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Biomedical subjects

E Holmberg

Publications and source records attributed to E Holmberg.

At least 55 records · Page 3Linked to original sources
PubMed1996

Differential allele loss on chromosome 9q22.3 in human non-melanoma skin cancer.

Familial predisposition to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are apparent in the autosomal dominant syndromes naevoid basal cell carcinoma syndrome (NBCCS) and multiple self-healing squamous epitheliomata (MSSE) respectively. The gene responsible for NBCCS has been proposed to be a tumour-suppressor gene and is mapped to the same 2 Mb interval on 9q22.3 as the MSSE gene ESS1. In an attempt to further map the NBCCS gene, we have examined loss of heterozygosity (LOH) in 16 sporadic BCCs and two familial BCCs using microsatellite markers located within the candidate gene region. The overall frequency of LOH observed was 67% in the BCCs and partial or interstitial deletions were found in eight tumours, with the highest LOH frequency at markers D9S280, D9S287 and D9S180. To determine if the same genomic region also shows frequent LOH in tumours with a squamous phenotype, we have examined 11 SCCs, four actinic keratoses and 13 cases of Bowen's disease for LOH at 9q22.3. An overall LOH frequency of 50% was observed at D9S180, and occurred in all types of squamous tumours. In contrast, a much lower LOH frequency of only 6% was found at the D9S287 locus. Our observation of different patterns of LOH at 9q22.3 in sporadic BCCs and SCCs implies that more than one tumour-suppressor gene might be located in this genomic region.

Alleles↗
PubMed1996

Measurement of health-related quality of life in multiple myeloma. Nordic Myeloma Study Group.

When a randomized trial (NMSG 4/90) comparing treatment with melphalan/prednisone to melphalan/ prednisone + interferon alpha-2b in newly diagnosed multiple myeloma was initiated in 1990, a quality-of-life assessment was integrated into the study. We used the questionnaire (QLQ-C30) developed by the European Organization of Research and Treatment of Cancer (EORTC) Study Group on Quality of Life. The QLQ-C30 incorporates five functional scales, three symptom scales, a global health and quality-of life scale and some single symptom measures. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 524 (90.2%) of 581 patients enrolled in the NMSG 4/90 completed the first questionnaire, and 484 (83.3%) completed all questionnaires given to them. All but one of the scales met the minimum criteria of reliability (Cronbach's alpha >/ 0.70). Validity was shown by (1) the ability of the scales to discriminate clearly between patients differing in clinical status as defined by pretreatment W.H.O. performance index and Durie & Salmon stage, and (2) the sensitivity to changes in objective disease status (response and relapse). This is the first report of the measurement of health-related quality of life in a prospective clinical trial in multiple myeloma. The results demonstrate that the QLQ-C30 is a reliable and valid instrument for the measurement of quality of life in these patients. The data will be used for a cost-utility analysis of the results of the NMSG 4/90 trial.

Aged↗
PubMed1996

Clinical outcome of radioiodine treatment of hyperthyroidism: a follow-up study.

OBJECTIVES: To study the clinical outcome of treatment of hyperthyroid patients with radioiodine. DESIGN: Records of patients treated for hyperthyroidism with radioiodine from 1989 to 1992 were examined in 1994, and a questionnaire was sent to patients < or = 70 years with Graves' disease (GD) and toxic nodular goitre (TNG) to obtain information regarding thyroxine substitution, smoking habits and present state of health. SETTING: Outpatients in a thyroid unit; follow-up by primary care. SUBJECTS: Seven hundred and fifty-four patients with hyperthyroidism treated with radioiodine, 327 receiving the questionnaire, 72% response rate. INTERVENTION: Radioiodine treatment using a delivered absorbed dose method, aiming at an absorbed dose to the thyroid of 100-120 Gy. MAIN OUTCOME MEASURES: Statistical analysis of clinical records and results from questionnaire. RESULTS: Only 10% of the patients needed more than one treatment. At the time of follow-up, thyroxine supplementation was given to 178 (93%) of the GD and to 21 (47%) of the TNG patients. Smoking was more common in GD patients than in the general population (44% vs. 26%; P < 0.001). Smoking GD patients experienced eye discomfort more often than smoking TNG patients (53% vs. 7%; P < 0.001). Weight gain after therapy was a problem in 79% of the hyperthyroid individuals. CONCLUSIONS: Few patients needed retreatment and most of the GD patients had thyroxine after 1-5 years after therapy. Smoking patients, especially those with GD, had more eye symptoms. At follow-up, the euthyroid patients still consider themselves having a poorer health than individuals in the general population.

Adult↗
PubMed1996

A comparison of three statistical models for IDDM associations with HLA.

The association between HLA-DQ haplotypes and insulin-dependent diabetes mellitus (IDDM) was studied in 48 children from 44 families ascertained from the high incidence area around Umeå, Sweden. Numerous hypotheses have been proposed to explain associations between HLA and IDDM, but comparisons of statistical models based on these hypotheses have not been attempted. The aim of the present study was to compare the goodness-of-fit and predictive abilities among different statistical models. A likelihood-based analysis rather than a conventional analysis based on contingency tables was therefore adopted. We first used parental haplotype information in a conditional likelihood analysis (1) and then compared this analysis with that of an unaffected control group which used information on geographically matched controls. Under the analysis conditional on parental haplotype, a statistical model motivated by the hypothesis that the entire DQ heterodimer is involved in IDDM pathogenesis fit the data significantly better and had greater predictive ability than either a model motivated by the explanation that an IDDM gene is linked to DQB1 or that the DQB1 chain itself is involved in IDDM pathogenesis, or a model arising from the hypothesis that single amino acids at codon 57 of DQB1 and codon 52 of DQA1, respectively, confer susceptibility. Under the case-control analysis, the identity of the best-fitting or more predictive statistical model was not as clear, although both approaches to analyzing risk suggested that the single-amino-acids model had significantly poorer fit compared to the remaining two models.

Diabetes Mellitus, Type 1↗
PubMed1996

Isolation and characterization of a trisulfide variant of recombinant human growth hormone formed during expression in Escherichia coli.

A new variant of human growth hormone was recently found [Pavlu, B. & Gellerfors, P. (1993) Bioseparation 3, 257-265]. We report here the identification and the structural determination of this variant. The variant, which is formed during the expression of human growth hormone in Escherichia coli, was found to be more hydrophobic than rhGH as judged by its prolonged elution time by hydrophobic interaction chromatography. The rhGH hydrophobic variant (rhGH-HV) was isolated and subjected to trypsin digestion and RP-HPLC analysis, resulting in an altered retention time of one single tryptic peptide as compared to the corresponding fragment of rhGH. This tryptic peptide constitutes the C-terminus (aa 179-191) of hGH and contains one of the two disulfide bridges in hGH, viz. Cys182-Cys189. Amino acid sequences and composition analyses of the tryptic peptide from rhGH-HV (Tv18-19) and the corresponding tryptic peptide from rhGH (T18+19) were identical. Electrospray mass spectrometry (ES MS) of Tv18+19 isolated from rhGH-HV revealed a monoisotopic mass increase of 32.7, as compared to T18+19 from rhGH. A synthetic Tv18+19 peptide having a trisulfide bridge between Cys182 and Cys189 showed identical fragment in ES/MS compared to Tv18+19 isolated from rhGH-HV, i.e. m/z 617.7 and 682.9. These fragments are formed through a unique cleavage in the trisulfide (Cys182-SSS-Cys189) bridge not found in the corresponding T18+19 disulfide peptide. Furthermore, the synthetic Tv18+19 co-eluted in RP-HPLC with Tv18+19 isolated from rhGH-HV. Two-dimensional NMR spectroscopy of the synthetic T18+19 and Tv18+19 peptides were performed. Using these data all protons were assigned. The major chemical shift changes (delta delta > 0.05 ppm) observed were for the beta-protons of Cys182 and Cys189 in Tv18+19 as compared to T18+19. CD spectroscopy data were also in agreement with the above results. Based on these physico-chemical data rhGH-HV has been structurally defined as a trisulfide variant of rhGH. The receptor binding properties of rhGH-HV was studied by a biosensor device, BIAcore. The binding capacity of rhGH-HV was similar to rhGH with a binding stoichiometry to the rhGHBP of 1:1.6 and 1:1.5, respectively, indicating that the trisulfide modification did not affect its receptor binding properties.

Amino Acid Sequence↗
PubMed1996

Advanced laryngeal cancer T3-T4 in Sweden: a retrospective study 1986-1990. Survival and locoregional control related to treatment.

Different treatment modalities for advanced laryngeal cancer are much discussed in the literature. One-hundred-and-sixty patients with T3-4, N0-3, M0-1 laryngeal cancer diagnosed in Sweden between 1986 and 1990 were retrospectively analysed. One hundred (65 T3: 35 T4) received radical radiotherapy with salvage surgery (RRSS) in case of residual or recurrent disease. Thirty-eight (11T3: 27 T4) patients received surgery with or without radiotherapy (S +/- RT). Twenty-two patients received no treatment. After a median follow up of 4.4 years, the estimated 5-year actuarial corrected survival and 3-year locoregional control were 59% and 44% for T3 RRSS and 47% and 54% for T3 S +/- RT. No significant difference between the different treatment modalities was found. The 5-year corrected survival rate and the locoregional control at 3 years between T4-RRSS (32%; 26%) and T4-S + RT (58%; 68%) groups were significantly different (p < 0.05 and p < 0.01). This might suggest that surgery with or without radiotherapy still has its place as a treatment modality for patients with advanced T4 laryngeal carcinoma.

Adult↗
PubMed1995

Fifty probands with extra structurally abnormal chromosomes characterized by fluorescence in situ hybridization.

Extra structurally abnormal chromosomes (ESACs) are small supernumerary chromosomes often associated with developmental abnormalities and malformations. We present 50 probands with ESACs characterized by fluorescence in situ hybridization using centromere-specific probes and chromosome-specific libraries. ESAC-specific libraries were constructed by flow sorting and subsequent amplification by DOP-PCR. Using such ESAC-specific libraries we were able to outline the chromosome regions involved. Twenty-three of the 50 ESACs were inverted duplications of chromosome 15 [inv dup(15)], including patients with normal phenotypes and others with similar clinical symptoms. These 2 groups differed in size and shape of the inv dup(15). Patients with a large inv dup(15), which included the Prader-Willi region, had a high risk of abnormality, whereas patients with a small inv dup(15), not including the Prader-Willi region, were normal. ESACs derived from chromosomes 13 or 21 appeared to have a low risk of abnormality, while one out of 3 patients with an ESAC derived from chromosome 14 had discrete symptoms. One out of 3 patients with an ESAC derived from chromosome 22 had severe anomalies, corresponding to some of the manifestations of the cat eye syndrome. Small extra ring chromosomes of autosomal origin and ESACs identified as i(12p) or i(18p) were all associated with a high risk of abnormality.

Abnormalities, Multiple↗
PubMed1995

De novo mutation in the mitochondrial ATP synthase subunit 6 gene (T8993G) with rapid segregation resulting in Leigh syndrome in the offspring.

The mutation in the mitochondrial ATP synthase subunit 6 gene (ATP6 T8993G) was identified in a male infant who died at age 15 months of Leigh syndrome. He had 94% mutated mitochondrial DNA (mtDNA) in muscle and 92% in lymphocytes. His mother was healthy but had 37% mutated mtDNA in muscle and 38% in lymphocytes. The proband's brother, who was also healthy, had 44% mutated mtDNA in lymphocytes. No mutated mtDNA was detected in muscle and lymphocytes from the maternal grandmother of the proband or in lymphocytes from 15 other maternal relatives, showing that the first carrier of the ATP6 T8993G mutation in this family was the mother of the proband. This study shows that this point mutation may occur at substantial levels in a carrier of a de novo mutation and rapid segregation with high levels of mutated mtDNA causing neurodegenerative disease may occur in the second generation.

2,4-Dinitrophenol↗
PubMed1995

Patient accrual and quality of participation in a multicentre study on myeloma: a comparison between major and minor participating centres.

The participation of minor centres in randomized trials has been questioned because of inferior quality of participation. We have studied this issue in a multicentre trial on myeloma, in which 574 patients were included from 99 participating centres in Sweden, Norway and Denmark from 1 June 1990 until 4 November 1992. Two hundred and eight patients were entered from university hospitals (n = 13), 172 from major county hospitals (n = 25), defined by a population base of > or = 100,000 inhabitants, and 194 from minor county hospitals (n = 61) with a population base of < 100,000 inhabitants. The accrual rate was similar for the three hospital categories, averaging 54% of all reported cases, corresponding to 38% of the expected number of newly diagnosed cases. The adherence to the study protocol from an administrative point of view was judged by the completeness of follow-up forms and the delay in the notification of deaths, and from a clinical point of view by the dose intensity for the principal drugs of the study, melphalan and interferon. For all studied measures of quality, the values were similar for the three hospital categories. We conclude that with due informative and educational support, minor centres can make a considerable contribution to the patient material of a large randomized trial without impairing the quality of the study.

Adult↗
PubMed1995

Cancer incidence after radiotherapy for skin haemangioma during infancy.

An infant cohort treated for skin haemangioma with 226Ra between 1930 and 1965 (n = 11,807) was studied. The median age at treatment was 5-months and 88% were treated before 12 months of age. This cohort was followed up in the Swedish Cancer Registry during the years 1958 to 1989, giving 370,517 person-years at risk. A total number of 248 malignancies have been observed and the standardized incidence ratio (SIR) was 1.21 (confidence interval (CI) 95%, 1.06-1.37). Significantly increased numbers of cancers were found in the central nervous system, 34 cases (SIR = 1.85, CI 95% 1.28-2.59), the thyroid, 15 cases (SIR = 1.88, CI 95% 1.05-3.09) and other endocrine glands, 23 cases (SIR = 2.58, CI 95% 1.64-3.87). The absorbed dose in 11 specified risk organs has been estimated using a phantom of the size of a 5-6-month-old child. The mean absorbed dose in the thyroid was 0.12 Gy and the excess relative risk (ERR) for thyroid cancer was 7.5 per Gy (CI 95% 0.4-18.1). The mean dose in the central nervous system was 0.077 Gy and the ERR for brain tumours was 10.9 per Gy (CI 95% 3.7-20.5). This cohort gives a unique opportunity to analyse long-term effects of low-dose irradiation during infancy.

Adolescent↗
PubMed1995

Cancer morbidity in rheumatoid arthritis patients treated with Proresid or parenteral gold.

The cancer risk was studied by comparison of 305 rheumatoid arthritis (RA) patients exposed to Proresid during a mean time of 22 months and 305 RA patients exposed to sodium aurothiomalate during a mean time of 19 months with the regional cancer register. The mean observation time was 6.9 years (2,117 person-years) for the Proresid-treated and 7.5 years (2,293 person-years) for the gold-treated patients. No increased risk of total malignancies was observed for either group. However, looking at separate tumours, an increased risk of lymphoma and leukemia was found although only significant in the gold-treated group. It was not correlated to dosage or duration of either therapy. The increased risk is consistent with earlier reports of an increased risk of hematopoietic malignancies in RA patients. Marginal over and underreporting, particularly of hematopoietic malignancies, were observed, mainly due to clinicians' failure to report and to recall false reports.

Antineoplastic Agents↗
PubMed1995

New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome.

The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function.

Abnormalities, Multiple↗
PubMed1994

Prediction and site-specific mutagenesis of residues in transmembrane alpha-helices of proton-pumping nicotinamide nucleotide transhydrogenases from Escherichia coli and bovine heart mitochondria.

Nicotinamide nucleotide transhydrogenase from bovine heart consists of a single polypeptide of 109 kD. The complete gene for this transhydrogenase was constructed, and the protein primary structure was determined from the cDNA. As compared to the previously published sequences of partially overlapping clones, three residues differed: Ala591 (previously Phe), Val777 (previously Glu), and Ala782 (previously Arg). The Escherichia coli transhydrogenase consists of an alpha subunit of 52 kD and a beta subunit of 48 kD. Alignment of the protein primary structure of the bovine trashydrogenase with that of the transhydrogenase from E. coli showed an identity of 52%, indicating similarly folded structures. Prediction of transmembrane-spanning alpha-helices, obtained by applying several prediction algorithms to the primary structures of the revised bovine heart and E. coli transhydrogenases, yielded a model containing 10 transmembrane alpha-helices in both transhydrogenases. In E. coli transhydrogenase, four predicted alpha-helices were located in the alpha subunit and six alpha-helices were located in the beta subunit. Various conserved amino acid residues of the E. coli transhydrogenase located in or close to predicted transmembrane alpha-helixes were replaced by site-specific mutagenesis. Conserved negatively charged residues in predicted transmembrane alpha-helices possibly participating in proton translocation were identified as beta Glu82 (Asp655 in the bovine enzyme) and beta Asp213 (asp787 in the bovine enzyme) located close to the predicted alpha-helices 7 and 9 of the beta subunit. beta Glu82 was replaced by Lys or Gln and beta Asp213 by Asn or His. However, the catalytic as well as the proton pumping activity was retained. In contrast, mutagenesis of the conserved beta His91 residue (His664 in the bovine enzyme) to Ser, Thr, and Cys gave an essentially inactive enzyme. Mutation of alpha His450 (corresponding to His481 in the bovine enzyme) to Thr greatly lowered catalytic activity without abolishing proton pumping. Since no other conserved acidic or basic residues were predicted in transmembrane alpha-helices regardless of the prediction algorithm used, proton translocation by transhydrogenase was concluded to involve a basic rather than an acidic residue. The only conserved cysteine residue, beta Cys260 (Cys834 in the bovine enzyme), located in the predicted alpha-helix 10 of the E. coli transhydrogenase, previously suggested to function as a redox-active dithiol, proved not to be essential, suggesting that redox-active dithiols do not play a role in the mechanism of transhydrogenase.

Algorithms↗
PubMed1994

Swedish survey on extra structurally abnormal chromosomes in 39 105 consecutive prenatal diagnoses: prevalence and characterization by fluorescence in situ hybridization.

During 7 years (1985-1992), 39,105 consecutive prenatal diagnoses (34,908 amniocenteses and 4197 chorionic villus samples) were made at the five largest clinical genetic laboratories in Sweden. Thirty-one cases of extra structurally abnormal chromosomes (ESACs) were found, giving a total prevalence of 0.8 per 1000. Twelve ESACs were inherited, 14 were de novo and in five the parental origin was unknown. This gives an estimated prevalence of 0.3-0.4 per 1000 for familial and 0.4-0.5 per 1000 for de novo ESACs. Retrospectively, the ESACs were characterized by fluorescence in situ hybridization (FISH). In nine cases, no material was available for this analysis. In 21 of the remaining 22 cases, the chromosomal origin could be identified by FISH. Seventeen of these (81 per cent) were derived from the acrocentric chromosomes, of which 13 originated from chromosome 15 (62 per cent). The most common ESAC was the inv dup(15) (57 per cent). Two cases were derived from chromosome 22, one from chromosome 14, and one from either chromosome 13 or chromosome 21. The four remaining cases consisted to two i(18p)s and two small ring chromosomes derived from chromosomes 4 and 19, respectively.

Amniocentesis↗
PubMed1994

Inheritance of MHC class II genes in IDDM studied in population-based affected and control families.

The transmission of HLA-DR and DQ was compared between 46 families with at least one child affected by insulin dependent diabetes mellitis (IDDM) and 43 healthy control families. In the patient families, there was an increased transmission of DR4 (p < 0.025) and DQB1*0302 (p < 0.01) from both parents to the index patient. There was an increased transmission of DQB1*0302 (p < 0.03) from the mothers only. The non-inherited maternal haplotypes showed a significantly decreased frequency (p < 0.01) of positively associated haplotypes (DR4-DQA1* 0301-DQB1*0302, DR3-DQA1*0501-DQB1*0201) compared to all parental haplotypes in the control families. In the control families neither transmission rates nor frequencies of non-inherited haplotypes differed from those expected in the control families. In conclusion, the observed reduction of IDDM-positively associated haplotypes in patient non-inherited maternal haplotypes, but not in non-inherited paternal haplotypes, suggests that tolerance during fetal life to maternal non-inherited HLA molecules may be important to diabetes development.

Adolescent↗