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E Lundgren

Publications and source records attributed to E Lundgren.

At least 37 records · Page 2Linked to original sources
PubMed2001

Interferon-alpha promotes survival of human primary B-lymphocytes via phosphatidylinositol 3-kinase.

Signaling pathways for the antiviral and antiproliferative biological effects of type I interferons (IFN) are well established. In this report we demonstrate a novel signaling pathway for IFN-alpha, as it induced rapid phosphorylation of both PKB/Akt and its substrate forkhead. The PI3-kinase inhibitor LY294002 abolished these phosphorylations. PI3-kinase has been implicated in cell survival mediating its effect through the second messenger PIP3 and the subsequent activation of PKB/Akt. We could show that IFN-alpha inhibited spontaneous apoptosis of primary B-lymphocytes, in the absence of a mitogenic stimulus. This effect was inhibited by LY294002. Thus, our data suggests that IFN-alpha promotes survival of peripheral B-lymphocytes via the PI3-kinase-PKB/Akt pathway. In addition, IFN-alpha stimulation of anti-IgM activated cells resulted in downregulated expression of the cell cycle inhibitor p27/Kip1.

Apoptosis↗
PubMed2001

[Primary hyperparathyroidism is common among postmenopausal women. Identification of genetic risk factors can contribute to individualized treatment].

Primary hyperparathyroidism (pHPT) is commonly seen in postmenopausal women. Along with the clinical characterisation of the disease, studies of molecular genetics have contributed to increased understanding of the etiology of pHPT. Genetic association studies have revealed that certain vitamin D receptor polymorphisms relate to the development of sporadic pHPT. A new type of familial pHPT was recently discovered. Studies of parathyroid adenomas have demonstrated that the tumor suppressor gene MEN1 and the oncogene cyclinD1 are of importance for the tumorigenesis.

Aged↗
PubMed2001

[Ca2+](i) rise in Jurkat E6-1 cell lines from different sources as a response to 50 Hz magnetic field exposure as a reproducible effect and independent of poly-L-lysine treatment.

Jurkat E6-1 cells obtained from three different sources were compared with respect to intracellular calcium response to a 50 Hz, 0.15 mT, magnetic field, to treatment with poly-L-lysine and to protein expression at the cell surface. The fura-2 single cell measurements were a replication study performed by three members of our group. The cells responded to the applied magnetic fields, although the percentage of responding cells was lower than in earlier studies. The geomagnetic field was backed off without changing the outcome of the intracellular calcium measurements. Fluorometric analyses showed no difference between the E6-1 cells obtained from three sources with respect to the expression of cell surface marker molecules. The addition of the cell adhesive peptide, poly-L-lysine, did not itself cause any effects on the intracellular calcium concentration.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2001

Antibody recognition of amyloidogenic transthyretin variants in serum of patients with familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is a late-onset inherited disease characterized by the deposition of amyloid fibrils. FAP is associated with mutations on the transthyretin (TTR) gene. A monoclonal antibody, MAb 39-44, reacting with high molecular weight aggregates of TTR but not with tetrameric TTR has recently been generated and characterized. This antibody recognizes a cryptic epitope that is expressed in isolated recombinant amyloidogenic mutants and in ex vivo amyloid. In the present work we show that this amyloid-specific antibody specifically recognizes in a direct enzyme-linked immunoassay (ELISA) plasma TTR from carriers of various mutations associated with FAP, both in asymptomatic individuals and in patients. In contrast, it does not react with plasma TTR from healthy individuals or that from carriers of nonpathogenic mutations. Using the ELISA developed in this study we identified three different TTR mutations in Portuguese patients with neuropathy of unknown cause, later shown to have amyloid tissue deposition. This antibody recognizes conformations that express cryptic epitopes shared by amyloidogenic TTR variants associated with FAP, not present among nonpathogenic TTR molecules. This antibody will contribute to further identify and characterize intermediates of the amyloidogenic cascade. In addition, it will also be useful for screening amyloidogenic TTR mutations in patients with neuropathy of unknown cause, prior to precise molecular diagnosis using protein and/or DNA analysis.

Amino Acid Substitution↗
PubMed2001

Childbearing and the risk of parathyroid adenoma--a dominant cause for primary hyperparathyroidism.

OBJECTIVES: To explore possible associations between the reproductive history amongst women and the risk of parathyroid adenoma (PA). DESIGN: Two nationwide Swedish registries. The Fertility Register included data on more than 3.4 million livebirths between 1943 and 1992 amongst Swedish females born 1925-72. The Cancer Register encompasses more than 1800 women with a diagnosis of PA 1960 until 1992. SETTING: All women resident in Sweden 1960-92. SUBJECTS: Cases were all 1800 women born 1925-72 reported to the Swedish Cancer Registry with a histopathological diagnosis of PA. Five controls were selected at random for each case by matching for the month and year of birth. Conditional logistic regression was used to estimate relative risks of PA. MAIN OUTCOMES: Parathyroid adenoma. RESULTS: High parity (four or more live births) was associated with an increased risk of PA. Amongst women with a diagnosis of PA before menopause (i.e. the age of 50 years) there was an increased risk of PA with younger age at first childbirth. Nulliparous women were at increased risk for PA before menopause, and at decreased risk after menopause. CONCLUSIONS: There is an association between childbearing and the risk of PA, which has not previously been demonstrated, but the underlying biological mechanisms remain to be determined.

Adenoma↗
PubMed2001

The NeiI polymorphism in the cyclin D1 gene and sporadic primary hyperparathyroidism.

OBJECTIVES: The cell cycle regulator cyclin D1 plays an important role in parathyroid tumourigenesis. The NciI polymorphism in exon 4 has recently been associated with early onset of hereditary nonpolyposis colorectal cancer and is a prognostic indicator of nonsmall cell lung cancer and squamous cell carcinomas. Furthermore, a limited study of 28 primary hyperparathyroidism (pHPT) patients displayed a tendency of NciI influence on HPT development. We hypothesized that the NciI polymorphism may relate to a risk of developing pHPT. DESIGN, SETTING AND SUBJECTS: We genotyped 182 patients with sporadic pHPT and matched controls for the cyclin D1 polymorphism. A total of 88 pHPT patients and controls were recruited via a health-screening. RESULTS: The frequency distribution of the NciI genotypes NN, Ni, and ii were in pHPT patients and controls 22, 44 and 34%, and 26, 49 and 25%, respectively. The calculated allele frequencies were A = 0.56; G = 0.44 in cases and A = 0.49; G = 0.51 in controls. The frequency distributions did not differ comparing cases and controls when subgrouped after age and menopausal status. The NciI genotypes were not significantly associated with age of the individuals, serum (s)-calcium, s-parathyroid hormone (PTH), bone mineral density (BMD) or parathyroid tumour weight in any of the groups of pHPT patients or controls. CONCLUSIONS: No significant differences in distribution of the genotypes could be detected between the groups, suggesting that the polymorphism has minor or no pathogenic importance in the development of pHPT. Our results suggest that determination of the NciI polymorphism in the cyclin D1 gene is not a clinically useful tool for prediction of pHPT.

Aged↗
PubMed2001

Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years.

BACKGROUND: The natural history of mild hyperparathyroidism is incompletely clarified. METHODS: Consistent hypercalcemia was found in 172 patients (aged 28-86 years) participating in population-based screenings in both 1969 and 1971. Mortality until 1994 was compared with 344 matched, normocalcemic controls from the study population. Altogether, 55 case-control pairs underwent biochemical analysis in 1992, whereas 86 patients had died, 8 were lost to follow-up, and 23 had undergone parathyroid operation. RESULTS: Mortality was higher (P = .015) in patients younger than 70 years. Cardiovascular diseases were over-represented causes of death. The hazard ratio for hypercalcemia as an independent cause of cardiovascular mortality was 1.72 (95% CI, 1.24-2.37; P < .001). The initially mild hypercalcemia in patients (2.67 +/- 0.07 mmol/L) decreased over time (P = .0001), whereas the serum calcium value remained constant in the controls. Serum calcium and serum parathyroid hormone values in patients were higher than controls at the follow-up (P < .0001, .01, respectively). All but 17 patients were normocalcemic in 1992, and only 2 (1.4%) developed a serum calcium value higher than 3 mmol/L. CONCLUSIONS: Mild hypercalcemia in patients followed up for more than 2 decades is accompanied by premature cardiovascular death despite trends to spontaneous resolution. The principal cause of hypercalcemia probably is primary hyperparathyroidism, but mechanisms contributing to its regression over time are speculative.

Aged↗
PubMed2000

Search for intermediate structures in transthyretin fibrillogenesis: soluble tetrameric Tyr78Phe TTR expresses a specific epitope present only in amyloid fibrils.

Familial Amyloidotic Polyneuropathy (FAP) is caused by the assembly of TTR into an insoluble beta-sheet. The TTR tetramer is thought to dissociate into monomeric intermediates and subsequently polymerise into the pathogenic amyloid form. The biochemical mechanism behind this transformation is unknown. We characterised intermediate TTR structures in the in vitro amyloidogenesis pathway by destabilising the AB loop through substitution of residue 78. Changes at this residue, should destabilise the TTR tetrameric fold, based on the known crystallographic structure of a Leu55Pro transthyretin variant. We generated a soluble tetrameric form of TTR that is recognised by a monoclonal antibody, previously reported to react only with highly amyloidogenic mutant proteins lacking the tetrameric native fold and with amyloid fibrils. BIAcore system analysis showed that Tyr78Phe had similar binding properties as synthetic fibrils. The affinity of this interaction was 10(7) M(-1). We suggest that the tetrameric structure of Tyr78Phe is altered due to the loosening of the AB loops of the tetramer, leading to a structure that might represent an early intermediate in the fibrillogenesis pathway.

Amino Acid Substitution↗
PubMed2000

A comparative analysis of 23 structures of the amyloidogenic protein transthyretin.

Self-assembly of the human plasma protein transthyretin (TTR) into unbranched insoluble amyloid fibrils occurs as a result of point mutations that destabilize the molecule, leading to conformational changes. The tertiary structure of native soluble TTR and many of its disease-causing mutants have been determined. Several independent studies by X-ray crystallography have suggested structural differences between TTR variants which are claimed to be of significance for amyloid formation. As these changes are minor and not consistent between the studies, we have compared all TTR structures available at the protein data bank including three wild-types, three non-amyloidogenic mutants, seven amyloidogenic mutants and nine complexes. The reference for this study is a new 1.5 A resolution structure of human wild-type TTR refined to an R-factor/R-free of 18.6 %/21.6 %. The present findings are discussed in the light of the previous structural studies of TTR variants, and show the reported structural differences to be non-significant.

Crystallography, X-Ray↗
PubMed2000

Atomic-scale structure and catalytic reactivity of the RuO(2)(110) surface

The structure of RuO(2)(110) and the mechanism for catalytic carbon monoxide oxidation on this surface were studied by low-energy electron diffraction, scanning tunneling microscopy, and density-functional calculations. The RuO(2)(110) surface exposes bridging oxygen atoms and ruthenium atoms not capped by oxygen. The latter act as coordinatively unsaturated sites-a hypothesis introduced long ago to account for the catalytic activity of oxide surfaces-onto which carbon monoxide can chemisorb and from where it can react with neighboring lattice-oxygen to carbon dioxide. Under steady-state conditions, the consumed lattice-oxygen is continuously restored by oxygen uptake from the gas phase. The results provide atomic-scale verification of a general mechanism originally proposed by Mars and van Krevelen in 1954 and are likely to be of general relevance for the mechanism of catalytic reactions at oxide surfaces.

Journal Article↗
PubMed2000

The beta-slip: a novel concept in transthyretin amyloidosis.

Transthyretin is a tetrameric plasma protein associated with two forms of amyloid disease. The structure of the highly amyloidogenic transthyretin triple mutant TTRG53S/E54D/L55S determined at 2.3 A resolution reveals a novel conformation: the beta-slip. A three-residue shift in beta strand D places Leu-58 at the position normally occupied by Leu-55 now mutated to serine. The beta-slip is best defined in two of the four monomers, where it makes new protein-protein interactions to an area normally involved in complex formation with retinol-binding protein. This interaction creates unique packing arrangements, where two protein helices combine to form a double helix in agreement with fiber diffraction and electron microscopy data. Based on these findings, a novel model for transthyretin amyloid formation is presented.

Amino Acid Substitution↗
PubMed1999

Role of the leukocyte function antigen-1 conformational state in the process of human immunodeficiency virus type 1-mediated syncytium formation and virus infection.

Human immunodeficiency virus type 1 (HIV-1)-mediated syncytium formation is recognized as being highly dependent on intercellular adhesion molecule (ICAM)-1-leukocyte function-associated molecule 1 (LFA)-1 interaction, whereas the process of infection with cell-free virions is independent of such complementary interaction. Our group has recently demonstrated that an antibody-mediated induction of the high affinity state of LFA-1 for ICAM-1 renders target T cells more prone to HIV-1-dependent syncytium formation and infection by ICAM-1-bearing virions. To further substantiate these results, we made use of mutant cell lines expressing LFA-1 in either a low (parental HPB-ALL and HAmut) or a high affinity state for ICAM-1 (HAP4) and compared syncytium formation and virus infection. Cells expressing the activated form of LFA-1 were found to be more susceptible to HIV-1-induced syncytium formation and to infection by ICAM-1-bearing HIV-1 particles. The observed increase was solely due to the LFA-1 activation state because it was abrogated by anti-LFA-1 or anti-ICAM-1 antibodies and not due to variations in surface expression of LFA-1, CD4, or the chemokine coreceptor CXCR4. However, a linear relation was seen between the level of CXCR4 surface expression and susceptibility to syncytium formation/virus infection when ICAM-1-LFA-1 interaction was either absent (i.e., infection with ICAM-1-negative virions) or abrogated (treatment with anti-LFA-1 or anti-ICAM-1 antibodies). These results emphasize the important role of the LFA-1 activation state with respect to virus-induced syncytium formation and HIV-1 infection.

Cell Line↗
PubMed1999

[A Scandinavian multicenter study will investigate the question: surgery or not in mild primary hyperparathyroidism?].

Primary hyperparathyroidism is a common endocrine disease particularly prevalent among elderly women. A majority of these patients diagnosed today are mildly hypercalcaemic, and many seem to lack manifest symptoms or complications. In such cases, conservative follow-up rather than parathyroid surgery may be suggested. However, long-term follow-up may entail costly investigations and be difficult to accomplish. Moreover, conservative follow-up is associated with a risk of subsequent complications or even premature death due to cardiovascular disorders. A Scandinavian multicentre study has been initiated to assess survival, morbidity and quality of life in surgically vs. conservatively treated patients.

Aged↗
PubMed1999

Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants.

The structural requirements for generation of amyloid from the plasma protein transthyretin (TTR) are not known, although it is assumed that TTR is partly misfolded in amyloid. In a search for structural determinants important for amyloid formation, we generated a TTR mutant with high potential to form amyloid. We demonstrated that the mutant represents an intermediate in a series of conformational changes leading to amyloid. Two monoclonal antibodies were generated against this mutant; each displayed affinity to ex vivo TTR and TTR mutants with amyloidogenic folding but not to wild-type TTR or mutants exhibiting the wild-type fold. Two cryptic epitopes were mapped to a domain of TTR, where most mutations associated with amyloidosis occur and which we propose is displaced at the initial phase of amyloid formation, opening up new surfaces necessary for autoaggregation of TTR monomers. The results provide direct biochemical evidence for structural changes in an amyloidogenic intermediate of TTR.

Amino Acid Sequence↗
PubMed1999

Fraud, misconduct or normal science in medical research--an empirical study of demarcation.

OBJECTIVES: To study and describe how a group of senior researchers and a group of postgraduate students perceived the so-called "grey zone" between normal scientific practice and obvious misconduct. DESIGN: A questionnaire concerning various practices including dishonesty and obvious misconduct. The answers were obtained by means of a visual analogue scale (VAS). The central (two quarters) of the VAS were designated as a grey zone. SETTING: A Swedish medical faculty. SURVEY SAMPLE: 30 senior researchers and 30 postgraduate students. RESULTS: Twenty of the senior researchers and 25 of the postgraduate students answered the questionnaire. In five cases out of 14 the senior researchers' median was found to be clearly within the interval of the grey zone, compared with three cases for the postgraduate students. Three examples of experienced misconduct were provided. Compared with postgraduate students, established researchers do not call for more research ethical guidelines and restrictions. CONCLUSION: Although the results indicate that consensus exists regarding certain obvious types of misconduct the response pattern also indicates that there is no general consensus on several procedures.

Attitude of Health Personnel↗