Biomedical subjects

M Christiansen

Publications and source records attributed to M Christiansen.

At least 91 records · Page 5Linked to original sources

PubMed1999

Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene.

We describe a Swedish family with the proband and his brother suffering from severe Romano-Ward syndome (RWS) associated with compound heterozygosity for two mutations in the KVLQT1 (also known as KCNQ1 and KCNA9) gene (R518X and A525T). The mutations were found to segregate as heterozygotes in the maternal and the paternal lineage, respectively. None of the heterozygotes exhibited clinical long QT syndrome (LQTS). No hearing defects were found in the proband. The data strongly indicates that the compound heterozygosity for R518X and A525T is the cause of an autosomal recessive form of RWS in this family. Our findings support the implication of a higher frequency of gene carriers than previously expected. We suggest that relatives of 'sporadic RWS' patients should be considered potential carriers, at risk of dying suddenly from drug-induced LQTS.

Child, Preschool↗

PubMed1999

Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders.

OBJECTIVE: To examine the relationship between autoimmunity and extranodal lymphocytic infiltrates in different lymphoproliferative disorders with immunoglobulin alterations. SUBJECTS AND DESIGN: A clinical review combined with a retrospective cohort study of 380 patients, 28 with monoclonal gammopathy of undetermined significance, three with common variable immunodeficiency, 147 with chronic lymphocytic leukaemia, 57 with Waldenström's macroglobulinaemia and 145 with non-Hodgkin's malignant lymphoma. SETTING: A university hospital and The State Serum Institute in Copenhagen. INTERVENTION: Clinical examination of each patient with special attention to chronic inflammatory and autoimmune manifestations. Biopsies were taken from non-infectious infiltrates, some of which were additionally tested with PCR analysis for gene rearrangements. Serological screening with a test battery for various autoantibodies was used in combination with techniques for the detection of M-components and monoclonal B-cell proliferation. MAIN OUTCOME MEASURES: Clinical and/or serological autoimmune manifestations, M-component and other immunoglobulin alterations, and inflammatory tissue changes were studied in patients with chronic inflammatory, polyclonal or oligoclonal pseudolymphomas and in monoclonal, malignant extranodal lymphomas. RESULTS: In 380 consecutive patients, 49 (12.9%) had extranodal manifestations, of whom 47 also had autoimmune manifestations. Nearly half of the 47 patients had more than one autoimmune manifestation. There was a strong correlation between clinical signs and corresponding autoantibodies such as anti-SSA and -SSB antibodies in Sjögren's syndrome (10 cases), antithyroid peroxidase antibodies in thyroiditis and Graves' disease (10 cases), and parietal cell antibodies in gastric ulcers with maltoma (12 cases). Clinical and serological signs of autoimmunity correlated strongly with female sex (34, 72% women; and 13, 28% men) and with immunoglobulin alterations. CONCLUSIONS: To our knowledge this is the first systematic review of B-lymphoproliferative and autoimmune disorders indicating that pseudolymphoma and malignant lymphomas, including maltomas, may develop in the context of a permanent autoantigenic drive.

Aged↗

PubMed1999

Messenger ribonucleic acid levels of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein: expression in human reproductive and nonreproductive tissues.

PAPP-A/proMBP, the complex of pregnancy-associated plasma protein-A (PAPP-A) and the proform of eosinophil major basic protein (proMBP), circulates at increasing levels during pregnancy. The major site of synthesis is the placenta, in which PAPP-A mRNA has been localized to the syncytiotrophoblast and the placental X cells, whereas proMBP mRNA has been localized to the placental X cells only. The function of PAPP-A/proMBP and its components has remained speculative for years. Recently, however, it has been shown that PAPP-A specifically cleaves insulin-like growth factor (IGF) binding protein-4 in an IGF-dependent manner. Female reproductive and nonreproductive tissues have previously been reported to contain PAPP-A immunoreactivity, based on studies using preparations of anti(PAPP-A/proMBP), now known to recognize both PAPP-A and proMBP, and other irrelevant antigens. To analyze for the presence of PAPP-A and proMBP mRNA, a sensitive semiquantitative reverse transcription (RT) polymerase chain reaction (PCR) method was developed. Reverse-transcribed poly(A)(+) RNA was used as a template in a competitive PCR. PAPP-A and proMBP mRNA levels were normalized against the level of beta-actin mRNA. Both mRNA species were significantly more abundant in term placenta than in other tissues analyzed. All analyzed tissues, including endometrium, myometrium, colon, and kidney, contained both PAPP-A and proMBP mRNA.

Actins↗

PubMed1999

Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import.

Importin alpha plays a pivotal role in the classical nuclear protein import pathway. Importin alpha shuttles between nucleus and cytoplasm, binds nuclear localization signal-bearing proteins, and functions as an adapter to access the importin beta-dependent import pathway. In contrast to what is found for importin beta, several isoforms of importin alpha, which can be grouped into three subfamilies, exist in higher eucaryotes. We describe here a novel member of the human family, importin alpha7. To analyze specific functions of the distinct importin alpha proteins, we recombinantly expressed and purified five human importin alpha's along with importin alpha from Xenopus and Saccharomyces cerevisiae. Binding affinity studies showed that all importin alpha proteins from humans or Xenopus bind their import receptor (importin beta) and their export receptor (CAS) with only marginal differences. Using an in vitro import assay based on permeabilized HeLa cells, we compared the import substrate specificities of the various importin alpha proteins. When the substrates were tested singly, only the import of RCC1 showed a strong preference for one family member, importin alpha3, whereas most of the other substrates were imported by all importin alpha proteins with similar efficiencies. However, strikingly different substrate preferences of the various importin alpha proteins were revealed when two substrates were offered simultaneously.

Acetyltransferases↗

PubMed1999

Evidence that the insulin-like growth factor binding protein-4 protease in human ovarian follicular fluid is pregnancy associated plasma protein-A.

Ovarian insulin-like growth factor binding protein-4 (IGFBP-4) proteolysis is involved in the regulation of follicular development, but until now the identity of the responsible enzyme was unknown. In this study, we identify the IGFBP4 protease in human follicular fluid as pregnancy associated plasma protein-A (PAPP-A) based on distinctive IGFBP-4 cleavage pattern, the same protease inhibitor profile, specific inhibition and immunodepletion of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition by PAPP-A monoclonal antibodies in ELISA. Furthermore, PAPP-A levels in estrogen-dominant and androgen-dominant follicular fluids reflect their IGFBP-4 proteolytic activity. PAPP-A was also secreted by human granulosa cells, the reputed source of IGFBP-4 protease activity in follicular fluid. We have the molecular and biochemical tools to begin to delineate the regulation and biological function of PAPP-A in normal and dysregulated follicular development and atresia.

Culture Media, Conditioned↗

PubMed1999

Autoimmunity in Waldenström's macroglobulinaemia.

Fifty-seven consecutive patients with Waldenström's Macroglobuliemia were studied retrospectively for autoimmune manifestations. 28 patients or 51% (16 women and 13 men) had clinical and/or serological autoimmune manifestations, two or more of these being concomitant in 20 (12 women and 8 men). The predominant findings were Coombs' positive autoimmune hemolytic anemia (16%), seropositive rheumatoid arthritis (16%), inflammatory gastric ulcer with parietal cell autoantibodies (12%), and IgM-cardiolipin syndrome (11%). 40% of the autoimmune manifestations were present at the time of diagnosis of the Waldenström's Macroglobulinaemia and 60% were observed over a mean period of 4.7 years. All patients had an IgM M-component. There was no correlation between autoimmunity and the size of the M-component or the degree of hypo-IgG and hypo-IgA gammaglobulinemia. The only correlation between autoimmunity and infection was found in patients with gastric ulcer and parietal cell autoantibodies, in whom the infection was caused by Helicobacter pylori.

Aged↗

PubMed1999

SP1 in pregnancies with Down syndrome in the first trimester of pregnancy. International Prenatal Screening Research Group.

We conducted a study to determine the value of serum pregnancy-specific beta-1-glycoprotein (Schwangerschafts protein 1, SP1) as an antenatal screening test for Down syndrome in the first trimester. Serum samples collected from women at 8 to 14 weeks of pregnancy, immediately prior to having a chorionic villus sampling procedure on account of advanced maternal age, were retrieved from 96 women with Down syndrome pregnancies (cases) and from 480 women with unaffected pregnancies (controls). Cases and controls were ascertained at 21 obstetric centres in nine countries. Each case was matched with five controls for maternal age (same five-year age groups), duration of storage of the serum sample (same calendar year) and gestational age (usually the same week of pregnancy). The levels of SP1 were lower in pregnancies associated with Down syndrome: the median level was 0.86 multiples of the median level in the controls (95 per cent confidence interval 0.76 to 0.97). This difference, though statistically significant, was not large enough for SP1 to be a useful marker in screening, at least from 10 weeks onwards where most of our data lie.

Biomarkers↗

PubMed1998

Determination of serum tetranectin: technical and clinical evaluation of three sandwich immunoassays.

The performance of two sandwich-type immunoassays for the determination of the tumour marker tetranectin using monoclonal antibodies Hyb 130-13 and 130-14 as catching layer was compared with the performance of a polyclonal assay. Sensitivities were 0.4-0.6 microg/l, and intra- and inter-assay coefficients of variation were < 10% in all assays. One-hundred-and-ten blood donors were examined, and women had higher concentrations of tetranectin in serum than men when measured with monoclonal assays (P < 0.05). In preoperative serum samples from 43 patients with ovarian cancer, tetranectin concentrations were reduced (P < 0.001), and the mean tetranectin concentration decreased with increasing FIGO stage of the patients (P < 0.05). In sera from patients with ovarian cancer, tetranectin concentrations were lower in the polyclonal assay than in the monoclonal assays. This could, hypothetically, be explained by ligand-binding or other conformational changes in tetranectin, influencing the antigenicity of the molecule.

Adult↗

PubMed1998

Intrathecal activation of the complement system and disability in multiple sclerosis.

BACKGROUND: The pathogenesis of multiple sclerosis (MS) appears to involve autoimmune phenomena in the central nervous system. Activation of the complement system is suggested to be involved in the pathogenesis. PATIENTS AND METHODS: Cerebrospinal fluid (CSF) and plasma samples from 65 patients with acute optic neuritis (ON) as a possible first symptom of MS (n=18), ON (n=16) or other attacks of clinically definite MS (n=15), and neurological control subjects (n=16) were studied. Activation of the initial part of the complement activation cascade was assessed by measuring activation of the C3 molecule; terminal activation of the complement cascade was assessed by measuring the terminal complement complex (TCC). Demyelination was estimated by the CSF concentration of myelin basic protein and neurological disability was assessed with the Kurtzke expanded disability status scale (EDSS) score. RESULTS: Activation of the initial part of the complement activation cascade occurred in each of the three groups of patients with demyelinating disease, but was not correlated to demyelination or disability. Increased concentrations of TCC were detected in patients with attacks of MS other than ON. The CSF concentrations of TCC, myelin basic protein (MBP) and neurological disability correlated significantly. The strongest correlation was between neurological disability and the CSF concentration of TCC (r=0.55, P=0.003). INTERPRETATION: Full activation of the complement cascade during attacks of MS may be restricted to patients with more advanced disease and is significantly correlated to the degree of neurological disability. This suggests that specific treatment with agents that inhibit complement activation may interfere with mechanisms involved in the pathogenesis of neurological disability in patients with MS.

Acute Disease↗

PubMed1998

Novel donor splice site mutation in the KVLQT1 gene is associated with long QT syndrome.

INTRODUCTION: Inherited long QT syndrome (LQTS) recently has been associated with mutations in genes coding for potassium (KVLQT1, KCNE1, and HERG) or sodium (SCN5A) ion channels involved in regulating either sodium inward or potassium outward currents of heart cells, resulting in prolongation of the repolarization period. We describe a new mutation, a -1 donor splice site mutation in a kindred with two affected members (QTc = 0.61 and 0.54 sec). METHODS AND RESULTS: Single stranded conformation polymorphism (SSCP) analyses were performed on DNA fragments amplified by polymerase chain reaction from DNA extracted from whole blood. Aberrant conformers were analyzed by DNA sequencing. SSCP analysis of the KVLQT1 gene revealed an aberrant conformer in the affected family members. DNA sequencing confirmed the presence of a G-->A change in the last nucleotide of codon 344. This mutation does not cause an amino acid change, but a change of the splice site characteristics at the 3' end of exon 6. The mutation may affect, through deficient splicing, the putative sixth transmembrane segment of the K+ channel, and this type of mutation has not previously been described in KVLQT1. CONCLUSION: The clinical course of LQTS in the affected family members, in whom no deaths occurred despite 20 to 30 syncopes, can be explained by the ability of the cellular machinery to perform partial correct splicing in the mutant allele. This type of mutation may be misinterpreted as a normal variant, since it is a point mutation causing neither an amino acid change nor the introduction of a stop codon.

Aged↗

PubMed1998

The dominant epitope of Borrelia garinii outer surface protein C recognized by sera from patients with neuroborreliosis has a surface-exposed conserved structural motif.

Epitope mapping of outer surface protein C (OspC) by using sera from patients with neuroborreliosis led to the identification of one single major immunodominant epitope within the C-terminal 10 amino acid residues. Peptide binding studies and alanine replacement scanning of the C-terminal decapeptide, PVVAESPKKP, revealed a critical role for the PKKP sequence and its terminal carboxyl group for the binding of immunoglobulin M (IgM) antibodies from patients with Lyme borreliosis. Electron microscopy of antibody-labeled spirochetes indicated that the C-terminal region is exposed on the surface of the spirochete. Based on homology to proteins of known function, this region most probably adopts a polyproline II-like helix, which is found in surface-exposed structures involved in protein-protein interactions. This structural motif is highly conserved in Borrelia species causing Lyme borreliosis and subjected to purifying selection. We suggest that the abundance of the C-terminal region of OspC on the surface of B. burgdorferi allows a multimeric high-avidity interaction between the spirochete and surface Igs on B cells. The resulting cross-linking of surface Igs on B cells may induce a T-cell-independent B-cell activation without IgM-to-IgG switching, thus explaining the lack of IgG antibodies to OspC in neuroborreliosis.

Adolescent↗

PubMed1998

Peptide-based OspC enzyme-linked immunosorbent assay for serodiagnosis of Lyme borreliosis.

Sera from 210 patients with Lyme borreliosis (LB) were studied by an enzyme-linked immunosorbent assay (ELISA) based on a synthetic peptide (pepC10) comprising the C-terminal 10-amino-acid residues of OspC of Borrelia burgdorferi. We found that 36.3 and 45.0% of the serum samples from patients with erythema migrans (EM) and neuroborreliosis (NB), respectively, displayed immunoglobulin M (IgM) anti-pepC10 reactivities, while these samples rarely (</=8%) displayed IgG antibody reactivities. Sera from patients with acrodermatitis chronica atrophicans did not contain anti-pepC10 antibodies. The diagnostic performance of this newly developed peptide ELISA was compared with those of an ELISA based on the full-length recombinant OspC protein (rOspC) and a commercially available ELISA based on the B. burgdorferi flagellum (Fla). The sensitivity of the IgM pepC10 ELISA was slightly lower (P < 0.04) than that of the rOspC ELISA for EM patients (36.3 versus 43.8%), while there was no difference for NB patients (45.0 versus 48.0%). However, the optical density values obtained by the pepC10 ELISA were generally higher than those obtained by the rOspC ELISA, leading to a significantly better quantitative discrimination between seropositive patients with NB and controls (P < 0.008). The specificity of the pepC10 ELISA was similar to those of the rOspC ELISA and the Fla ELISA for relevant controls including patients with syphilis and mononucleosis. Although the overall diagnostic sensitivity of the Fla ELISA was superior, 8.8 and 12.0% of the EM and NB patients, respectively, were antibody positive only by the pepC10 ELISA. Thus, use of a diagnostic test for LB based on the detection of IgM antibodies to pepC10 and Fla has increased sensitivity for the diagnosis of early LB.

Adolescent↗

PubMed1998

Calculation of roc curves in multidimensional likelihood ratio based screening with Down's syndrome as a special case.

OBJECTIVES: The development of algorithms and computer programs for the analysis of screening performance in situations with multiple normally (Gaussian) distributed selection markers and a priori risks depending on a stratification of the population. METHODS: The S-PLUS programming language was used to construct programs producing distributions of log likelihood ratios based on the Monte Carlo simulation. These distributions were used to construct programs for the calculation of roc curves, including a possible stratification of the population. RESULTS: S-PLUS programs for the analysis of screening performance are listed and described. The programs can be used without any special knowledge of S-PLUS. An example of the use of the programs is given.

Adolescent↗

PubMed1998

MBP, anti-MBP and anti-PLP antibodies, and intrathecal complement activation in multiple sclerosis.

Intrathecal immunoglobulin synthesis and activation of the complement cascade occurs in patients with multiple sclerosis (MS). The present study aimed at further studying the relation between intrathecal immunoglobulin synthesis and complement activation. We compared total intrathecal synthesis of IgA, IgG, and IgM, the number of cells secreting anti-myelin basic protein (MBP) and anti-proteolipid protein (PLP) antibodies of the IgG isotype and intrathecal activation of the complement cascade in patients with possible onset symptoms of MS (n = 18) or clinically definite MS (n = 30). Early activation of the complement cascade correlated with intrathecal synthesis of IgM. Intrathecal IgG, IgA and IgM synthesis also correlated weakly with the presence of cells secreting anti-MBP or anti-PLP autoantibodies. Full activation of the complement cascade did not correlate with any measures of intrathecal antibody synthesis. These findings suggest a complex relation between different immunoglobulin isotypes and complement activation which may have similarly complex roles in the pathogenesis of MS.

Acute Disease↗

PubMed1998

Cerebrospinal fluid measures of disease activity in patients with multiple sclerosis.

The potential of magnetic resonance imaging to serve as a surrogate marker of disease activity in patients with multiple sclerosis (MS) is increasingly recognised. In contrast, the use of cerebrospinal fluid analysis has received less attention. We analysed the correlation between clinical data and cerebrospinal fluid parameters in 75 patients with acute optic neuritis (ON) as a possible first symptom of MS, as a symptom of clinically definite MS, and in patients with an attack of MS other than ON. The samples were obtained within 30 days from the onset of an exacerbation. The concentration of myelin basic protein (MBP) in cerebrospinal fluid was significantly correlated with the visual acuity in patients with ON and the Kurtzke EDSS score in patients with MS. The concentration of MBP in CSF also correlated positively with the CSF leukocyte count, intrathecal IgG synthesis, and the CSF-serum albumin concentration quotient. The concentration of MBP in CSF correlated negatively with intrathecal IgA synthesis. The results support the use of the concentration of MBP in CSF as a surrogate marker of disease activity during acute exacerbations of MS; the data also link the presence of MBP in CSF to neuroimmunological parameters.

Adolescent↗

PubMed1998

Mutation Detection by Cleavase in Combination With Capillary Electrophoresis Analysis: Application to Mutations Causing Hypertrophic Cardiomyopathy and Long-QT Syndrome.

Background: Genetic screening requires methods for mutation detection that are sensitive, precise, and robust. In population screening for complex genetic diseases in which large genes and/or several genes may be affected, automation of the mutation detection analysis is desirable. Methods and Results: The combined use of Cleavase nuclease and analysis of the DNA cleavage pattern by capillary electrophoresis was evaluated with respect to sensitivity, reproducibility, and dependency of experimental conditions in detecting mutations in the human genes MYH7 and KVLQT1 (KCNA9). The cleavage patterns obtained by capillary electrophoresis were very reproducible and robust. Conclusions: The combination of a sensitive enzymatic mutation detection method capillary electrophoresis may prove to be a useful system for automated, large-scale genetic screening.

Journal Article↗

PubMed1998

Inclusion of serum marker measurements from a previous pregnancy improves Down syndrome screening performance.

A predisposition for high or low levels of serum marker concentrations in second trimester Down syndrome screening reflecting itself in consecutive pregnancies in the same woman has been demonstrated, but hitherto the possible effect of including previous marker results in a current risk evaluation has been considered negligible. Using published data on correlations between the markers AFP, hCG and uE3 in different normal pregnancies in the same women and age-related a priori probabilities we found, that in triple marker screening the inclusion of results from a previous pregnancy in a likelihood ratio based risk calculation could increase the detection rate for women having had an earlier pregnancy from 68.0 per cent to 70.2 per cent at a risk cut-off = 1:250. The screen positive rate for normals for the same population of women, being on average older than the total population, fell from 7.1 per cent to 6.8 per cent. These figures, that are based on an assumption of the same correlations between one normal and one Down syndrome pregnancy as between two normal pregnancies, corresponds to an expected reduction, in the population considered, of the number of children born with Down syndrome of 6.7 per cent and of the number of screen positive normals of 4.7 per cent. Considering that this can be achieved at no extra cost, it is concluded that implementation of a procedure for taking information from previous pregnancies into account in second trimester screening should be considered at centres that can handle the software problems involved in doing so. However, better data on the correlations between a normal and a subsequent Down syndrome pregnancy in the same woman should probably be awaited before this is done.

Biomarkers↗

PubMed1997

[Serum screening of pregnant women reveals Down syndrome. Analysis of biochemical markers for earlier detection].

Second trimester maternal serum screening for fetal Down's syndrome (DS), using the AFP (alpha-fetoprotein), hCG (human chorionic gonadotrophin) and uE3 (unconjugated oestriol) triple test, is as well documented procedure associated with a DS-detection rate of about 70 per cent, for an amniocentesis rate of about 7 per cent. The triple test is relatively little used in the Nordic countries, though its wider use would result in more efficient diagnosis of DS and various fetal malformtions. The maternal age indication currently used leaves gravidae under 35 years of age without prenatal diagnostics, although it is in just this age group that the majority (70 per cent) of cases of fetal DS occur. In Denmark, where 12 per cent of gravidae undergo invasive diagnostic procedures, the proportion of induced abortions due to the procedures is far too high, in relation to the DS detection rates obtained. Maternal serum screening yields a much better ratio between the risk of abortion after amniocentesis and the likelihood of DS detection than does maternal age alone. Maternal serum screening at 7-14 weeks of gestation, using pregnancy-associated plasma protein A and free hCG beta subunit concentrations, will become available within the next few years, thus reducing the incidence of some of the psychological and technical problems associated with second trimester screening, especially that of third trimester abortion. Irrespective of whether it is performed in the first or the second trimester, maternal serum screening will be the cornerstone of prenatal DS diagnosis in the future.

Biomarkers↗