Biomedical subjects
Publications and source records attributed to L Holmberg.
Eight derivatives of methyl alpha-D-glucopyranoside, in which the substituents are part of cyclic structures, have been prepared as model substances for possible structural elements formed on reaction of polysaccharides with epichlorohydrin. The substances were converted into the permethylated alditol-1-d acetates and characterised by CIMS and EIMS.
To determine the relationships among nutrients intake, bone mass, and bone turnover in women we have investigated these issues in a population-based, cross-sectional, observational study in one county in central Sweden. A total of 175 women aged 28-74 at entry to the study were included. Dietary assessment was made by both a semiquantitative food frequency questionnaire and by four 1-week dietary records. Dual energy X-ray absorptiometry was performed at five sites: total body, L2-L4 region of the lumbar spine, and three regions of the proximal femur. Serum concentrations of osteocalcin (an osteoblast-specific protein reflecting bone turnover) were measured by a radioimmunoassay. Linear regression models, with adjustment for possible confounding factors were used for statistical analyses. A weak positive association was found between dietary calcium intake as calculated from the semiquantitative food frequency questionnaire and total body bone mineral density (BMD) among premenopausal women. No association emerged between dietary calcium intake and site-specific bone mass, i.e., lumbar spine and femoral neck, nor was an association found between dietary calcium intake and serum osteocalcin. BMD at some of the measured sites was positively associated with protein and carbohydrates and negatively associated with dietary fat. In no previous studies of diet and bone mass have dietary habits been ascertained so carefully and the results adjusted for possible confounding factors. Neither of the two methods of dietary assessment used in this study revealed any effect of calcium intake on BMD at fracture-relevant sites among these healthy, mostly middle-aged women.(ABSTRACT TRUNCATED AT 250 WORDS)
Randomized clinical trials are powerful tools to refute old prejudices and establish new therapeutic regimes. We propose that they should be afforded a more widespread application in modern clinical medicine.
The complete coding region of the p53 gene was sequenced from 316 consecutively presented breast cancers, of which 97 were lymph node positive and 206 were node negative. The p53 status was related to prognosis and effect of adjuvant therapy. In all, 69 individual mutations, 29 in node-positive tumours, were demonstrated throughout the whole coding sequence. The mutation sites were partly different for node-positive and node-negative patients. p53 mutations in the evolutionary conserved regions II and V were associated with significantly worse prognosis. Adjuvant systemic therapy, especially with tamoxifen, along with radiotherapy seemed to be of less value to p53 mutation- and lymph node-positive tumours.
BACKGROUND: The role of diet as a risk factor for osteoporotic fractures is unclear. Earlier studies have yielded conflicting results. METHODS: In two counties in central Sweden we investigated the association between dietary intake and the risk of proximal femoral fractures in a case-control study nested in a cohort. Women born in 1914-1948 were asked to fill out a food frequency questionnaire when invited to attend for mammographic screening between the years 1987 and 1990. More than 65,000 women completed the questionnaire. Those who had participated in the enquiry and subsequently sustained a first hip fracture were defined as cases. For every case, four individually matched controls, by age and county of residence, were selected from the cohort. A second questionnaire concerning confounding factors was mailed to controls and cases. In all, 247 cases and 893 controls could finally be included. Monthly intake of foods and daily intake of nutrients were calculated. RESULTS: When highest quartile of intake was compared to lowest, intakes of iron (adjusted odds ratio [OR] of 3.3, 95% confidence interval [CI]: 1.6-6.9), magnesium (adjusted OR = 2.7, 95% CI: 1.3-6.0) and vitamin C (adjusted OR = 1.9, 95% CI: 1.2-3.1) were found to be independent risk factors for hip fracture. High calcium intake did not protect against hip fracture. Smoking, low physical activity in leisure time, low body mass index, earlier fracture of the distal forearm and diabetes were all risk factors while postmenopausal hormone replacement therapy protected against hip fracture. DISCUSSION: This large study indicates new dietary risk factors for hip fracture. The association between high dietary intake of iron, magnesium and vitamin C and risk of hip fracture has not been reported previously. Further clinical and experimental studies are needed to confirm these findings and to investigate their mechanism of action.
Because older ages of both mothers and fathers have been hypothesized by others to increase the subsequent risk of breast cancer in female babies, we analyzed the association between maternal and paternal age at birth and mortality from breast cancer in a cohort of 384,796 American women. Cox proportional hazards modeling accounted for age, family history of breast cancer in first-degree relatives, age at menarche, age at first pregnancy, and parity. We found little association between paternal age at birth and death from breast cancer. Although there was no clear linear trend for higher risk with increasing age of the mothers at birth, women born to mothers age 45 years or older had a relative hazard of 1.30 (95% confidence interval = 0.85-1.98), compared with women born to mothers under the age of 20 years. Although these findings are of little public health significance, they may indicate a hormonal profile in older mothers that predisposes female offspring to a higher risk of breast cancer in later years.
A new diagnostic technique based on DNA heteroduplex analysis has been used to identify specific point mutations in the von Willebrand's factor (vWF) gene of patients with von Willebrand's disease type 2B. Molecular analysis in these patients has shown previously that their mutations are clustered in a short region of sequence in exon 28 of the vWF gene. The principle of the method involves heteroduplex formation between amplified genomic sequence containing the defect and an exon 28 vWF gene universal heteroduplex generator (UHG). The UHG is a synthetic vWF gene exon 28 homologue which contains a number of sequence mismatches designed to generate allele specific heteroduplexes for each type 2B mutation. Individual mutant genotypes are identified by characteristic banding patterns following polyacrylamide minigel electrophoresis. The technique is rapid, simple, inexpensive, and is ideally suited for adoption by non-specialist haematology laboratories for screening purposes.
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PURPOSE AND METHODS: Primary breast cancer tumors without axillary metastases from 206 consecutive patients in a population-based cohort were investigated with regard to the presence of an intact p53 gene using a cDNA-based sequencing method. Clinical follow-up data and outcome of node-negative patients without any adjuvant systemic therapy (n = 168) were related to locoregional radiotherapy and p53 status. RESULTS: Mutations in p53 occurred in 31 node-negative breast cancer patients who did not receive any systemic adjuvant treatment, but were treated with postoperative locoregional radiotherapy or nothing. Node-negative breast cancer patients with p53 mutations had significantly improved relapse-free survival (P = .0007), breast cancer-corrected survival (P = .01), and overall survival (P = .02) rates when treated with locoregional radiotherapy. In node-negative breast cancer patients with wild-type p53, there was no statistically significant difference in outcome between patients who received locoregional radiotherapy and those who did not. Cox proportional hazards models indicate that mutant p53 is associated with worse prognosis independent of response to radiotherapy and that response to radiotherapy is qualitatively different in tumors with p53 mutations compared with those with wild-type p53. CONCLUSION: Our clinical findings define a group of breast cancer patients in whom locoregional radiotherapy improves relapse-free, breast cancer-corrected, and overall survival. The outcome for irradiated node-negative breast cancer patients with p53 alterations indicates that irradiation can induce cell death even in the presence of p53 mutations.
Surgery is still the single most important treatment modality for breast cancer. Even if some patients with early stage cancer are treated, and in a clinical sense cured, by surgery alone, adjuvant local and systemic treatments are required for most patients for the best possible tumor control. Surgery must be compatible and timed with other treatment modalities. It helps provide local control, which in some cases is enough for cure but in others is limited to being a means of palliation. Surgery provides the clinical team with material for diagnosis, for prognostication and for help in clinical decision making. The choice of the surgical procedure and its performance should be handled by surgeons, knowledgeable and interested in the field in order to obtain the best possible functional and cosmetic results. An algorithm for deciding the appropriate surgical treatment of the breast is presented. Surgical treatment of the axilla is controversial. Current debate indicates that exploration of the axilla can be safely omitted in some patient groups, but more research is needed. Other important areas for clinical surgical research are use of immediate breast reconstruction, choice of management when margins are involved with tumor growth after breast-sparing operations, and surgical approach to tumors which have been treated with chemotherapy preoperatively.
Radiotherapy effectively prevents local recurrences, but on the other hand still over 80% of non irradiated women are free from local relapse 5 years after breast surgery aiming at radical removal of the primary tumor. So far, there are no indications that radiotherapy to the breast after breast conservation saves lives. The marginal monetary cost for prevention of one local recurrence is about $41,000. Thus, one clinically relevant question is if there is a group of women where the benefits of radiotherapy after breast conservation is outweighed by psychosocial and medical side-effects. Unfortunately, we still lack information from several areas, which makes a detailed cost-benefit analysis uncertain today. The problem situation would change: 1) If we knew more about the pathogenesis of local recurrences and thus also could undertake preventive measures other than radiotherapy. 2) If there was more information on risk factors for local recurrence, and we could identify a low-risk group that could be spared treatment. 3) If there were more valid empirical information on the psychosocial side-effects--both of a local recurrence and of the radiotherapy. 4) If the long-term--positive and negative--effects of radiotherapy were better quantified. Until we have new information, postoperative radiotherapy after breast conservation remains the standard.
Fifty-five patients were included in an extended follow-up after radical radiation therapy (RRT) for localized prostatic cancer (T1-3, Nx, M0). Local cure was assessed by a combination of digital rectal examination (DRE), transrectal ultrasound (TRUS) and systematic 'mapping' with TRUS-guided core biopsies (TGCB). After a mean follow-up of 6.8 years, 33% (18/55) of the patients were locally free of tumour, while in 67% (37/55) of cases residual cancer was demonstrated in the biopsies. Endocrine treatment did not influence the local cure rate, nor did the T stage of tumour grade at diagnosis or the cumulative radiation effect (CRE) values within the range of the present study. The sensitivity of DRE and TRUS was low; 37% and 20% respectively, while the specificity of the DRE and TRUS methods was 83% and 94% respectively. The conclusion of the study is that residual tumour was found in the high proportion of biopsied patients nearly 7 years after RRT and that multiple, TRUS-guided core biopsies are mandatory in the assessment of local cure in patients irradiated for prostatic cancer; both DRE and TRUS on their own are less reliable.
Research regarding the relationship between alcohol intake and breast cancer risk has suggested an association between the two, although the data are inconsistent regarding dose effects and susceptible populations. To clarify these issues, we investigated the association of breast cancer risk with alcohol intake at various ages in a population-based case-control study nested within a screening cohort in Sweden. Subjects were women 40-75 years old who participated in a screening program in central Sweden. Information about personal characteristics, diet, and alcohol intake was obtained by a questionnaire sent out at the invitation to the screening interview and at a supplementary interview conducted among a sample of women who did and did not develop breast cancer. Alcohol intake did not affect breast cancer risk among women under 50 years old. However, among those over 50 years of age, ever-drinking conferred a relative risk of 1.8 (95% confidence interval = 1.2-2.6). Current and former drinkers had similar increases in risk. No particular latent period of alcohol effect was identified, but drinking later in life to have a bigger effect than did drinking earlier in life.
The involvement of ribosomal RNA in the binding of eukaryotic elongation factor eEF-2 to the ribosome was investigated. eEF-2 was complexed to empty reassociated 80S ribosomes in the presence of the nonhydrolyzable GTP analogue GuoPP[CH2]P. The formed complex was treated with dimethyl sulfate, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, and micrococcus nuclease to allow specific modification at single-stranded regions of the rRNAs. The sites of modification were localized by primer extension using complementary deoxynucleotide primers and reverse transcriptase. The modification pattern was compared to that obtained from 80S ribosomes lacking bound eEF-2. Binding of the factor to the ribosome resulted in the protection of specific sites in both 18S and 28S rRNA, while the reactivity of 5.8S rRNA was unchanged. In 18S rRNA, the affected nucleotides were localized to the 5'- and 3'-domains, and in 28S rRNA the protected nucleotides were seen in domains II, IV, and V. The alpha-sarcin/ricin loop in domain VI of 28S rRNA was inaccessible for chemical modification even in the absence of bound eEF-2. However, the bound factor protected A4256, located in the alpha-sarcin/ricin loop, from ricin-induced depurination.
Five derivatives of methyl alpha-D-glucopyranoside, in which the substituents form noncyclic structures, have been prepared as model substances for possible structural elements formed on reaction of polysaccharides with epichlorohydrin. The substances were converted into the permethylated alditol-1-d derivatives and characterised by CIMS and EIMS.
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BACKGROUND: We describe an epidemiologic analytical study of the relationship between current diet and breast cancer risk. METHOD: The study design is a case-control analysis. Cases were recruited from a mammography screening program used within the national health care system; the control subjects were selected from subjects free of breast cancer in the same population. A total of 380 cases and 525 control subjects, frequency-matched for age, month of mammography, and county of residence, were identified. Of these, 265 cases and 432 control subjects were included in this analysis. Odds ratios for breast cancer in relation to food and nutrient intake were the main outcome measures. RESULTS: Exposure in the highest quartile of beta-carotene intake gave an odds ratio of 0.6 (95% confidence interval, 0.4 to 1.0). No increased risk was noted with high fat intake. Breast cancer risk was associated with alcohol intake only when alcohol was analyzed in quartiles: odds ratio, 1.6 (95% confidence interval, 1.0 to 2.4) for the highest quartile of intake vs the lowest. Stratified analyses showed that a high fat intake might decrease the protective effect of beta-carotene intake. Risks did not change appreciably with adjustment for total energy intake or known breast cancer risk factors. CONCLUSIONS: As in most other studies, no strong risk factors for breast cancer have been identified in the current diet. The negative association between breast cancer risk and beta-carotene intake may be supported by a plausible mechanism, but our finding concerning alcohol should be interpreted cautiously since there was no dose-response relationship and the biological mechanism for a threshold effect at very low levels of consumption is unclear.
The participation of 18S, 5.8S and 28S ribosomal RNA in subunit association was investigated by chemical modification and primer extension. Derived 40S and 60S ribosomal subunits isolated from mouse Ehrlich ascites cells were reassociated into 80S particles. These ribosomes were treated with dimethyl sulphate and 1-cyclohexyl-3-(morpholinoethyl) carbodiimide metho-p-toluene sulfonate to allow specific modification of single strand bases in the rRNAs. The modification pattern in the 80S ribosome was compared to that of the derived ribosomal subunits. Formation of complete 80S ribosomes altered the extent of modification of a limited number of bases in the rRNAs. The majority of these nucleotides were located to phylogenetically conserved regions in the rRNA but the reactivity of some bases in eukaryote specific sequences was also changed. The nucleotides affected by subunit association were clustered in the central and 3'-minor domains of 18S rRNA as well as in domains I, II, IV and V of 5.8/28S rRNA. Most of the bases became less accessible to modification in the 80S ribosome, suggesting that these bases were involved in subunit interaction. Three regions of the rRNAs, the central domain of 18S rRNA, 5.8S rRNA and domain V in 28S rRNA, contained bases that showed increased accessibility for modification after subunit association. The increased reactivity indicates that these regions undergo structural changes upon subunit association.