Showing papers by "University of Bergen published in 2004"

Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma

Abstract: Purpose: Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors. Experimental Design: To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings. Results: Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins ( versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis. Conclusions: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.

Processing Fluency and Aesthetic Pleasure: Is Beauty in the Perceiver's Processing Experience?

Abstract: We propose that aesthetic pleasure is a function of the perceiver’s processing dynamics: The more fluently perceivers can process an object, the more positive their aesthetic response. We review variables known to influence aesthetic judgments, such as figural goodness, figure–ground contrast, stimulus repetition, symmetry, and prototypicality, and trace their effects to changes in processing fluency. Other variables that influence processing fluency, like visual or semantic priming, similarly increase judgments of aesthetic pleasure. Our proposal provides an integrative framework for the study of aesthetic pleasure and sheds light on the interplay between early preferences versus cultural influences on taste, preferences for both prototypical and abstracted forms, and the relation between beauty and truth. In contrast to theories that trace aesthetic pleasure to objective stimulus features per se, we propose that beauty is grounded in the processing experiences of the perceiver, which are in part a function of stimulus properties.

Nanotubular Highways for Intercellular Organelle Transport

Abstract: Cell-to-cell communication is a crucial prerequisite for the development and maintenance of multicellular organisms. To date, diverse mechanisms of intercellular exchange of information have been documented, including chemical synapses, gap junctions, and plasmodesmata. Here, we describe highly sensitive nanotubular structures formed de novo between cells that create complex networks. These structures facilitate the selective transfer of membrane vesicles and organelles but seem to impede the flow of small molecules. Accordingly, we propose a novel biological principle of cell-to-cell interaction based on membrane continuity and intercellular transfer of organelles.

Rivastigmine for Dementia Associated with Parkinson's Disease

Abstract: background Cholinergic deficits are prominent in patients who have dementia associated with Parkinson’s disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. methods Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson’s disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and Alzheimer’s Disease Cooperative Study–Clinician’s Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer’s Disease Cooperative Study–Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini–Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. results A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer’s disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). conclusions In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson’s disease but also with higher rates of nausea, vomiting, and tremor.

Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion

Abstract: Background: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The purpose of this review is to provide an international expert opinion on the practical aspects of total homocysteine determinations in clinical practice and in the research setting and on the relevance of total homocysteine measurements as diagnostic or screening tests in several target populations. Methods: Published data available on Medline were used as the basis for the recommendations. Drafts of the recommendations were critically discussed at meetings over a period of 3 years. Outcome: This review is divided into two sections: (a) determination of homocysteine (methods and their performance, sample collection and handling, biological determinants, reference intervals, within-person variability, and methionine loading test); and (b) risk assessment and disease diagnosis (homocystinuria, folate and cobalamin deficiencies, cardiovascular disease, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects, and screening of elderly and newborns). Each of these subsections concludes with a separate series of recommendations to assist the clinician and the research scientist in making informed decisions. The review concludes with a list of unresolved questions.

Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer

Abstract: A basal epithelial phenotype is found in not more than 15% of all invasive breast cancers. Microarray studies have shown that this phenotype is associated with breast cancers that express neither estrogen receptor (ER) nor erbB-2 (HER2/neu) (i.e., ER/erbB-2-negative tumors). The ER/erbB-2- negative phenotype is also found in breast cancers occurring in BRCA1 mutation carriers (i.e., BRCA1-related breast cancers). We tested the hypothesis that BRCA1-related breast cancers are more likely than non-BRCA1/ 2-related breast cancer to express a basal epithelial phenotype. Among 292 breast cancer specimens previously analyzed for ER, erbB-2, p53, and germline mutations in BRCA1 and BRCA2, we identified 76 that did not overexpress ER or erbB-2. Of the 72 specimens with sufficient material for testing, 40 expressed stratified epithelial cytokeratin 5 and/or 6 (5/6). In univariate analysis, the expression of cytokeratin 5/6 was statistically significantly associated with BRCA1-related breast cancers (odds ratio = 9.0, 95% confidence interval = 1.9 to 43; P =.002, two-sided Fisher's exact test). Thus, germline BRCA1 mutations appear to be associated with a distinctive breast cancer phenotype.

The prevalence of urinary incontinence in women in four European countries

Abstract: OBJECTIVE To determine the prevalence, type and treatment behaviour of women with urinary incontinence in four European countries. SUBJECTS AND METHODS Data were collected using a postal survey which was sent to 29 500 community-dwelling women aged ≥ 18 years in France, Germany, Spain and the UK. Subjects were asked about the type of urinary incontinence they had experienced and their treatment behaviour. RESULTS Of the women who responded, 35% reported involuntary loss of urine in the preceding 30 days; stress urinary incontinence was the most prevalent type. The lowest prevalence was in Spain (23%), while the prevalence was 44%, 41% and 42% for France, Germany and the UK, respectively. About a quarter of women with urinary incontinence in Spain (24%) and the UK (25%) had consulted a doctor about it; in France (33%) and Germany (40%) the percentages were higher. Overall, < 5% of the women had ever undergone surgery for their condition. While pads were used by half of the women, there were some differences among the countries. CONCLUSIONS Millions of women in Europe have urinary incontinence; the consultation and treatment rates were low in the European countries included in this study.

Influenza Virus: Immunity and Vaccination Strategies. Comparison of the Immune Response to Inactivated and Live, Attenuated Influenza Vaccines

Abstract: Influenza virus is a globally important respiratory pathogen which causes a high degree of morbidity and mortality annually. The virus is continuously undergoing antigenic change and thus bypasses the host's acquired immunity to influenza. Despite the improvement in antiviral therapy during the last decade, vaccination is still the most effective method of prophylaxis. Vaccination induces a good degree of protection (60-90% efficacy) and is well tolerated by the recipient. For those at risk of complications from influenza, annual vaccination is recommended due to the antigenic changes in circulating strains. However, there is still room for improvement in vaccine efficacy, long-lasting effect, ease of administration and compliance rates. The mucosal tissues of the respiratory tract are the main portal entry of influenza, and the mucosal immune system provides the first line of defence against infection. Secretory immunoglobulin A (SIgA) and IgM are the major neutralizing antibodies directed against mucosal pathogens. These antibodies work to prevent pathogen entry and can function intracellularly to inhibit replication of virus. This review describes influenza virus infection, epidemiology, clinical presentation and immune system response, particularly as it pertains to mucosal immunity and vaccine use. Specifically, this review provides an update of the current status on influenza vaccination and concentrates on the two main types of influenza vaccines currently in use, namely the cold-adapted vaccine (CAV) given intranasally/orally, and the inactivated vaccine (IV) delivered subcutanously or intramuscularly. The commercially available trivalent IV (TIV) elicits good serum antibody responses but induces poorly mucosal IgA antibody and cell-mediated immunity. In contrast, the CAV may elicit a long-lasting, broader immune (humoral and cellular) response, which more closely resembles natural immunity. The immune response induced by these two vaccines will be compared in this review.

Culture-Level Dimensions of Social Axioms and Their Correlates across 41 Cultures

Abstract: Leung and colleagues have revealed a five-dimensional structure of social axioms across individuals from five cultural groups. The present research was designed to reveal the culture level factor structure of social axioms and its correlates across 41 nations. An ecological factor analysis on the 60 items of the Social Axioms Survey extracted two factors: Dynamic Externality correlates with value measures tapping collectivism, hierarchy, and conservatism and with national indices indicative of lower social development. Societal Cynicism is less strongly and broadly correlated with previous values measures or other national indices and seems to define a novel cultural syndrome. Its national correlates suggest that it taps the cognitive component of a cultural constellation labeled maleficence, a cultural syndrome associated with a general mistrust of social systems and other people. Discussion focused on the meaning of these national level factors of beliefs and on their relationships with individual level factors of belief derived from the same data set.

Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials

Abstract: Objective To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee. Design Systematic review and meta-analysis of randomised placebo controlled trials. Studies reviewed 23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years. Main outcome measure Change in overall intensity of pain. Results Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31). Conclusion NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended.

Psychiatric distress and symptoms of PTSD among victims of bullying at work

Abstract: Distress and symptoms of Post-Traumatic Stress Disorder (PTSD) were investigated among targets of experienced bullying at work, that is, the exposure to persistent or recurrent oppressive, offensive, abusive behaviour where the aggressor may be a superior or a colleague. The participants in the present study were all recruited from two associations of bullied victims (n� /102, response rate� /57%). A high level of distress and symptoms of PTSD was revealed in the sample, both according to recommended cut point scores for HSCL-25, PTSS-10 and IES-R, and when comparing the sample with traumatised samples. Three out of four victims reported an HSCL-25 level higher than the recommended threshold for psychiatric disease. Sixty and 63% of the sample reported a high level of IES intrusion and IES avoidance, correspondingly. The level of bullying, operationalised as the frequency of negative acts the individual had been exposed to at work, showed a stronger interconnection with distress and PTSD than a more unspecified, subjective measure of bullying, as well as the time since the bullying took place and the duration of the bullying episode. Those still being pestered reported a higher level of distress and PTSD than victims in which the bullying episodes were terminated more than 1 year ago, but the findings were somewhat mixed. Positive affectivity (PA) and especially negative affectivity (NA) contributed significantly to the explained variance of distress and PTSD in various regression analysis models, but did not interact with measures of bullying. Nor were mediator effects found between bullying, PA/NA and traumatic stress reactions. Implications of the findings are discussed. During the last decade there has been a growing awareness of the detrimental effects on employee health and well-being caused by exposure to bullying and non-sexual harassment in the workplace (Einarsen, 1999; Einarsen et al., 2003; Hoel et al.,

Genomic Insights into Methanotrophy: The Complete Genome Sequence of Methylococcus capsulatus (Bath)

Abstract: Methanotrophs are ubiquitous bacteria that can use the greenhouse gas methane as a sole carbon and energy source for growth, thus playing major roles in global carbon cycles, and in particular, substantially reducing emissions of biologically generated methane to the atmosphere. Despite their importance, and in contrast to organisms that play roles in other major parts of the carbon cycle such as photosynthesis, no genome-level studies have been published on the biology of methanotrophs. We report the first complete genome sequence to our knowledge from an obligate methanotroph, Methylococcus capsulatus (Bath), obtained by the shotgun sequencing approach. Analysis revealed a 3.3-Mb genome highly specialized for a methanotrophic lifestyle, including redundant pathways predicted to be involved in methanotrophy and duplicated genes for essential enzymes such as the methane monooxygenases. We used phylogenomic analysis, gene order information, and comparative analysis with the partially sequenced methylotroph Methylobacterium extorquens to detect genes of unknown function likely to be involved in methanotrophy and methylotrophy. Genome analysis suggests the ability of M. capsulatus to scavenge copper (including a previously unreported nonribosomal peptide synthetase) and to use copper in regulation of methanotrophy, but the exact regulatory mechanisms remain unclear. One of the most surprising outcomes of the project is evidence suggesting the existence of previously unsuspected metabolic flexibility in M. capsulatus, including an ability to grow on sugars, oxidize chemolithotrophic hydrogen and sulfur, and live under reduced oxygen tension, all of which have implications for methanotroph ecology. The availability of the complete genome of M. capsulatus (Bath) deepens our understanding of methanotroph biology and its relationship to global carbon cycles. We have gained evidence for greater metabolic flexibility than was previously known, and for genetic components that may have biotechnological potential.

LSimpute: accurate estimation of missing values in microarray data with least squares methods.

Abstract: Microarray experiments generate data sets with information on the expression levels of thousands of genes in a set of biological samples. Unfortunately, such experiments often produce multiple missing expression values, normally due to various experimental problems. As many algorithms for gene expression analysis require a complete data matrix as input, the missing values have to be estimated in order to analyze the available data. Alternatively, genes and arrays can be removed until no missing values remain. However, for genes or arrays with only a small number of missing values, it is desirable to impute those values. For the subsequent analysis to be as informative as possible, it is essential that the estimates for the missing gene expression values are accurate. A small amount of badly estimated missing values in the data might be enough for clustering methods, such as hierachical clustering or K-means clustering, to produce misleading results. Thus, accurate methods for missing value estimation are needed. We present novel methods for estimation of missing values in microarray data sets that are based on the least squares principle, and that utilize correlations between both genes and arrays. For this set of methods, we use the common reference name LSimpute. We compare the estimation accuracy of our methods with the widely used KNNimpute on three complete data matrices from public data sets by randomly knocking out data (labeling as missing). From these tests, we conclude that our LSimpute methods produce estimates that consistently are more accurate than those obtained using KNNimpute. Additionally, we examine a more classic approach to missing value estimation based on expectation maximization (EM). We refer to our EM implementations as EMimpute, and the estimate errors using the EMimpute methods are compared with those our novel methods produce. The results indicate that on average, the estimates from our best performing LSimpute method are at least as accurate as those from the best EMimpute algorithm.

Heart rate variability and its relation to prefrontal cognitive function: the effects of training and detraining

Abstract: The aim of the present study was to investigate the relationship between physical fitness, heart rate variability (HRV) and cognitive function in 37 male sailors from the Royal Norwegian Navy. All subjects participated in an 8-week training program, after which the subjects completed the initial cognitive testing (pre-test). The subjects were assigned into a detrained group (DG) and a trained group (TG) based on their application for further duty. The DG withdrew from the training program for 4 weeks after which all subjects then completed the cognitive testing again (post-test). Physical fitness, measured as maximum oxygen consumption (VO2max), resting HRV, and cognitive function, measured using a continuous performance task (CPT) and a working memory test (WMT), were recorded during the pre-test and the post-test, and the data presented as the means and standard deviations. The results showed no between-group differences in VO2max or HRV at the pre-test. The DG showed a significant decrease in VO2max from the pre- to the post-test and a lower resting HRV than the TG on the post-test. Whereas there were no between-group differences on the CPT or WMT at the pre-test, the TG had faster reaction times and more true positive responses on tests of executive function at the post-test compared to the pre-test. The DG showed faster reaction times on non-executive tasks at the post-test compared to the pre-test. The results are discussed within a neurovisceral integration framework linking parasympathetic outflow to the heart to prefrontal neural functions.

Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy.

Abstract: Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2alpha kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive K(+) channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg. kg(-1). day(-1), insulin was discontinued. Blood glucose did not deteriorate, and HbA(1c) was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment.

On the evolution of the nuclear modification factors with rapidity and centrality in d + Au collisions at s(NN)**(1/2) = 200-GeV

Abstract: We report on a study of the transverse momentum dependence of nuclear modification factors ${R}_{d\mathrm{A}\mathrm{u}}$ for charged hadrons produced in $\mathrm{\text{deuteron}}\text{ }\text{ }+\text{ }\text{ }\mathrm{\text{gold}}$ collisions at $\sqrt{{s}_{NN}}=200\text{ }\text{ }\mathrm{G}\mathrm{e}\mathrm{V}$, as a function of collision centrality and of the pseudorapidity ($\ensuremath{\eta}=0$, 1, 2.2, 3.2) of the produced hadrons. We find a significant and systematic decrease of ${R}_{d\mathrm{A}\mathrm{u}}$ with increasing rapidity. The midrapidity enhancement and the forward rapidity suppression are more pronounced in central collisions relative to peripheral collisions. These results are relevant to the study of the possible onset of gluon saturation at energies reached at BNL RHIC.

The association between anxiety, depression, and somatic symptoms in a large population: The HUNT-II study

Abstract: Objective Somatic symptoms are prevalent in the community, but at least one third of the symptoms lack organic explanation. Patients with such symptoms have a tendency to overuse the health care system with frequent consultations and have a high degree of disability and sickness compensation. Studies from clinical samples have shown that anxiety and depression are prevalent in such functional conditions. The aim of this study is to examine the connection between anxiety, depression, and functional somatic symptoms in a large community sample. Method The HUNT-II study invited all inhabitants aged 20 years and above in Nord-Trondelag County of Norway to have their health examined and sent a questionnaire asking about physical symptoms, demographic factors, lifestyle, and somatic diseases. Anxiety and depression were recorded by the Hospital Anxiety and Depression Scale. Of those invited, 62,651 participants (71.3%) filled in the questionnaire. A total of 10,492 people were excluded due to organic diseases, and 50,377 were taken into the analyses. Results Women reported more somatic symptoms than men (mean number of symptoms women/men: 3.8/2.9). There was a strong association between anxiety, depression, and functional somatic symptoms. The association was equally strong for anxiety and depression, and a somewhat stronger association was observed for comorbid anxiety and depression. The association of anxiety, depression, and functional somatic symptoms was equally strong in men and women (mean number of somatic symptoms men/women in anxiety: 4.5/5.9, in depression: 4.6/5.9, in comorbid anxiety and depression: 6.1/7.6, and in no anxiety or depression: 2.6/3.6) and in all age groups. The association between number of somatic symptoms and the total score on Hospital Anxiety and Depression Scale was linear. Conclusion There was a statistically significant relationship between anxiety, depression, and functional somatic symptoms, independent of age and gender.

Early Life Recorded in Archean Pillow Lavas

Abstract: Pillow lava rims from the Mesoarchean Barberton Greenstone Belt in South Africa contain micrometer-scale mineralized tubes that provide evidence of submarine microbial activity during the early history of Earth. The tubes formed during microbial etching of glass along fractures, as seen in pillow lavas from recent oceanic crust. The margins of the tubes contain organic carbon, and many of the pillow rims exhibit isotopically light bulk-rock carbonate δ 13 C values, supporting their biogenic origin. Overlapping metamorphic and magmatic dates from the pillow lavas suggest that microbial life colonized these subaqueous volcanic rocks soon after their eruption almost 3.5 billion years ago.