Biomedical subjects

T Brenn

Publications and source records attributed to T Brenn.

At least 19 recordsLinked to original sources

PubMed2006

Postradiation vascular proliferations: an increasing problem.

The occurrence of cutaneous vascular lesions is a rare but well-documented complication of radiation treatment and may be associated with significant morbidity as well as mortality. The overall incidence is low but appears to be rising due to a change in the prevailing treatment of breast carcinoma with increased use of radiation in the setting of breast-conserving therapy for stage 1 and 2 disease. The spectrum of postradiation vascular lesions is wide and ranges from atypical vascular lesions with reportedly benign clinical behaviour to frank cutaneous angiosarcoma. There is, however, significant clinical as well as histological overlap. It is frequently difficult to classify these postradiation vascular lesions accurately and they create an emerging diagnostic and therapeutic challenge to both pathologists and clinicians. Experience with these vascular lesions is very limited, and this article aims to provide an overview of our current understanding and concept of radiation-associated vascular lesions with focus on their clinical and histological presentation as well as behaviour and treatment.

Diagnosis, Differential↗

PubMed2001

Multi-exon deletions of the FBN1 gene in Marfan syndrome.

BACKGROUND: Mutations in the fibrillin -1 gene (FBN1) cause Marfan syndrome (MFS), an autosomal dominant multi-system connective tissue disorder. The 200 different mutations reported in the 235 kb, 65 exon-containing gene include only one family with a genomic multi-exon deletion. METHODS: We used long-range RT-PCR for mutation detection and long-range genomic PCR and DNA sequencing for identification of deletion breakpoints, allele-specific transcript analyses to determine stability of the mutant RNA, and pulse-chase studies to quantitate fibrillin synthesis and extracellular matrix deposition in cultured fibroblasts. Southern blots of genomic DNA were probed with three overlapping fragments covering the FBN1 coding exons RESULTS: Two novel multi-exon FBN1 deletions were discovered. Identical nucleotide pentamers were found at or near the intronic breakpoints. In a Case with classic MFS, an in-frame deletion of exons 42 and 43 removed the C-terminal 24 amino acids of the 5th LTBP (8-cysteine) domain and the adjacent 25th calcium-binding EGF-like (6-cysteine) domain. The mutant mRNA was stable, but fibrillin synthesis and matrix deposition were significantly reduced. A Case with severe childhood-onset MFS has a de novo deletion of exons 44-46 that removed three EGF-like domains. Fibrillin protein synthesis was normal, but matrix deposition was strikingly reduced. No genomic rearrangements were detected by Southern analysis of 18 unrelated MFS samples negative for FBN1 mutation screening. CONCLUSIONS: Two novel deletion cases expand knowledge of mutational mechanisms and genotype/phenotype correlations of fibrillinopathies. Deletions or mutations affecting an LTBP domain may result in unstable mutant protein cleavage products that interfere with microfibril assembly.

Journal Article↗

PubMed1999

Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes.

Fibrillin-1 (FBN1) contains 47 epidermal growth factor (EGF)-like domains characterized by six conserved cysteine residues. Cysteine substitutions that disrupt one of the three disulfide bonds are frequent causes of Marfan syndrome (MFS). We identified 19 new substitutions involving cysteine residues in each of the six positions of EGF-like domains. Allele-specific mRNA assays revealed equal abundance of mutant and normal FBN1 transcripts in all 10 individuals studied. Quantitative pulse-chase analysis of fibrillin protein was performed on 25 mutant fibroblast strains with substitutions of 22 different cysteine residues in 18 different EGF-like domains spanning the entire gene. Normal synthesis and stability of mutant fibrillin molecules was seen in 20/25 individuals, 11 of whom showed delayed intracellular processing and/or secretion. In the remaining five cases, the mutant protein was apparently unstable. In four of these five cases, the second or third disulfide bond of EGF-like domains immediately preceding an 8-cysteine or hybrid domain was affected. All but two mutations caused severe reduction of matrix deposition, which was attributed to a dominant-negative effect of mutant molecules. For genotype/phenotype comparisons, clinical data on 25 probands and 19 mutation-positive family members were analyzed. Ocular manifestations were among the most consistent features (ectopia lentis in 86%, myopia in 80%). Nine mutations encoded by exons 26-32 resulted in early-onset classic MFS and, in one case, neonatal-lethal MFS. Mutations outside this region were associated with variable clinical phenotypes, including individuals with fibrillinopathies not meeting diagnostic criteria for MFS.

Adolescent↗

PubMed1999

Self-reported seasonal variation in depression at 78 degree north. The Svalbard Study.

STUDY OBJECTIVES: To explore and compare the one year prevalence of self-reported depression in two ethnically different populations. DESIGN: A cross-sectional study of each population (1988-89 and 1993). SETTING: Norwegians living in Longyearbyen, Svalbard, and Russians living in Barentsburg and Pyramiden, Svalbard, both representing the world's two northern most regularly inhabited settlements. PARTICIPANTS: 506 Norwegians (327 men and 179 women) and 446 Russians (314 men and 132 women), all 18 years or older, living on Svalbard. MAIN RESULTS: Among Russians, the one year prevalence of self-reported depression lasting for at least 2 weeks was 26.8% for men and 44.7% for women. Corresponding figures for the Norwegians were 10.7 and 15.6%. For the period with polar night the figures were 5.5 and 6.7% for Norwegians, and 21.7 and 37.1% for Russian men and women, respectively. Depression was most common in the youngest age-group among Russians and in the oldest age-group among the Norwegians. CONCLUSION: The one year prevalence of depression was 2-3 times higher among Russians compared to Norwegians living on Svalbard. For the period with polar night, the figures were 4-5 times higher for Russians. As both populations are exposed to the same amount of daylight, seasonal depression may therefor not solely be a matter of lack of daylight. Because the Russian population came from lower latitudes than the Norwegians, we hypothesize that insufficient acclimatization after migration to the north is essential for the understanding of seasonal variation in depression.

Adolescent↗

PubMed1997

Physical activity and the risk of breast cancer.

BACKGROUND: Because physical activity may affect hormonal concentrations and energy balance, we decided to investigate whether everyday exercise is related to the risk of breast cancer. METHODS: During 1974 to 1978 and 1977 to 1983, a total of 25,624 women, 20 to 54 years of age at entry, enrolled in health surveys and answered questionnaires about leisure-time and work activity. RESULTS: During a median follow-up of 13.7 years, we identified 351 cases of invasive breast cancer among the 25,624 women in the cohort. Greater leisure-time activity was associated with a reduced risk of breast cancer, after adjustments for age, body-mass index (the weight in kilograms divided by the square of the height in meters), height, parity, and county of residence (relative risk, 0.63; 95 percent confidence interval, 0.42 to 0.95), among women who exercised regularly, as compared with sedentary women (P for trend=0.04). In regularly exercising women, the reduction in risk was greater in premenopausal women than in postmenopausal women, and greater in younger women (<45 years at study entry) than in older women (> or =45 years) (relative risk, 0.38; 95 percent confidence interval, 0.19 to 0.79). In stratified analyses the risk of breast cancer was lowest in lean women (body-mass index, <22.8) who exercised at least four hours per week (relative risk, 0.28; 95 percent confidence interval, 0.11 to 0.70). The risk was also reduced with higher levels of activity at work, and again there was a more pronounced effect among premenopausal than postmenopausal women. CONCLUSIONS: Physical activity during leisure time and at work is associated with a reduced risk of breast cancer.

Adult↗

PubMed1997

[Daily number of births in Norway 1989-93. Variations across months, day of week, phase of the moon and changes in leave entitlements].

The variation in the daily numbers of births across month, day of week, phase of the moon and maternity leave entitlements have been studied for all births in Norway between 1989 and 1993, a total of 302,209 newborn children. The number of births was highest in the spring and lowest in November and December. A secondary birth maximum was observed in September, possibly related to activities during Christmas and New Year celebrations nine months before. Furthermore, births were least numerous at weekends and were concentrated in the middle of the week. This pattern probably reflects less active obstetric intervention at weekends. The number of births does not seem to vary with phase of the moon. At the time of the latest, and largest increase in national birth maternity leave entitlements, fewer births occurred in the days before and correspondingly more births in the days immediately after the date when the change came into force.

Adult↗

PubMed1997

Adult family members and their resemblance of coronary heart disease risk factors: the Cardiovascular Disease Study in Finnmark.

Coronary heart disease tends to run in families, and the familial resemblance of major risk factors for the disease was examined among various types of adult family members. Family units were assembled from a total of 4,738 men and women who took part in a cross sectional health survey in four Norwegian municipalities where all inhabitants between 20 and 52 years of age were invited. After adjusting for age and other confounders, correlation coefficients were derived as a measure of the degree of resemblance. Viewed across all types of investigated familial relationships, similarity was found to be stronger for total cholesterol than for high-density lipoprotein cholesterol and triglycerides, and also stronger for systolic than for diastolic blood pressure. Between husbands and wives (3,060 subjects), correlations were small (between 0.02 and 0.06), except for 0.11 for total cholesterol. Lipid and blood pressure correlations ranged from 0.13 to 0.27 for parents and their offspring (471 subjects, p < 0.05) and from 0.11 to 0.22 among siblings (2,166 subjects, p < 0.01). Sibling correlations were consistent across age groups. Furthermore, reports from each individual on daily smoking (yes or no) revealed that husbands and wives had similar habits in 63.5% of all marriages as compared with the expected 49.4% had no smoking similarity at all been present. Smoking concordance was also demonstrated among siblings (p < 0.01). The persistent pattern of lipid and blood pressure aggregation among genetically related individuals from 20 to 52 years of age and the much weaker such similarity between husbands and wives, point towards genes or commonly shared environment at early ages as a major reason why coronary heart disease runs in families.

Adult↗

PubMed1997

Sleeping problems at 78 degrees north: the Svalbard Study.

The aim of this study, was to compare the prevalence of sleeping problems in two ethnically different populations living under the same extreme arctic climate. A total of 453 Norwegians (319 males and 134 females) were compared with 450 Russians (317 males and 133 females), all aged 18 years or older, living on Svalbard, the northernmost regular settlement in the world. Among Russians, 81% of the male subjects and 77% of the female subjects reported sleeping problems lasting for at least 2 weeks. The corresponding figures for the Norwegians were 22% (for males) and 25% (for females). Among Russians, sleeping problems decreased with increasing age, but no such age trend was found in Norwegians. Whereas sleeping problems among Norwegians were approximately equally frequent throughout the year, the Russians reported more problems during the polar night. 'Problems falling asleep', 'not feeling rested in the morning' and 'walking up several times during the night' were the most frequent types of sleeping problems in both groups. Depression, shift work, loneliness, ability to concentrate, alcohol consumption and quality of life were associated with sleeping problems in Norwegian subjects, whereas depression, shift work, ability to concentrate, and worry were associated with sleeping problems in Russians. The prevalence of sleeping problems was nearly fourfold higher among Russian subjects than among Norwegians living on Svalbard. As the Russians were recruited from a lower latitude than the Norwegians, we postulate that their problems should be interpreted in terms of inadequate acclimatization after migration to the north.

Adult↗

PubMed1996

Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe marfan syndrome.

Marfan syndrome (MFS), a heritable connective tissue disorder, is caused by mutations in the gene coding for fibrillin-1 (FBN1), an extracellular matrix protein. One of the three major categories of FBN1 mutations involves exon-skipping. To rapidly detect such mutations, we developed a long RT-PCR method. Either three segments covering the entire FBN1 coding sequence or a single 8.9 kb FBN1 coding segment were amplified from reverse-transcribed total fibroblast RNA. Restriction fragment patterns of these RT-PCR products were compared and abnormal fragments were directly sequenced. Six exon-skipping mutations were identified in a panel of 60 MFS probands. All skipped exons encode calcium binding epidermal growth factor (EGF)-like domains and maintain the reading frame. In five probands, exon-skipping was due to point mutations in splice site sequences, and one had a 6 bp deletion in a donor splice site. Pulse-chase analysis of labelled fibrillin protein revealed normal levels of synthesis but significantly reduced matrix deposition. This dominant-negative effect of the mutant monomers is considered in the light of current models of fibrillin assembly. Probands with this type of FBN1 mutation include the most severe forms of MFS, such as neonatally lethal presentations.

Epidermal Growth Factor↗

PubMed1996

Intracoronary Doppler flow velocity measurements in two patients with solitary coronary ostium: is there true obstruction?

BACKGROUND: Coronary anomalies in the absence of other major cardiac malformations are rare, with an incidence of less than 1-1.5%. Although most have been incidental findings without clinical relevance, a subgroup of anomalies has been identified that are associated with cardiac symptoms or even sudden cardiac death. This subgroup includes an ectopic origin and abnormal course of the left coronary artery from the right sinus of Valsalva. RESULTS: We examined two patients with this anomaly. In patient I the left main coronary artery took a deep intramural course anterior to the pulmonary trunk, and in patient II the left anterior descending coronary artery took its course between the pulmonary trunk and ascending aorta. Both anomalies were identified by coronary angiography and that in patient I was confirmed by surgery. Intracoronary Doppler flow velocity measurements during cardiac catheterization, including atrial pacing in patient II, demonstrated significant flow acceleration in both patients. This occurred within the intramural segment (in patient I) and in the segment between the pulmonary artery and ascending aorta (in patient II). CONCLUSIONS: These findings indicate that external vessel compression is one pathophysiological mechanism that leads to ischaemia and a longstanding history of cardiac symptoms in these patients. Invasive haemodynamic measurements such as these have not previously been available.

Blood Flow Velocity↗

PubMed1996

Blood serum analyses in population studies: parallel analyses and degree of agreement in a Norwegian-Russian co-project. The Svalbard Study.

In a survey of more than 300 russian coal workers living on Svalbard, parallel laboratory analyses of gamma-glutamyltransferase, serum total cholesterol, high density lipoprotein, and triglycerides were performed in Tromsö, Norway and in Archangelsk, Russia. Mean values for gamma-glutamyltransferase and serum total cholesterol were significantly higher in Tromsö than in Archangelsk while mean values of triglycerides and high density lipoproteins were significantly lower in Tromsö than in Archangelsk. Linear regression plots revealed both systematical and arbitrary differences between the two laboratories. Because no "true" standards were available, we were unable to assess the accuracy of laboratory results. We conclude that laboratory measurements from Norway and Russia are not directly comparable. Future research programs between the two laboratories should attempt to include calibrated standards of test serum from which to identify sources of variation. Alternatively, the serum tests should always only be analyzed at one site.

Adult↗

PubMed1996

Dermal fibroblast culture as a model system for studies of fibrillin assembly and pathogenetic mechanisms: defects in distinct groups of individuals with Marfan's syndrome.

Most patients with Marfan's syndrome (> 95%) and 75% of patients with uncertain diagnosis can be classified into four groups (Aoyama et al, 1994, 1995) based on abnormal patterns of synthesis, intracellular transport, and/or matrix deposition of fibrillin-1 in fibroblast cultures. Herein we report a systematic study of fibrillin assembly in normal and Marfan's syndrome fibroblasts and correlations between pulse-chase, immunofluorescence, and immunoelectron microscopic data. Normal control fibroblasts were grown at confluent conditions from 2 to 10 days before passage and then maintained at hyperconfluent cell densities for an additional period of 1 to 6 days before assaying. Maximum deposition in the extracellular matrix of pulse-labeled fibrillin required at least 6 days of confluent and 4 to 5 days of hyperconfluent culture. This result is explained by immunofluorescence studies with fibrillin-1-specific antibodies, because 1 day after seeding cells at hyperconfluency, patches of regular immunostained structures were already present. Within these patches, fluorescence intensity and fibrillar material increased over 3 to 4 days, and after only 5 days, fibrillar networks extended throughout the culture. We propose that fibrillin-containing microfibrillar material is passaged together with the cells, newly synthesized fibrillin molecules are deposited onto preexisting microfibrillar assemblies, and several additional days of culture at high cell density are necessary for the cells to construct a sufficient microfibrillar network binding and detection of pulse-labeled fibrillin molecules in insoluble form during a 20-hour chase period. This fraction is decreased to a varying extent in fibroblast cultures of four biosynthetically distinct groups of Marfan's syndrome patients, but only Groups II and IV clearly showed reduction in immunostainable microfibrils. In long-term cultures, immunoelectron microscopy of the extracellular matrix with fibrillin antibodies also detected differences among these groups and in comparison to normal controls with respect to the arrangement of fibrillin-containing microfibrils, thickness of microfibrillar bundles, and the presence of amorphous material. The data support the idea of different pathogenetic mechanisms for each biosynthetically defined group of Marfan's syndrome, which depends on the nature of fibrillin-1 mutations.

Antibodies↗

PubMed1995

The Svalbard study 1988-89: a unique setting for validation of self-reported alcohol consumption.

The Norwegian island of Spitzbergen, Svalbard offers a unique setting for validation studies on self-reported alcohol consumption. No counterfeit production or illegal import exists, thus making complete registration of all sources of alcohol possible. In this study we recorded sales from all agencies selling alcohol on Svalbard over a 2-month period in 1988. During the same period all adults living permanently on Svalbard were invited to take part in a health screening. As part of the screening a self-administered questionnaire on alcohol consumption was introduced to the participants. We found that the self-reported volume accounted for approximately 40 percent of the sales volume. Because of the unique situation applying to Svalbard, the estimate made in this study is believed to be more reliable compared to other studies using sales volume to validate self-reports.

Adolescent↗

PubMed1995

Expression of a mutant human fibrillin allele upon a normal human or murine genetic background recapitulates a Marfan cellular phenotype.

The Marfan syndrome (MFS) is a connective tissue disorder inherited as an autosomal dominant trait and caused by mutations in the gene encoding fibrillin, a 350-kD glycoprotein that multimerizes to form extracellular microfibrils. It has been unclear whether disease results from a relative deficiency of wild-type fibrillin; from a dominant-negative effect, in which mutant fibrillin monomers disrupt the function of the wild-type protein encoded by the normal allele; or from a dynamic and variable interplay between these two pathogenetic mechanisms. We have now addressed this issue in a cell culture system. A mutant fibrillin allele from a patient with severe MFS was expressed in normal human and murine fibroblasts by stable transfection. Immunohistochemical analysis of the resultant cell lines revealed markedly diminished fibrillin deposition and disorganized microfibrillar architecture. Pulse-chase studies demonstrated normal levels of fibrillin synthesis but substantially reduced deposition into the extracellular matrix. These data illustrate that expression of a mutant fibrillin allele, on a background of two normal alleles, is sufficient to disrupt normal microfibrillar assembly and reproduce the MFS cellular phenotype. This underscores the importance of the fibrillin amino-terminus in normal microfibrillar assembly and suggests that expression of the human extreme 5' fibrillin coding sequence may be sufficient, in isolation, to produce an animal model of MFS. Lastly, this substantiation of a dominant-negative effect offers mutant allele knockout as a potential strategy for gene therapy.

Alleles↗

PubMed1995

A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection.

Ascending aortic disease, ranging from mild aortic root enlargement to aneurysm and/or dissection, has been identified in 10 individuals of a kindred, none of whom had classical Marfan syndrome (MFS). Single-strand conformation analysis of the entire fibrillin-1 (FBN1) cDNA of an affected family member revealed a G-to-A transition at nucleotide 3379, predicting a Gly1127Ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. This mutation was present in 9 of 10 affected family members and in 1 young unaffected member but was not found in other unaffected members, in 168 chromosomes from normal controls, and in 188 chromosomes from other individuals with MFS or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a Gly1127Ser carrier. We postulate that the Gly1127Ser FBN1 mutation is responsible for reduced matrix deposition. We suggest that mutations such as this one may disrupt EGF-like domain folding less drastically than do substitutions of cysteine or of other amino acids important for calcium-binding that cause classical MFS. The Gly1127Ser mutation, therefore, produces a mild form of autosomal dominantly inherited weakness of elastic tissue, which predisposes to ascending aortic aneurysm and dissection later in life.

Adult↗

PubMed1994

Genetic and environmental effects on coronary heart disease risk factors in northern Norway. The cardiovascular disease study in Finnmark.

This study comprised 1377 first degree relatives in 575 families ascertained through a comprehensive screening of the general population from 20 to 52 years of age. Path analysis using parsimonious models gave evidence of significant biologic and environmental transmission for total cholesterol (genetic and cultural heritabilities were 0.46 and 0.05, respectively), high density lipoprotein cholesterol (0.42, 0.10), triglycerides (0.21, 0.07), and systolic (0.48, 0.04) and diastolic (0.35, 0.05) blood pressure. Compared with other studies employing the same path analytic model, heritability estimates in general were among the highest reported, except for the somewhat lower genetic component in total cholesterol and triglycerides. For the first time in a single sample from the general population, lipid and blood pressure variables were investigated applying the same methodology, and good agreement was illustrated by the result that identical parsimonious models were reached for all phenotypes, with the exception of a single additional parameter for total cholesterol. About one fourth to one half of the total phenotypic variance could be ascribed to genetic sources, whereas the contribution from shared familial environment was much smaller.

Adult↗

PubMed1992

New alcohol markers--how useful are they in population studies: the Svalbard Study 1988-89.

Regular high consumption of alcohol in selected populations have, with high precision, been identified by two new alcohol markers; carbohydrate-deficient transferrin and mitochondrial aspartate aminotransferase. To test these markers in an unselected population, gamma-glutamyltransferase (GGT), carbohydrate-deficient transferrin (CDT), and mitochondrial aspartate aminotransferase (mAST) were measured in the Norwegian population, 310 males and 171 females, aged 18 to 60 years, living at Svalbard. Using self-reported alcohol intake as gold standard, sensitivity, specificity, positive predictive value, and likelihood-ratio were estimated according to different cutoff-points for alcohol intake and for the tests. In contrast to earlier studies, the sensitivity was in general low. With a specificity of 90% or higher, the sensitivity did not exceed 26% for any of the tests. Whereas CDT showed its best discriminatory power at lower intake of alcohol, GGT discriminated best at higher levels. Parallel and serial analysis of CDT and GGT indicated a conditional independence between the tests, as well as at higher and at lower levels of alcohol consumption. mAST was judged as not suitable in population studies.

Adolescent↗

PubMed1991

Nicotine-induced release of noradrenaline and neuropeptide Y in guinea-pig heart: role of calcium channels and protein kinase C.

The role of calcium, calcium influx through calcium channels, and activation of protein kinase C for the nicotine-induced release of noradrenaline and of the sympathetic co-transmitter neuropeptide Y (NPY) was investigated in the guinea-pig isolated perfused heart. In the coronary venous overflow noradrenaline and NPY were determined by high-pressure liquid chromatography and radioimmunoassay, respectively. In the presence of extracellular calcium (1.85 mmol/l) nicotine (1-100 mumol/l) evoked a concentration-dependent overflow of both transmitters with a molar ratio of approximately 1500 (noradrenaline):1 (NPY). The nicotine-induced (100 mumol/l) overflow of noradrenaline and NPY was in a linear manner related (r = 0.79 and 0.90, respectively; p less than 0.05) to the extracellular calcium concentration (0-1.85 mmol/l), and it was prevented by calcium-free perfusion. The L-type calcium channel blocker felodipine (100 nmol/l) did not affect the nicotine-induced (100 mumol/l) transmitter overflow. On the other hand, the neuronal (N-type) calcium channel blockers omega-conotoxin (100 nmol/l) and cadmium chloride (50 mumol/l) reduced the nicotine-induced (100 mumol/l) transmitter overflow to 20% of the control value, suggesting a role of N-type calcium channels in mediating the calcium influx for the nicotine-induced transmitter release. The nicotine-induced (30 mumol/l) overflow of both transmitters was two- to three-fold increased by activation of protein kinase C (phorbol 12-myristate 13-acetate; 100 nmol/l). The transmitter overflow was unaffected by 4 alpha-phorbol 12,13-didecanoate (100 nmol/l), a phorbol ester which does not stimulate protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗