Showing papers by "University of Copenhagen published in 1999"

The Danish National Hospital Register. A valuable source of data for modern health sciences.

Abstract: The Danish National Hospital Register (LPR) has collected nationwide data on all somatic hospital admissions since 1977, and since 1995 data on outpatients and emergency patients have been included as well. Numerous research projects have been undertaken in the national Danish context as well as in collaboration with international teams, and the LPR is truly a valuable source of data for health sciences, especially in epidemiology, health services research and clinical research. Nearly complete registration of somatic hospital events in Denmark is combined with ideal conditions for longterm follow-up due to the existence of a national system of unique person identification in a population of relative demographic stability. Examples of studies are provided for illustration within three main areas: I: Using LPR for surveillance of the occurrence of diseases and of surgical procedures, II: Using the Register as a sampling frame for longitudinal population based and clinical research, and III: Using the Register as a data source for monitoring outcomes. Data available from the Register as well as studies of the validity of the data are mentioned, and it is described how researchers may get access to the Register. The Danish National Hospital Register is well suited to contribute to international comparative studies with relevance for evidence-based medicine.

Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group.

Abstract: Background Prophylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. We performed a meta-analysis to determine whether prophylactic cranial irradiation prolongs survival. Methods We analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival. Results The relative risk of death in the treatment group as compared with the control group was 0.84 (95 percent confidence interval, 0.73 to 0.97; P= 0.01), which corresponds to a 5.4 percent increase in the rate of survival at three years (15.3 percent in the control group vs. 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased the rate of disease-free survival (relative risk of recurrence or death, 0.75; 95 percent confidence interval, 0.65 to 0.86; P<0.001) and decreased the cumulative incidence of brain metastasis (relative risk, 0.46; 95 percent confidence interval, 0.38 to 0.57; P<0.001). Larger doses of radiation led to greater decreases in the risk of brain metastasis, according to an analysis of four total doses (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy) (P for trend=0.02), but the effect on survival did not differ significantly according to the dose. We also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with earlier administration of cranial irradiation after the initiation of induction chemotherapy. Conclusions Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission.

Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.

Abstract: The recessive autosomal disorder known as ICF syndrome (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant: juxtacentromeric heterochromatin is greatly elongated and thread-like in metaphase chromosomes, which is associated with the formation of complex multiradiate chromosomes. The same juxtacentromeric regions are subject to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei. Abnormalities are largely confined to tracts of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues. ICF syndrome is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns. Here we show that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6). Cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin, and this methylation appears to be carried out by an enzyme specialized for the purpose.

Influence of body temperature on the development of fatigue during prolonged exercise in the heat

Abstract: We investigated whether fatigue during prolonged exercise in uncompensable hot environments occurred at the same critical level of hyperthermia when the initial value and the rate of increase in bo...

Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

Abstract: Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-γ–inducible protein of 10 kDa (IP-10); monokine induced by interferon-γ (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine–chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

Extraction of Cholesterol with Methyl-β-Cyclodextrin Perturbs Formation of Clathrin-coated Endocytic Vesicles

Abstract: The importance of cholesterol for endocytosis has been investigated in HEp-2 and other cell lines by using methyl-beta-cyclodextrin (MbetaCD) to selectively extract cholesterol from the plasma membrane. MbetaCD treatment strongly inhibited endocytosis of transferrin and EGF, whereas endocytosis of ricin was less affected. The inhibition of transferrin endocytosis was completely reversible. On removal of MbetaCD it was restored by continued incubation of the cells even in serum-free medium. The recovery in serum-free medium was inhibited by addition of lovastatin, which prevents cholesterol synthesis, but endocytosis recovered when a water-soluble form of cholesterol was added together with lovastatin. Electron microscopical studies of MbetaCD-treated HEp-2 cells revealed that typical invaginated caveolae were no longer present. Moreover, the invagination of clathrin-coated pits was strongly inhibited, resulting in accumulation of shallow coated pits. Quantitative immunogold labeling showed that transferrin receptors were concentrated in coated pits to the same degree (approximately sevenfold) after MbetaCD treatment as in control cells. Our results therefore indicate that although clathrin-independent (and caveolae-independent) endocytosis still operates after removal of cholesterol, cholesterol is essential for the formation of clathrin-coated endocytic vesicles.

Prognostic value of nutritional status in chronic obstructive pulmonary disease

Abstract: The association between low body mass index (BMI) and poor prognosis in patients with chronic obstructive pulmonary disease (COPD) is a common clinical observation. We prospectively examined whether BMI is an independent predictor of mortality in subjects with COPD from the Copenhagen City Heart Study. In total, 1,218 men and 914 women, aged 21 to 89 yr, with airway obstruction defined as an FEV(1)-to-FVC ratio of less than 0.7, were included in the analyses. Spirometric values, BMI, smoking habits, and respiratory symptoms were assessed at the time of study enrollment, and mortality from COPD and from all causes during 17 yr of follow-up was analyzed with multivariate Cox regression models. After adjustment for age, ventilatory function, and smoking habits, low BMI was predictive of a poor prognosis (i.e., higher mortality), with relative risks (RRs) in underweight subjects as compared with that in subjects of normal weight of 1.64 (95% confidence interval [CI]: 1.20 to 2.23) in men and 1.42 (95% CI: 1.07 to 1.89) in women. However, the association between BMI and survival differed significantly with stage of COPD. In mild and moderate COPD there was a nonsignificant U-shaped relationship, with the lowest risk occurring in normal-weight to overweight subjects, whereas in severe COPD, mortality continued to decrease with increasing BMI (test for trend: p < 0.001). Similar results were found for COPD-related deaths, with the strongest associations found in severe COPD (RR for low versus high BMI: 7.11 [95% CI: 2.97 to 17.05]). We conclude that low BMI is an independent risk factor for mortality in subjects with COPD, and that the association is strongest in subjects with severe COPD.

Randomized trial on protein vs carbohydrate in ad libitum fat reduced diet for the treatment of obesity

Abstract: OBJECTIVE: To study the effect on weight loss in obese subjects by replacement of carbohydrate by protein in ad libitum consumed fat-reduced diets. DESIGN: Randomized dietary intervention study over six months comparing two ad libitum fat reduced diets (30% of total energy) strictly controlled in composition: High-carbohydrate (HC, protein 12% of total energy) or high-protein (HP, protein 25% of total energy). SETTING AND PARTICIPANTS: Subjects were 65 healthy, overweight and obese subjects (50 women, 15 men, aged 18–55 y) randomly assigned to HC (n=25), HP (n=25) or a control group (C, n=15). All food was provided by self-selection in a shop at the department, and compliance to the diet composition was evaluated by urinary nitrogen excretion. MAIN OUTCOME MEASURE: Change in body weight, body composition and blood lipids. RESULTS: More than 90% completed the trial. Weight loss after six months was 5.1 kg in the HC group and 8.9 kg in the HP group (difference 3.7 kg, 95% confidence interval (CI)(1.3–6.2 kg) P 10 kg in the HP group (35 %) than in the HC group (9 %). The HP diet only decreased fasting plasma triglycerides and free fatty acids significantly. CONCLUSIONS: Replacement of some dietary carbohydrate by protein in an ad libitum fat-reduced diet, improves weight loss and increases the proportion of subjects achieving a clinically relevant weight loss. More freedom to choose between protein-rich and complex carbohydrate-rich foods may allow obese subjects to choose more lean meat and dairy products, and hence improve adherence to low-fat diets in weight reduction programs.

Some tests for parameter constancy in cointegrated VAR-models

Abstract: Some methods for the evaluation of parameter constancy in cointegrated vectorautoregressive (VAR) models are discussed. Two different ways of re-estimating the VAR-model are proposed; one in which all parameters are estimated recursively based upon the likelihood function for the first observations, and another in which the cointegrating relations are estimated recursively from a likelihood function, where the short-run parameters have been concentrated out. We suggest graphical procedures based on recursively estimated eigenvalues to evaluate the constancy of the long-run parameters in the model. Specifically,we look at the time paths of the eigenvalues using a new result on the asymptotic distribution of the estimated eigenvalues. Furthermore, we show that the fluctuation test by Ploberger et al. (1989) and the Lagrange multiplier (LM) type test for constancy of parameters by Nyblom (1989) can be applied to test the constancy of the long-run parameters in the cointegrated VAR-model. All results are illustrated using a model for the term structure of interest rates on US Treasury securities.

A Family of Insulin-Like Growth Factor II mRNA-Binding Proteins Represses Translation in Late Development

Abstract: Insulin-like growth factor II (IGF-II) is a major fetal growth factor. The IGF-II gene generates multiple mRNAs with different 5' untranslated regions (5' UTRs) that are translated in a differential manner during development. We have identified a human family of three IGF-II mRNA-binding proteins (IMPs) that exhibit multiple attachments to the 5' UTR from the translationally regulated IGF-II leader 3 mRNA but are unable to bind to the 5' UTR from the constitutively translated IGF-II leader 4 mRNA. IMPs contain the unique combination of two RNA recognition motifs and four hnRNP K homology domains and are homologous to the Xenopus Vera and chicken zipcode-binding proteins. IMP localizes to subcytoplasmic domains in a growth-dependent and cell-specific manner and causes a dose-dependent translational repression of IGF-II leader 3 -luciferase mRNA. Mouse IMPs are produced in a burst at embryonic day 12.5 followed by a decline towards birth, and, similar to IGF-II, IMPs are especially expressed in developing epithelia, muscle, and placenta in both mouse and human embryos. The results imply that cytoplasmic 5' UTR-binding proteins control IGF-II biosynthesis during late mammalian development.

Potential of biobased materials for food packaging

Abstract: During the last decade, joint efforts by the packaging and the food industries have reduced the amount of food packaging materials. Nonetheless, used packaging materials are still very visible to the consumer in the context of disposal. Environmental issues are becoming increasingly important to the European consumer. Consequently, consumer pressure may trigger the use of biobased packaging materials as an alternative to materials produced from non-renewable resources. Biologically based packaging is defined as packaging containing raw materials originating from agricultural sources, i. e. produced from renewable, biological raw materials such as starch and bioderived monomers. These materials are not necessarily biodegradable. Consequently, this review is not limited to biodegradable packaging. To date, biodegradable packaging has commanded great attention, and numerous projects are under way in this field. One important reason for this attention is the marketing of environmentally friendly packaging materials. Furthermore, use of biodegradable packaging materials has the greatest potential in countries where landfill is the main waste management tool. Biobased packaging materials include both edible films and edible coatings along with primary and secondary packaging materials. Excellent in-depth reviews on edible films and coatings are already available 1 , 2 , 3 . Therefore, this review focuses on biobased primary packaging materials for foods. Several concerns must be addressed prior to commercial use of biobased primary food packaging materials. These concerns include degradation rates under various conditions, changes in mechanical properties during storage, potential for microbial growth, and release of harmful compounds into the packaged food product. Furthermore, the biopackaging must function as food packaging and meet the requirements of the individual food product. This review evaluates the suitability of biobased packaging for foods. Additionally, it identifies the challenges involved when using biobased packaging for different foods.

A mid-european decadal isotope-climate record from 15,500 to 5000 years B.P

Abstract: Oxygen-isotope ratios of precipitation (delta18OP) inferred from deep-lake ostracods from the Ammersee (southern Germany) provide a climate record with decadal resolution. The record in detail shows many of the rapid climate shifts seen in central Greenland ice cores between 15,000 and 5000 years before the present (B.P.). Negative excursions in the estimated delta18OP from both of these records likely reflect short weakenings of the thermohaline circulation caused by episodic discharges of continental freshwater into the North Atlantic. Deviating millennial-scale trends, however, indicate that climate gradients between Europe and Greenland changed systematically, reflecting a gradual rearrangement of North Atlantic circulation during deglaciation.

Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine.

Abstract: The insulinotropic hormone glucagon-like peptide-1 (GLP-1) is stored in the intestinal L cell in an active form, GLP-1-(7-36)amide, but more than half of the endogenous peptide circulates in an inactive, N-terminally truncated form, GLP-1-(9-36)amide. This study examined the GLP-1 newly secreted from the porcine ileum, in vitro (isolated perfused preparation) and in vivo (anesthetized pig), to determine where this conversion occurs. Although the GLP-1 extractable from the porcine ileum is predominantly the intact peptide (94.6+/-1.7%), a large proportion of the GLP-1 that is secreted has already been degraded to the truncated form both in vitro (53.8+/-0.9% intact) and in vivo (32.9+/-10.8% intact). In the presence of a specific dipeptidyl peptidase IV (DPP IV) inhibitor (valine-pyrrolidide), the proportion of intact GLP-1 released from the perfused ileum was increased under both basal (99% intact; P < 0.05) and stimulated (86-101% intact; P < 0.05) conditions. Immunohistochemical and histochemical studies revealed specific DPP IV staining in the brush border epithelium as well as in the capillary endothelium. Double staining showed juxtapositioning of DPP IV-positive capillaries and GLP-1-containing L cells. From these results, we suggest that GLP-1 is degraded as it enters the DPP IV containing blood vessels draining the intestinal mucosa.

Three dimensions of vocabulary development

Abstract: Progress toward establishing a model of lexical development to guide vocabulary acquisition research requires more precise specification of the various dimensions of lexical competence, the interrelationships among them, and how they interface with processes of word learning and use. Three dimensions of lexical competence are proposed: (a) partial to precise knowledge, (b) depth of knowledge, and (c) receptive to productive use ability. The relationship between the two knowledge dimensions and the acquisition of word meaning is considered, with emphasis on the complexity of the semantization1 process and on the need for redefining lexical development as both item-learning and system-changing. The adequacy of the three-dimensional description as a reflection of the process of vocabulary development is then discussed. Consideration of the nature of the developmental interrelationships among the dimensions raises two further questions: (a) Is depth of knowledge a prerequisite for developing precise comprehension? and (b) Are precise knowledge and depth of knowledge prerequisites for a word to become productive?

Mucoid conversion of Pseudomonas aeruginosa by hydrogen peroxide: a mechanism for virulence activation in the cystic fibrosis lung.

Abstract: The leading cause of mortality in patients with cystic fibrosis (CF) is respiratoy failure due in large part to chronic lung infection with Pseudomonas aeruginosa strains that undergo mucoid conversion, display a biofilm mode of growth in vivo and resist the infiltration of polymorphonuclear leukocytes (PMNs), which release free oxygen radicals such as H2O2. The mucoid phenotype among the strains infecting CF patients indicates overproduction of a linear polysaccharide called alginate. To mimic the inflammatory environment of the CF lung, P. aeruginosa PAO1, a typical non-mucoid strain, was grown in a biofilm. This was treated with low levels of H2O2, as if released by the PMNs, and the formation of mucoid variants was observed. These mucoid variants had mutations in mucA, which encodes an anti-σ factor; this leads to the deregulation of an alternative σ factor (σ22, AlgT or AlgU) required for expression of the alginate biosynthetic operon. All of the mucoid variants tested showed the same mutation, the mucA22 allele, a common allele seen in CF isolates. The mucoid mucA22 variants, when compared to the smooth parent strain PA01, produced 2--6-fold higher levels of alginate|ii) exhibited no detectable differences in growth rate|iii) showed an unaltered LPS profile|iv) were ~72% reduced in the amount of inducible-β-lactamase and (v) secreted little no LasA protease and only showed 44% elastase activity. A characteristic ~54 kDa protein associated with alginate overproducing strains was identified as AlgE (Alg76) by N-terminal sequence analysis. Thus, the common phenotype of the mucoid variants, which included a genetically engineered mucA22 mutant, suggested that the only mutation incurred as a result of H2O2 treatment was in mucA. When a P. aeruginosa biofilm was repeatedly expose to activated PMNs in vitro, mucoid variants were also observed, mimicking in vivo observations. Thus, PMNs and their oxygen by-products may cause P. aeruginosa to undergo the typical adaptation to the intractable mu- coid form in the CF lung. These findings indicate that gene activation in bacteria by toxic oxygen radicals, similar to that found in plants and mammalian cells, may serve as a defence mechanism for the bacteria. This suggests that mucoid conversion is a response to oxygen radical exposure and that this response is mechanism of defence by the bacteria. This is the first report to show that PMNs and their oxygen radicals can cause this phenotypic and genotypic change which is so typical of the intractable form of P. aeruginosa in the CF lung. These findings may provide a basis for the development of anti-oxidant and anti-inflammatory therapy for the early stages of infection in CF patients

Energization of plant cell membranes by H+-pumping ATPases. Regulation and biosynthesis

Abstract: The circulation of ions across biological membranes is a fundamental process of cellular energetics ([Harold, 1986][1]). Indeed, ion currents play the key role in energy capture during respiration and photosynthesis. They mediate the interconversion of chemical, osmotic, and electrical forms of

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men.

Abstract: BACKGROUND: Peripheral administration of glucagon-like peptide-1 (GLP-1) for four hours, to normal weight and obese humans, decreases food intake and suppresses appetite. OBJECTIVE: The aim of this study was to assess the effect of an eight hour infusion of GLP-1 on appetite and energy intake at lunch and dinner in obese subjects. DESIGN: Randomised, blinded cross-over design with intravenous infusion of GLP-1 (0.75 pmol·kg−1·min−1) or saline. SUBJECTS: Eight obese (body mass index, BMI, 45.5±2.3 kg/m2) male subjects. MEASUREMENTS: Ad libitum energy intake at lunch (12.00 h) and dinner (16.00 h) after an energy fixed breakfast (2.4 MJ) at 08.00 h. Appetite sensations using visual analogue scales, (VAS) immediately before and after meals and hourly in-between. Blood samples for the analysis of glucose, insulin, C-peptide, GLP-1 and peptide YY. Gastric emptying after breakfast and lunch using a paracetamol absorption technique. RESULTS: Hunger ratings were significantly lower with GLP-1 infusion. The summed ad libitum energy intake at lunch and dinner was reduced by 1.7±0.5 MJ (21±6%) by GLP-1 infusion (P=0.01). Gastric emptying was delayed by GLP-1 infusion, and plasma glucose concentrations decreased (baseline: 6.6±0.35 mmol/L; nadir: 5.3±0.15 mmol/L). No nausea was recorded during GLP-1 infusion. CONCLUSIONS: Our results demonstrate that GLP-1 decreases feelings of hunger and reduces energy intake in obese humans. One possible mechanism for this finding might be an increased satiety primarily mediated by gastric vagal afferent signals.

Astrocytes: glutamate producers for neurons.

Abstract: In order for the brain to use the common amino acid glutamate as a neurotransmitter, it has been necessary to introduce a series of innovations that greatly restrict the availability of glutamate, so that it cannot degrade the signal-to-noise ratio of glutamatergic neurons. The most far-reaching innovations have been: i) to exclude the brain from access to glutamate in the systemic circulation by the blood-brain barrier, thereby making the brain autonomous in the production and disposal of glutamate; ii) to surround glutamatergic synapses with glial cells and endow these cells with much more powerful glutamate uptake carriers than the neurons themselves, so that most released transmitter glutamate is rapidly inactivated by uptake in glial cells; iii) to restrict to glial cells a key enzyme (glutamine synthetase) that is involved in the return of accumulated glutamate to neurons by amidation to glutamine, which has no transmitter activity, and can be safely released to the extracellular space, returned to neurons and deaminated to glutamate; iv) to restrict to glial cells two key enzymes (pyruvate carboxylase and cytosolic malic enzyme) that are involved in, respectively, de novo synthesis (from glucose) of the carbon skeleton of glutamate, and the return of the carbon skeleton of excess glutamate to the metabolic pathway for glucose oxidation. As a consequence of these innovations, neurons constantly require new carbon skeletons from glial to sustain their TCA cycle. When these supplies are withdrawn, neurons are unable to generate amino acid transmitters and their rate of oxidative metabolism is impaired. Given the commensalism that exists between neurons and glia, it may be fruitful to view brain function not just as a series of interactions between neurons, but also as a series of interactions between neurons and their collaborating glial cells.

A high plasma concentration of TNF-alpha is associated with dementia in centenarians.

Abstract: BACKGROUND: Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of age-associated diseases such as dementia and atherosclerosis. The purpose of this study was to evaluate the plasma concentration of tumor necrosis factor (TNF)-alpha in a large cohort of centenarians and to look for its possible associations with cognitive function, atherosclerosis, and general health status. Furthermore, we investigated whether the concentration of TNF-alpha was correlated with the blood concentration of leucocyte subsets or the plasma concentrations of interleukin (IL)-6, soluble TNF receptor 11 (sTNFR-H) (75 kDa) and C-reactive protein (CRP). METHODS: Plasma TNF-alpha was measured by ELISA in 126 centenarians, 45 subjects aged 81 years, 23 subjects aged 55-65 years, and 38 subjects aged 18-30 years. Atherosclerosis was evaluated by the ankle-brachial blood pressure index, and general health status was evaluated by the body mass index and the number of diagnoses present. RESULTS: The concentration of TNF-alpha was significantly increased in 126 centenarians compared to younger control groups, and a high concentration of TNF-alpha was associated with both Alzheimer's disease and generalized atherosclerosis in the centenarians. The concentration of TNF-alpha was positively correlated with the concentrations of plasma IL-6, sTNFR-II, and CRP. No associations were found with increased leucocyte subsets or the body mass index. CONCLUSION: This study demonstrates that, even in apparently healthy subjects, age-associated immune activation indicated by raised levels of pro-inflammatory cytokines may reflect age-associated pathological processes that develop over decades.

Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals.

Abstract: The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17beta++-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17beta-Estradiol, 17alpha-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds--tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p'-DDT, p,p'-DDE, endosulfan, chlomequat chloride, and ethanol--varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods.

Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis

Abstract: Mannose-binding lectin (MBL) is a key factor in innate immunity, and lung infections are the leading cause of morbidity and mortality in cystic fibrosis (CF). Accordingly, we investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, we estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes. Presence of MBL variant alleles is therefore associated with poor prognosis and early death in patients with CF. J. Clin. Invest. 104:431-437 (1999).

Dynamic Programming and Strong Bounds for the 0-1 Knapsack Problem

Abstract: Two new algorithms recently proved to outperform all previous methods for the exact solution of the 0-1 Knapsack Problem. This paper presents a combination of such approaches, where, in additi on, valid inequalities are generated and surrogate relaxed, and a new initial core problem is adopted. The algorithm is able to solve all classical test instances, with up to 10,000 variables, in less than 0.2 seconds on a HP9000-735/99 computer. The C language implementation of the algorithm is available on the internet.

Lactate transport in skeletal muscle — role and regulation of the monocarboxylate transporter

Abstract: Skeletal muscle is the major producer of lactic acid in the body, but its oxidative fibres also use lactic acid as a respiratory fuel. The stereoselective transport of L-lactic acid across the plasma membrane of muscle fibres has been shown to involve a proton-linked monocarboxylate transporter (MCT) similar to that described in erythrocytes and other cells. This transporter plays an important role in the pH regulation of skeletal muscle. A family of eight MCTs has now been cloned and sequenced, and the tissue distribution of each isoform varies. Skeletal muscle contains both MCT1 (the only isoform found in erythrocytes but also present in most other cells) and MCT4. The latter is found in all fibre types, although least in more oxidative red muscles such as soleus, whereas expression of MCT1 is highest in the more oxidative muscles and very low in white muscles that are almost entirely glycolytic. The properties of MCT1 and MCT2 have been described in some detail and the latter shown to have a higher affinity for substrates. MCT4 has been less well characterized but has a lower affinity for L-lactate (i.e. a higher Km of 20 mM) than does MCT1 (Km of 5 mM). MCT1 expression is increased in response to chronic stimulation and either endurance or explosive exercise training in rats and humans, whereas denervation decreases expression of both MCT1 and MCT4. The mechanism of regulation is not established, but does not appear to be accompanied by changes in mRNA concentrations. However, in other cells MCT1 and MCT4 are intimately associated with an ancillary protein OX-47 (also known as CD147). This protein is a member of the immunoglobulin superfamily with a single transmembrane helix, whose expression is known to be increased in a range of cells when their metabolic activity is increased.

Parafac2 : part i. a direct fitting algorithm for the parafac2 model

Abstract: PARAFAC is a generalization of principal component analysis (PCA) to the situation where a set of data matrices is to be analysed. If each data matrix has the same row and column units, the resulting data are three-way data and can be modelled by the PARAFAC1 model. If each data matrix has the same column units but different (numbers of) row units, the PARAFAC2 model can be used. Like the PARAFACI model, the PARAFAC2 model gives unique solutions under certain mild assumptions, whereas it is less severely constrained than PARAFAC 1. It may therefore also be used for regular three-way data in situations where the PARAFAC1 model is too restricted. Usually the PARAFAC2 model is fitted to a set of matrices with cross-products between the column units. However, this model-fitting procedure is computationally complex and inefficient. In the present paper a procedure for fitting the PARAFAC2 model directly to the set of data matrices is proposed. It is shown that this algorithm is more efficient than the indirect fitting algorithm. Moreover, it is more easily adjusted so as to allow for constraints on the parameter matrices, to handle missing data, as well as to handle generalizations to sets of three- and higher-way data. Furthermore, with the direct fitting approach we also gain information on the row units, in the form of 'factor scores'. As will be shown, this elaboration of the model in no way limits the feasibility of the method. Even though full information on the row units becomes available, the algorithm is based on the usually much smaller cross-product matrices only. Copyright (C) 1999 john Wiley & Sons, Ltd.