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Biomedical subjects

G Paulsen

Publications and source records attributed to G Paulsen.

At least 19 recordsLinked to original sources
PubMed1999

Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial.

OBJECTIVE: Rheumatoid arthritis (RA) causes substantial morbidity and mortality, and current treatments are suboptimal. Recent studies have demonstrated the short-term efficacy of minocycline in the treatment of patients with early RA. This study was undertaken to compare patients treated with conventional therapy in the early phase of their RA and those treated with minocycline, after 4 years of followup. METHODS: Forty-six patients with seropositive RA of <1 year's duration had been enrolled in a double-blind study of minocycline (100 mg twice daily) versus placebo. After the blinded portion of the study (3-6 months, depending upon response), all patients were treated with conventional therapy. This report compares those patients randomized to receive placebo for 3 months and then conventional therapy for the duration of 4 years versus those originally randomized to receive minocycline. RESULTS: Twenty of the 23 original minocycline-treated patients and 18 of the 23 original placebo-treated patients were available for followup (mean 4 years). At followup, RA was in remission (American College of Rheumatology criteria) without disease-modifying antirheumatic drug (DMARD) or steroid therapy in 8 of the patients originally treated with minocycline compared with 1 patient in the placebo group (P = 0.02). Ten patients in the minocycline group versus 16 in the original placebo group currently require DMARD therapy (P = 0.02). CONCLUSION: Among patients with seropositive RA, remissions are more frequent and the need for DMARD therapy is less in those treated early in the disease course with minocycline compared with those treated with conventional therapy delayed by an average of only 3 months. Minocycline appears to be an effective therapy for early RA; further investigation into its mechanism of action is needed.

Anti-Bacterial Agents↗
PubMed1998

The P9 pocket of HLA-DQ2 (non-Aspbeta57) has no particular preference for negatively charged anchor residues found in other type 1 diabetes-predisposing non-Aspbeta57 MHC class II molecules.

Susceptibility and resistance to type 1 diabetes are associated with MHC class II alleles that carry non-Asp and Asp at residue 57 of their beta chain respectively. The effect of Asp or non-Aspbeta57 may relate to a differential ability of distinct class II molecules to bind specific immuno-pathogenic peptides. Recent studies in man and mouse have revealed that some type 1 diabetes-predisposing non-Aspbeta57 class II molecules (i.e. DQ8, DR4Dw15 and I-Ag7) preferentially bind peptides with a negatively charged anchor residue at P9. It has been suggested that this is a common feature of type 1 diabetes-predisposing class II molecules. The molecular explanation for such a phenomenon could be that class II beta chains with Aspbeta57 form a salt bridge between Aspbeta57 and a conserved Arg of the a chain, whereas in non-Aspbeta57 molecules the Arg is unopposed and free to interact with negatively charged P9 peptide anchor residues. We have investigated the specificity of the P9 pocket of the type 1 diabetes-associated DQ2 molecule and in particular examined for charge effects at this anchor position. Different approaches were undertaken. We analyzed binding of a high-affinity binding ligand and P9-substituted variants of this peptide, and we analyzed the binding of a set of synthetic random peptide libraries. The binding analyses were performed with wild-type DQ2 and a mutated DQ2 with Ala at beta57 substituted with Asp. Our results indicate that the wild-type DQ2 (non-Aspbeta57) prefers large hydrophobic residues at P9 and that there is no particular preference for binding peptides with negatively charged residues at this position. The specificity of the P9 pocket in the mutated DQ molecule is altered, indicating that the beta57 residue contributes to determining the specificity of the P9 pocket. Our data do not lend support to the hypothesis that all non-Asp beta57 class II molecules predispose to development of disease by binding peptides with negatively charged P9 anchor residues.

Alanine↗
PubMed1996

Gastroprotective effect of ranitidine bismuth citrate is associated with increased mucus bismuth concentration in rats.

BACKGROUND: Antisecretory and bismuth compounds protect the gastric mucosa from injury resulting from non-steroidal anti-inflammatory drugs. AIM: To study the mechanism underlying the gastroprotective effects of ranitidine bismuth citrate (GG311) in rats. METHODS: Indomethacin rat injury model and in vivo microscopy in which acid output, surface cell intracellular pH (pHi), gastric mucus gel thickness, and mucosal blood flow were measured simultaneously. RESULTS: In injury studies, GG311 dose dependently protected against severe injury induced by indomethacin (60 mg/kg subcutaneously). In in vivo microscopic studies, indomethacin significantly decreased mucus gel thickness and increased the initial rate of acidification of gastric surface cells when the superfusate pH was lowered from 7.4 to 1.0, and impaired pHi during acid exposure. Indomethacin had no effect on mucosal blood flow or acid output. GG311 alone had no effect on gel thickness, blood flow, or pHi homeostasis during acid exposure, but improved the initial acidification rate and pHi during superfusion with pH 1.0 solutions in the presence of indomethacin. In separate experiments, indomethacin pretreatment considerably increased gastric mucus bismuth concentrations in rats given GG311. CONCLUSIONS: The gastroprotective effect of GG311 against indomethacin induced gastric injury is associated with high and prolonged gastric mucus bismuth concentrations, which may impair proton permeation across the mucus gel.

Analysis of Variance↗
PubMed1995

HLA-DQ2-restricted T-cell recognition of gluten-derived peptides in celiac disease. Influence of amino acid substitutions in the membrane distal domain of DQ beta 1*0201.

CD is precipitated in susceptible individuals by ingestion of wheat gluten. The disease is strongly associated to the HLA-DQ(alpha 1*0501, beta 1*0201) (DQ2) heterodimer, where both the DQ alpha and DQ beta chains are required for susceptibility. We have recently shown that gluten-specific CD4+ T cells from the small intestinal mucosa of CD patients are predominantly restricted by the CD-associated HLA-DQ(alpha 1*0501, beta 1*0201) heterodimer. Here we report studies on the influence of aa substitutions in the DQ beta 1*0201 chain on DQ2-restricted T-cell recognition of gluten antigens. A B-LCL expressing the DQ(alpha 1*501, beta 1*0301) heterodimer was transfected with the DQB1*0201 gene, or with DQB1*0201 genes altered by site-directed mutagenesis. Surface expression of the wild-type or mutated DQ(alpha 1*0501, beta 1*0201) heterodimers was observed in the transfectants. Seven DQ2-restricted, gluten-specific TCCs were then investigated with respect to their ability to recognize antigen presented by the transfectants. All TCCs were sensitive to one or more of the aa substitutions induced but showed different response patterns. The results demonstrate that single aa substitutions of the DQ beta 1*0201 chain at positions in the peptide-binding cleft of DQ(alpha 1*0501, beta 1*0201) may affect binding of gluten-derived peptides and/or interfere with T-cell recognition. Because all seven TCCs studied were differently affected, they probably differ with respect to glutenpeptide and/or DQ(alpha 1*0501, beta 1*0201) restriction fine specificity.

Amino Acid Sequence↗
PubMed1995

Characterization of an HLA-DQ2-specific monoclonal antibody. Influence of amino acid substitutions in DQ beta 1*0202.

The HLA-DQ(alpha 1*0501, beta 1*0201) and-DQ(alpha 1*0501, beta 1*0202) (i.e., DQ2) heterodimers are probably involved in the pathogenesis of celiac disease and several other HLA-DQ-associated diseases. To obtain a tool for studies of these molecules, a mAb of the IgG1 isotype, 2.12.E11, was produced by immunization with purified DQ(alpha 1*0501, beta 1*0201) molecules and murine NIH 3T3 cells transfected with both DQA1*05011 and DQB1*0202. Panel cell studies with HLA homozygous B-lymphoblastoid cells and HLA-transfected murine cells demonstrated that 2.12.E11 bound only to cells expressing HLA-DQ beta 1*0201 or 0202, irrespective of the accompanying DQ alpha chain (i.e., DQ alpha 1*0501 or DQ alpha 1*0201). Another DQ2-specific mAb (XIII 358.4) and the broadly HLA class-II-reactive mAb Tü39 strongly inhibited binding of 2.12.E11. Epitope mapping employing mutants with single aa substitutions of DQ beta 1*0202 indicated that position 37 may be of some importance for 2.12.E11 binding. A triple mutant (45G-->E, 46E-->V, 47F-->Y) failed to bind 2.12.E11, suggesting a crucial role for one or more of these residues in the epitope. However, the expression of the mutant beta chain could not be formally proved, as none of the DQ2-reactive mAbs recognized this transfectant.

3T3 Cells↗
PubMed1995

Influence on antibody recognition of amino acid substitutions in the cleft of HLA-DQ2 molecules. Suggestive evidence of peptide-dependent epitopes.

The purpose of this study was to identify polymorphic residues of DQ2 beta chains which are involved in the epitopes recognized by DQ2-reactive mAbs. Binding studies were performed on a panel of DQ2 mutant cells made by transfection of a DQ (alpha 1*0501, beta 1*0301)-positive B-LCL with DQB1 genes encoding either wild-type or mutated DQ beta 1 *0202. Several aa substitutions were found to influence the binding of DQ2 mAbs. All but one of the mAbs were clearly sensitive to the introduced aa substitutions, but individual mAbs were differentially influenced, suggesting that they recognized different epitopes on the DQ2 molecule. Substitutions in positions 30 and 37 of the peptide-binding cleft were also found to influence the binding of some mAbs. Second, two mAbs, NFLD.M71 and NFLD.M102, which bound to DQ(alpha 1*0501, beta 1*0202) expressed in human cells and were sensitive to the introduction of aa substitutions in the cleft, bound weakly to the DQ(alpha 1*0501, beta 1*0202) heterodimer when expressed in a transfected murine NIH 3T3 cell line. Together this indicates that some DQ2-reactive mAbs may recognize peptide-dependent epitopes.

3T3 Cells↗
PubMed1995

Gliadin-specific T cell responses in peripheral blood of healthy individuals involve T cells restricted by the coeliac disease associated DQ2 heterodimer.

Coeliac disease (CD) is probably caused by an abnormal immune response towards wheat gliadin in the small intestine. We found that gliadin-specific T cells from the small intestinal mucosa of HLA-DQ2 positive CD patients were almost exclusively restricted by the disease-associated DQ2 molecule. In the peripheral blood of CD patients, a large proportion of gliadin-specific T cells were found to be restricted by DQ molecules, including DQ2, but many were instead restricted by DR or DP molecules of the patient. We have now investigated gliadin-specific T cell responses in peripheral blood from healthy individuals. Four of 20 persons tested had strong in vitro responses and were used as donors for gliadin-specific T cell clones. We found gliadin-specific T cells restricted by the CD-associated DQ2 molecule in peripheral blood for two of these four individuals. It is the presence of such T cells also in the small intestinal mucosa which seems typical of CD.

Antibodies, Monoclonal↗
PubMed1994

Effect of dietary coenzyme Q10 as an antioxidant in human plasma.

A human study including 22 volunteers was conducted to investigate the antioxidative effect in blood of dietary coenzyme Q10 supplementation. The levels of alpha-tocopherol, ascorbic acid, lipid peroxidation (measured as TBARS) and the redox status of CoQ10 (reduced CoQ10/total CoQ10) were measured in plasma as markers for the antioxidative status once a week during the study period. To introduce an increased oxidative stress, a fish oil supplementation was given. The levels of alpha-tocopherol and ascorbic acid and the redox status did not change upon CoQ10 supplementation, while the level of TBARS decreased. The decrease in TBARS might be ascribed to an antioxidative effect of the supplied CoQ10. The constant redox level of CoQ10 during the CoQ10 supplementation shows that the exogenous CoQ10 is reduced during absorption and subsequent incorporation into lipoproteins, which is a prerequisite for its antioxidative function. The fish oil supplementation resulted in a higher TBARS level and a lower alpha-tocopherol level, but the redox level of CoQ10 was unchanged. In conclusion, the CoQ10 supplementation resulted in a higher plasma level of reduced CoQ10 and a lower TBARS level, but sparing of other plasma antioxidants (i.e. ascorbic acid and alpha-tocopherol) was not observed.

Administration, Oral↗
PubMed1994

Antioxidative effect of dietary coenzyme Q10 in human blood plasma.

The effect of an oral dose of 90 mg/day coenzyme Q10 on the antioxidative status in 22 healthy young subjects (9 men and 13 women) was investigated before and after induction of an oxidative stress by fish oil supplementation. The levels of oxidised and reduced coenzyme Q10, alpha-tocopherol, ascorbate, TBARS and the fatty acid composition of phospholipids were determined in plasma. The total amount of plasma coenzyme Q10 increased significantly from 0.7 +/- 0.1 mumol/l before supplementation to 1.7 +/- 0.3 mumol/l after one week of supplementation while the redox status (reduced CoQ10/total CoQ10) remained constant, even during a following fish oil supplementation. The level of TBARS decreased during the first 2 weeks of CoQ10 ingestion while the content of alpha-tocopherol increased in the second week and ascorbate did not change. The decrease of TBARS and the presence of the majority of the orally supplemented CoQ10 in the reduced form in plasma seem to indicate an antioxidative role of CoQ10 in blood plasma.

Adult↗
PubMed1993

Gliadin-specific, HLA-DQ(alpha 1*0501,beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients.

Celiac disease (CD) is most probably an immunological disease, precipitated in susceptible individuals by ingestion of wheat gliadin and related proteins from other cereals. The disease shows a strong human HLA association predominantly to the cis or trans encoded HLA-DQ(alpha 1*0501,beta 1*0201) (DQ2) heterodimer. T cell recognition of gliadin presented by this DQ heterodimer may thus be of immunopathogenic importance in CD. We therefore challenged small intestinal biopsies from adult CD patients on a gluten-free diet in vitro with gluten (containing both gliadin and other wheat proteins), and isolated activated CD25+ T cells. Polyclonal T cell lines and a panel of T cell clones recognizing gluten were established. They recognized the gliadin moiety of gluten, but not proteins from other cereals. Inhibition studies with anti-HLA antibodies demonstrated predominant antigen presentation by HLA-DQ molecules. The main antigen-presenting molecule was established to be the CD-associated DQ(alpha 1*0501, beta 1*0201) heterodimer. The gluten-reactive T cell clones were CD4+, CD8-, and carried diverse combinations of T cell receptor (TCR) V alpha and V beta chains. The findings suggest preferential mucosal presentation of gluten-derived peptides by HLA-DQ(alpha 1*0501, beta 1*0201) in CD, which may explain the HLA association.

Amino Acid Sequence↗
PubMed1992

Preoperative and late postoperative psychosocial state following coronary artery bypass surgery.

In a prospective study of psychological and neurological reactions to coronary artery bypass surgery, 45 patients were examined preoperatively, postoperatively, and 21 to 27 months after, using a variety of neurological, psychiatric, and psychological investigations. Within the follow-up sample, three subgroups of patients could be identified by cluster analysis who differed with respect to their emotional status and life satisfaction. One group (24% of the total sample) was characterized by high levels of anxiety, depression and life dissatisfaction and appears as a risk population. The other groups could be described as either average (42%) or stable (33%). At the follow up, the risk group further indicated a preference for depressive coping styles, a slightly higher degree of cognitive impairment, more neurological and psychopathological symptoms (specifically giving-up and hostility), a considerably lower return-to-work rate, more subjective physical complaints and a poorer attitude toward the outcome. While postoperative measurements (obtained 2-3 and 6-8 days after surgery) as well as intraoperative parameters did not reveal significant group differences, the analysis yielded an increased impairment within the risk group already prior to surgery, especially emotional problems, specific health-related cognitions and a more fatalistic attitude. The results are in line with those of other studies investigating the late postoperative psychological status with regard to the proportion of patients showing psychological impairments as well as to their specific psychological characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Psychological↗
PubMed1991

Partial DNA sequences derived from two previously unknown HLA class I genes.

Genomic DNA of HLA class I gene segments was amplified by the polymerase chain reaction (PCR). The amplified 0.8 kb gene segment encompassed sequences corresponding to an exon 2 (alpha 1 domain), an intron 2 and an exon 3 (alpha 2 domain). The PCR product was cloned in M13 and sequenced. Two previously unknown sequences were found. One of them (DAN2) had an open reading frame and intact intron splice sites, but we did not find evidence for transcription. Best homology (87.5%) was found with HLA-BeWo C.1, a recently described HLA-C gene. The other sequence (DAN4) is derived from a pseudogene, because the putative 3' splice site of intron 2 was changed from AG to ATG and the sequence corresponding to exon 3 had a shift in reading frame resulting in a stop codon.

Amino Acid Sequence↗
PubMed1990

Early neurological abnormalities following coronary artery bypass surgery. A prospective study.

A prospective analysis of 78 patients undergoing coronary artery bypass surgery (CABS) was carried out to assess clinically the frequency and course of cerebral complications during the 1st postoperative week. Detailed evaluation of the patients showed that neurological abnormalities after CABS were common, occurring in 40 of the 78 patients (51%). However, there were no serious cerebral complications. Changes in reflexes and new focal signs were found in 26 and 25 cases respectively; in 7 patients (9%) they were confined to the first postoperative days. There was no statistically significant correlation between postoperative outcome and age, preoperative neurological state or bypass time. However, some strong associations could be calculated between a history of cerebrovascular signs or symptoms and the appearance of persisting focal signs or development reflexes during the 1st week after CABS.

Adult↗
PubMed1988

Microcirculatory stasis precedes tissue necrosis in ethanol-induced gastric mucosal injury in the rat.

The relation of blood flow stasis to the development of unequivocal histologic necrosis (loss of parietal cells from the column of contiguous cells) in ethanol-induced gastric mucosal injury was studied in anesthetized rats. The most rapid vascular change that occurred when the gastric mucosa was exposed to 100% ethanol was a severe segmental constriction of the large submucosal venules. At 22 sec, the average venular diameter was 52.2 +/- 6.0% of the original one. This was followed by complete superficial mucosal blood flow stasis at 49 +/- 4 sec and appearance of histologic evidence of necrosis in one of seven rats at 2.5 min, four of six rats at 10 min, and seven of seven rats at 60 min. We conclude that in ethanol-induced gastric mucosal injury, submucosal venular constriction occurs first, followed by cessation of mucosal blood flow to be followed later on with histologic evidence of necrosis.

Animals↗
PubMed1988

HLA-DQw3.1 and DQw3.2 associated exon polymorphisms detected by oligonucleotide probes.

HLA class II polymorphisms have been analyzed on the genomic level by two oligonucleotide probes corresponding to the DNA sequence coding for the amino acids 23-30 in the first domain of the beta chain of DQw3.1 and DQw3.2. Specific hybridization to single endonuclease fragments of DNA from some HLA homozygous cells was detected. Here we report the distribution of these DNA exon sequences among different DQ alleles, and demonstrate that the probes may be used to type for DQw3.1 and DQw3.2 respectively.

DNA↗
PubMed1987

Identification in blood stains through DNA typing with C4 and HLA-DR probes.

A restriction fragment length polymorphism analysis using double digestion of DNA preparations with XbaI and BglII restriction enzymes and hybridization with C4 and HLA-DR probes is described. The typing conditions selected reveal extensive individual variation in both C4 and DR gene regions. In our panel of 46 unrelated individuals, 37 different phenotypic patterns were recognized when both probes were used, and preliminary discriminative power values of 0.865 and 0.914 were calculated for C4 and DR beta, respectively. The probability of a chance match using both systems is probably about 1.5.10(-2). The potential of this method for individual identification of blood stains was demonstrated on DNA prepared from 6-month-old dried blood stains from seven panel individuals. The seven individuals were all identified when comparing stain DNA patterns with panel control patterns. No RFLP pattern changes were observed following storage of blood stains. Based on these experiments with C4 and DR beta DNA typing under laboratory conditions, it is concluded that DNA typing with such probes may become a powerful tool in future stain identification analyses.

Blood Grouping and Crossmatching↗
PubMed1987

Genomic HLA-DQ beta polymorphism associated with insulin-dependent diabetes mellitus. Analysis of possible functional significance.

Twelve insulin-dependent diabetes mellitus (IDDM) patients and healthy controls, who all carried the serologically defined DR3 and DR4 antigens, were compared with respect to other HLA polymorphisms. No significant differences between patients and controls were found by typing for HLA-Dw determinants by homozygous cell typing, nor by studies of their genomic DR beta polymorphism using different restriction enzymes. In contrast, certain DR beta polymorphism using different restriction enzymes. In contrast, certain DR4-associated genomic DQ beta fragments had a significantly different distribution among the IDDM patients than among the controls. Furthermore, when the distribution of all DQ beta-specific fragments which demonstrated polymorphism in our material was taken into account, nine of the 12 DR3, 4 IDDM patients demonstrated a similar DQ beta polymorphism compared with only two out of the 12 DR3, 4 controls (P = 0.006; corrected P = 0.037). Cells from patients and controls who demonstrated this IDDM-associated DQ beta polymorphism stimulated each other significantly less in reciprocal MLC tests, compared with the responses seen when their cells were confronted with cells from the DR3, 4 individuals with other genomic DQ beta polymorphisms.

Adult↗