrees of disease manifestation of the patients in whom they were found. Arg356 is located in a region which recently has been implicated in redox partner interaction, by modelling the structure of two other members of the cytochrome P450 superfamily. Of the 11 previously described missense mutations, three affect arginine residues within this protein domain. With the addition of R356P and R356Q, there is a clear clustering of five mutations to three closely located basic amino acids. This supports the model in which this protein domain is involved in redox partner interaction, which takes places through electrostatic interactions between charged amino acid residues.

Adrenal Hyperplasia, Congenital↗
PubMed1997

Analysis of Tie receptor tyrosine kinase in haemopoietic progenitor and leukaemia cells.

We generated a panel of monoclonal antibodies against the extracellular domain of the Tie receptor tyrosine kinase and studied its expression in human haemopoietic and tumour cell lines and in samples from leukaemia patients. Most of the erythroblastic/megakaryoblastic (6/8), 2/7 myeloid and 3/6 B-lymphoblastic leukaemia cell lines were Tie-positive. The erythroblastic/megakaryoblastic leukaemia cell lines also expressed the related Tie-2/Tek gene and, surprisingly, its recently cloned ligand gene angiopoietin-1, which was located in chromosome 8q23.1. In addition, 16% of freshly isolated leukaemia samples were Tie positive. Peripheral blood mononuclear cells were Tie negative, but a few Tie positive cells were found in immunoperoxidase staining of mobilized peripheral blood stem cells. Long-term culture of isolated umbilical cord blood CD34+ Tie+ and CD34+ Tie- cells indicated that the Tie+ fraction contained a slightly higher frequency of cobblestone area forming cells (CAFC). Thus, Tie is expressed on haemopoietic progenitor cells and some leukaemic blasts. The coexpression of Tie-2 and angiopoietin-1 in megakaryoblastic leukaemia cell lines suggests the existence of an autocrine ligand/receptor signalling loop in these cells.

Angiopoietin-1↗
PubMed1997

Itraconazole decreases renal clearance of digoxin.

Itraconazole strongly interacts with some drugs metabolized by cytochrome P450 3A4, for example, felodipine and lovastatin, by inhibiting their metabolism. A concomitant use of itraconazole increases the serum concentrations of digoxin, although digoxin is excreted mainly unchanged in urine. To reveal the mechanism of the itraconazole-digoxin interaction, the effect of itraconazole on the serum concentrations and urinary excretion of digoxin was studied. Ten healthy volunteers in a double-blind, randomized, two-phase crossover study received either 200 mg itraconazole or placebo orally once a day for 5 days. On day 3, each volunteer ingested a single 0.5-mg oral dose of digoxin. The serum concentrations of digoxin and its excretion into urine as well as plasma concentrations of itraconazole were determined up to 72 hours after dosing. The mean area under the serum digoxin concentration-time curve, AUC(0-72), was approximately 50% higher (P < 0.001) during the itraconazole phase than during the placebo phase. In addition, the renal clearance of digoxin decreased about 20% (P < 0.01) by itraconazole. The increases in digoxin Cmax and T(1/2) by itraconazole were not statistically significant. The decreased renal clearance of digoxin during the itraconazole phase partially explains increased concentrations of digoxin during their concomitant use and may be caused by the inhibition of P-glycoprotein-mediated digoxin secretion in the renal tubular cells.

Administration, Oral↗
PubMed1997

Canine major histocompatibility complex genes DQA and DQB in Irish setter dogs.

Information about genetic variation within the canine major histocompatibility complex (MHC) class II genes is limited. In common with most other vertebrate species the canine MHC, or DLA, includes genes which are homologous to human DR, DQ, and DP. Recently, at least one functional DLA DQ gene-pair has been characterized, but so far systematic screening efforts have been lacking. In the present study, we sequenced both cDNA and genomic clones derived from DLA DQ genes of Irish setter dogs. This breed was of interest, since it shows a high prevalence of gluten sensitive enteropathy (GSE), which may be a useful animal model for celiac disease (CD) of man. Interestingly, few of the alleles found in Irish setters were identical to those previously detected in other breeds. Three novel DLA DQA and four novel DLA DQB alleles were discovered in 19 unrelated dogs. Strong association between certain HLA DQ alleles and CD of man prompted us to screen the DQ alleles of members of a family of gluten-sensitive Irish setter dogs. No haplotypes or alleles were shared by all affected dogs, but one frequent haplotype in this family was also detected in an unrelated gluten-sensitive Irish setter; this haplotype was absent in the healthy dogs. This observation warrants further investigation by screening the DQ alleles of a large population of unrelated gluten-sensitive Irish setters.

Alleles↗
PubMed1997

Puumala hantavirus genome in patients with nephropathia epidemica: correlation of PCR positivity with HLA haplotype and link to viral sequences in local rodents.

Reverse transcription-PCR was used to analyze specimens from 20 Finnish nephropathia epidemica (NE) patients hospitalized during the period from October 1994 to January 1995. Blood and/or urine sediment specimens from seven patients were found to be positive for the genome sequences of Puumala hantavirus (PUU). PCR positivity of the specimens from the patients correlated well with the HLA-DRB1*0301 and HLA B8 alleles, which previously were shown to associate with severe courses of NE. Genetic analysis of the partial M-and/or S-segment sequences obtained from three severely ill NE patients revealed three PUU strains related to but distinct from previously reported strains from Finland. The M-segment sequence of PUU from bank voles trapped near the probable site of infection for one of the patients showed 98.2% identity to that of the PUU strain obtained from the patient, suggesting a link between wild-type PUU from the natural focus and the NE case. The S-segment sequences from the patient and the bank voles, however, showed substantially lower identity (95.8%). As this difference in diversity for M and S genes (1.8 and 4.2%) is atypical for PUU genetic drift, one possibility is that the strain acquired at the putative place of infection is a reassortant one.

Adult↗
PubMed1997

Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population.

We report a population-wide analysis of all patients with 21-hydroxylase deficiency (21-OHD) found in Finland, a country with a genetically well defined population, in which the effects of other genetic and environmental factors on the phenotype can be expected to be low. In total, 120 patients were identified, and their clinical status was evaluated. Blood samples for CYP21 genotype determination could be obtained from 78 (65%) patients, and their phenotypes were compared with their genotypes. In general, the severity of gene defects correlated well with clinical expression. All patients carrying mutations with the most drastic effects on enzymatic activity had the salt-wasting form of 21-OHD. The I2 splice mutation, which in some reports has been connected with clinical variation, was constantly associated with severe mineralocorticoid deficiency. However, patients with I172N as the determining mutation expressed a wide spectrum of phenotypes; the variation could not be attributed to additional mutations. Although genetically affected males with the nonclassical form had not been clinically diagnosed, our study suggests that nonclassical 21-OHD is substantially more rare in Finland than elsewhere, as indicated by both clinical evaluation and mutational screening.

Adrenal Hyperplasia, Congenital↗
PubMed1997

Alloimmunization against platelet antigens in renal transplant patients with acute vascular rejection.

Acute vascular rejection (AVR) of a kidney graft, in which the graft vascular endothelium is main target for the injury, is considered antibody-mediated. Integrins of vascular endothelium and platelets have several alloantigenic epitopes in common, e.g. human platelet alloantigen (HPA) 1 on beta(3) integrin of glycoprotein (GP) IIbIIIa and HPA-5 on alpha(2) of GP IaIIa. The clinical significance of HPA expression by vascular endothelial cells is unknown. Platelet antibodies in serum samples from 26 renal allograft recipients with AVR and 30 patients without AVR were studied. Also the HPA-types of the patients and their respective graft donors were determined. Strong platelet alloantibodies were observed in seven of the 26 AVR patients (27%). In five of these cases the antibodies had HPA-specificity. No reference patient without AVR had strong platelet antibodies. In two AVR patients strong HPA-5b antibodies coexisted with an HPA-5b-positive graft. Despite acute rejection episodes, neither of the grafts was lost. It seems likely that, with current immunosuppressive treatment, anti-HPA-5b does not necessarily cause permanent dysfunction of a graft originating from HPA-5b-positive donor.

Acute Disease↗
PubMed1996

ERPs reveal deficits in automatic cerebral stimulus processing in patients with NIDDM.

We compared auditory event-related potentials (ERPs) and neuropsychological test scores in nine patients with non-insulin-dependent diabetes mellitus (NIDDM) and in nine control subjects. The measures of automatic stimulus processing, habituation of auditory N100 and mismatch negativity (MMN) were impaired in patients. No differences were observed in the N2b and P3 components, which presumably reflect conscious cognitive analysis of the stimuli. A trend towards impaired performance in the Digit Span backward was found in diabetic subjects, but in the tests of secondary or long-term memory the groups were comparable. Patients with NIDDM may have defects in arousal and in the automatic ability to redirect attention, which can affect their cognitive performance.

Acoustic Stimulation↗
PubMed1996

The in vitro response to human fibroblast-derived extracellular matrix proteins is restricted by specific HLA class II genes. Relevance for coeliac disease.

Coeliac disease is an immunologic disease of the small intestine which is caused by ingestion of wheat gliadin, the disease-promoting agent. The disease associates strongly with the particular HLA type, HLA-DQA1*0501, DQB1*0201 alleles. Further specific autoantibodies against reticulin and endomysium are found in patients; these autoantibodies appear to be disease specific. An extracellular matrix noncollagenous protein reacts specifically with CD patients' serum immunoglobulin A and is the target of antireticulin antibodies. In this study the immune response to this matrix protein was analyzed in vitro in normal, healthy individuals. Our study shows that the immune response to Fb-CDAP is strictly regulated by the HLA-DR3, DQA1*0501, DQB1*0201 alleles, and that only those cells which were positive for these alleles produced an immune response. On the other hand, half of the cells positive for these HLA alleles were responders. Monoclonal antibodies to DR and DQ inhibited the response in an additive way, showing that both DR and DQ can act as an antigen-presenting structure. The immune response to gliadin has been shown to associate with the same HLA type as CD, but the association is not as strong. Our results show that the immune responses to Fb-CDAP can be generated in vitro in genetically predisposed persons in the absence of CD.

Adult↗