Showing papers by "Karolinska Institutet published in 2004"

Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.

Abstract: The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.

Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.

Abstract: This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

Large-Scale Copy Number Polymorphism in the Human Genome

Abstract: The extent to which large duplications and deletions contribute to human genetic variation and diversity is unknown. Here, we show that large-scale copy number polymorphisms (CNPs) (about 100 kilobases and greater) contribute substantially to genomic variation between normal humans. Representational oligonucleotide microarray analysis of 20 individuals revealed a total of 221 copy number differences representing 76 unique CNPs. On average, individuals differed by 11 CNPs, and the average length of a CNP interval was 465 kilobases. We observed copy number variation of 70 different genes within CNP intervals, including genes involved in neurological function, regulation of cell growth, regulation of metabolism, and several genes known to be associated with disease.

High interstitial fluid pressure — an obstacle in cancer therapy

Abstract: Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.

JASPAR: an open‐access database for eukaryotic transcription factor binding profiles

Abstract: The analysis of regulatory regions in genome sequences is strongly based on the detection of potential transcription factor binding sites. The preferred models for representation of transcription factor binding specificity have been termed position-specific scoring matrices. JASPAR is an open-access database of annotated, high-quality, matrix-based transcription factor binding site profiles for multicellular eukaryotes. The profiles were derived exclusively from sets of nucleotide sequences experimentally demonstrated to bind transcription factors. The database is complemented by a web interface for browsing, searching and subset selection, an online sequence analysis utility and a suite of programming tools for genome-wide and comparative genomic analysis of regulatory regions. JASPAR is available at http://jaspar. cgb.ki.se.

An active and socially integrated lifestyle in late life might protect against dementia.

Abstract: The recent availability of longitudinal data on the possible association of different lifestyles with dementia and Alzheimer's disease (AD) allow some preliminary conclusions on this topic. This review systematically analyses the published longitudinal studies exploring the effect of social network, physical leisure, and non-physical activity on cognition and dementia and then summarises the current evidence taking into account the limitations of the studies and the biological plausibility. For all three lifestyle components (social, mental, and physical), a beneficial effect on cognition and a protective effect against dementia are suggested. The three components seem to have common pathways, rather than specific mechanisms, which might converge within three major aetiological hypotheses for dementia and AD: the cognitive reserve hypothesis, the vascular hypothesis, and the stress hypothesis. Taking into account the accumulated evidence and the biological plausibility of these hypotheses, we conclude that an active and socially integrated lifestyle in late life protects against dementia and AD. Further research is necessary to better define the mechanisms of these associations and better delineate preventive and therapeutic strategies.

Gene expression profiling identifies clinically relevant subtypes of prostate cancer

Abstract: Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing ≈26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with “aggressive” clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

Applied bioinformatics for the identification of regulatory elements

Abstract: The compilation of multiple metazoan genome sequences and the deluge of large-scale expression data have combined to motivate the maturation of bioinformatics methods for the analysis of sequences that regulate gene transcription. Historically, these bioinformatics methods have been plagued by poor predictive specificity, but new bioinformatics algorithms that accelerate the identification of regulatory regions are drawing disgruntled users back to their keyboards. However, these new approaches and software are not without problems. Here, we introduce the purpose and mechanisms of the leading algorithms, with a particular emphasis on metazoan sequence analysis. We identify key issues that users should take into consideration in interpreting the results and provide an online training example to help researchers who wish to test online tools before taking an independent foray into the bioinformatics of transcription regulation.

Principles for modulation of the nuclear receptor superfamily

Abstract: Nuclear receptors are major targets for drug discovery and have key roles in development and homeostasis, as well as in many diseases such as obesity, diabetes and cancer. This review provides a general overview of the mechanism of action of nuclear receptors and explores the various factors that are instrumental in modulating their pharmacology. In most cases, the response of a given receptor to a particular ligand in a specific tissue will be dictated by the set of proteins with which the receptor is able to interact. One of the most promising aspects of nuclear receptor pharmacology is that it is now possible to develop ligands with a large spectrum of full, partial or inverse agonist or antagonist activities, but also compounds, called selective nuclear receptor modulators, that activate only a subset of the functions induced by the cognate ligand or that act in a cell-type-selective manner.

Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-|[gamma]| and RelA

Abstract: The human gut microflora is important in regulating host inflammatory responses and in maintaining immune homeostasis. The cellular and molecular bases of these actions are unknown. Here we describe a unique anti-inflammatory mechanism, activated by nonpathogenic bacteria, that selectively antagonizes transcription factor NF-kappaB. Bacteroides thetaiotaomicron targets transcriptionally active NF-kappaB subunit RelA, enhancing its nuclear export through a mechanism independent of nuclear export receptor Crm-1. Peroxisome proliferator activated receptor-gamma (PPAR-gamma), in complex with nuclear RelA, also undergoes nucleocytoplasmic redistribution in response to B. thetaiotaomicron. A decrease in PPAR-gamma abolishes both the nuclear export of RelA and the anti-inflammatory activity of B. thetaiotaomicron. This PPAR-gamma-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation.

Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.

Abstract: Hutchinson–Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LAΔ50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LAΔ50. Introduction of LAΔ50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LAΔ50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.

GGDEF and EAL domains inversely regulate cyclic di-GMP levels and transition from sessility to motility.

Abstract: Cyclic nucleotides represent second messenger molecules in all kingdoms of life. In bacteria, mass sequencing of genomes detected the highly abundant protein domains GGDEF and EAL. We show here that the GGDEF and EAL domains are involved in the turnover of cyclic-di-GMP (c-di-GMP) in vivo whereby the GGDEF domain stimulates c-di-GMP production and the EAL domain c-di-GMP degradation. Thus, most probably, GGDEF domains function as c-di-GMP cyclase and EAL domains as phosphdiesterase. We further show that, in the pathogenic organism Salmonella enterica serovar Typhimurium, the nosocomial pathogen Pseudomonas aeruginosa and the commensal species Escherichia coli, GGDEF and EAL domains mediate similar phenotypic changes related to the transition between sessility and motility. Thus, the data suggest that c-di-GMP is a novel global second messenger in bacteria the metabolism of which is controlled by GGDEF and EAL domain proteins.

Brain Cholesterol: Long Secret Life Behind a Barrier

Abstract: Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450-generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far. In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed.

Urinary bladder contraction and relaxation: Physiology and pathophysiology

Abstract: The detrusor smooth muscle is the main muscle component of the urinary bladder wall. Its ability to contract over a large length interval and to relax determines the bladder function during filling and micturition. These processes are regulated by several external nervous and hormonal control systems, and the detrusor contains multiple receptors and signaling pathways. Functional changes of the detrusor can be found in several clinically important conditions, e.g., lower urinary tract symptoms (LUTS) and bladder outlet obstruction. The aim of this review is to summarize and synthesize basic information and recent advances in the understanding of the properties of the detrusor smooth muscle, its contractile system, cellular signaling, membrane properties, and cellular receptors. Alterations in these systems in pathological conditions of the bladder wall are described, and some areas for future research are suggested.

Regression models for relative survival.

Abstract: Four approaches to estimating a regression model for relative survival using the method of maximum likelihood are described and compared. The underlying model is an additive hazards model where the total hazard is written as the sum of the known baseline hazard and the excess hazard associated with a diagnosis of cancer. The excess hazards are assumed to be constant within pre-specified bands of follow-up. The likelihood can be maximized directly or in the framework of generalized linear models. Minor differences exist due to, for example, the way the data are presented (individual, aggregated or grouped), and in some assumptions (e.g. distributional assumptions). The four approaches are applied to two real data sets and produce very similar estimates even when the assumption of proportional excess hazards is violated. The choice of approach to use in practice can, therefore, be guided by ease of use and availability of software. We recommend using a generalized linear model with a Poisson error structure based on collapsed data using exact survival times. The model can be estimated in any software package that estimates GLMs with user-defined link functions (including SAS, Stata, S-plus, and R) and utilizes the theory of generalized linear models for assessing goodness-of-fit and studying regression diagnostics.

Inparanoid: a comprehensive database of eukaryotic orthologs.

Abstract: The Inparanoid eukaryotic ortholog database (http:// inparanoid.cgb.ki.se/)isacollectionofpairwiseortholog groups between 17 whole genomes; Anopheles gambiae, Caenorhabditis briggsae, Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Takifugu rubripes, Gallus gallus, Homo sapiens, Mus musculus, Pan troglodytes, Rattus norvegicus, Oryza sativa, Plasmodium falciparum, Arabidopsis thaliana,Escherichia coli,Saccharomyces cerevisiae and Schizosaccharomyces pombe. Complete proteomes for these genomes were derived from Ensembl and UniProt and compared pairwise using Blast, followed by a clustering step using the Inparanoid program. An Inparanoid cluster is seeded by areciprocally best-matching ortholog pair, around which inparalogs (should they exist) are gathered independently, while outparalogs are excluded. The ortholog clusters can be searched on the website using Ensembl gene/protein or UniProt identifiers, annotation text or by Blast alignment against our protein datasets. The entire dataset can be downloaded, as can the Inparanoid program itself.

Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors.

Abstract: In tumors that retain wild-type p53, its tumor-suppressor function is often impaired as a result of the deregulation of HDM-2, which binds to p53 and targets it for proteasomal degradation. We have screened a chemical library and identified a small molecule named RITA (reactivation of p53 and induction of tumor cell apoptosis), which bound to p53 and induced its accumulation in tumor cells. RITA prevented p53-HDM-2 interaction in vitro and in vivo and affected p53 interaction with several negative regulators. RITA induced expression of p53 target genes and massive apoptosis in various tumor cells lines expressing wild-type p53. RITA suppressed the growth of human fibroblasts and lymphoblasts only upon oncogene expression and showed substantial p53-dependent antitumor effect in vivo. RITA may serve as a lead compound for the development of an anticancer drug that targets tumors with wild-type p53.

Is job strain a major source of cardiovascular disease risk

Abstract: Empirical studies on job strain and cardiovascular disease (CVD), their internal validity, and the likely direction of biases were examined. The 17 longitudinal studies had the highest validity ratings. In all but two, biases towards the null dominated. Eight, including several of the largest, showed significant positive results; three had positive, nonsignificant findings. Six of nine case-control studies had significant positive findings; recall bias leading to overestimation appears to be fairly minimal. Four of eight cross-sectional studies had significant positive results. Men showed strong, consistent evidence of an association between exposure to job strain and CVD. The data of the women were more sparse and less consistent, but, as for the men, most of the studies probably underestimated existing effects. Other elements of causal inference, particularly biological plausibility, corroborated that job strain is a major CVD risk factor. Additional intervention studies are needed to examine the impact of ameliorating job strain upon CVD-related outcomes.

The facilitated processing of threatening faces : an ERP analysis

Abstract: Threatening, friendly, and neutral faces were presented to test the hypothesis of the facilitated perceptual processing of threatening faces. Dense sensor event-related brain potentials were measured while subjects viewed facial stimuli. Subjects had no explicit task for emotional categorization of the faces. Assessing early perceptual stimulus processing, threatening faces elicited an early posterior negativity compared with nonthreatening neutral or friendly expressions. Moreover, at later stages of stimulus processing, facial threat also elicited augmented late positive potentials relative to the other facial expressions, indicating the more elaborate perceptual analysis of these stimuli. Taken together, these data demonstrate the facilitated perceptual processing of threatening faces. Results are discussed within

Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis

Abstract: Obesity is a risk factor for the development of many severe human diseases such as cardiovascular disorders, diabetes, and cancer, which are tightly linked to angiogenesis. The adipose tissue produces several growth factors/hormones including leptin, tumor necrosis factor α, and adiponectin. It has been found that adiponectin levels are reduced in obesity. Here, we report a unique function of adiponectin as a negative regulator of angiogenesis. In vitro, adiponectin potently inhibits endothelial cell proliferation and migration. In the chick chorioallantoic membrane and the mouse corneal angiogenesis assays, adiponectin remarkably prevents new blood vessel growth. Further, we demonstrate that the antiendothelial mechanisms involve activation of caspase-mediated endothelial cell apoptosis. Adiponectin induces a cascade activation of caspases-8, -9, and -3, which leads to cell death. In a mouse tumor model, adiponectin significantly inhibits primary tumor growth. Impaired tumor growth is associated with decreased neovascularization, leading to significantly increased tumor cell apoptosis. These data demonstrate induction of endothelial apoptosis as an unique mechanism of adiponectin-induced antiangiogenesis. Adiponectin, as a direct endogenous angiogenesis inhibitor, may have therapeutic implications in the treatment of angiogenesis-dependent diseases.

Nitrate, bacteria and human health.

Abstract: Nitrate is generally considered a water pollutant and an undesirable fertilizer residue in the food chain Research in the 1970s indicated that, by reducing nitrate to nitrite, commensal bacteria might be involved in the pathogenesis of gastric cancers and other malignancies, as nitrite can enhance the generation of carcinogenic N-nitrosamines More recent studies indicate that the bacterial metabolism of nitrate to nitrite and the subsequent formation of biologically active nitrogen oxides could be beneficial Here, we will consider the evidence that nitrate-reducing commensals have a true symbiotic role in mammals and facilitate a previously unrecognized but potentially important aspect of the nitrogen cycle

DNA damage-induced apoptosis.

Abstract: Unicellular organisms respond to the presence of DNA lesions by activating cell cycle checkpoint and repair mechanisms, while multicellular animals have acquired the further option of eliminating damaged cells by triggering apoptosis. Defects in DNA damage-induced apoptosis contribute to tumorigenesis and to the resistance of cancer cells to a variety of therapeutic agents. The intranuclear mechanisms that signal apoptosis after DNA damage overlap with those that initiate cell cycle arrest and DNA repair, and the early events in these pathways are highly conserved. In addition, multiple independent routes have recently been traced by which nuclear DNA damage can be signalled to the mitochondria, tipping the balance in favour of cell death rather than repair and survival. Here, we review current knowledge of nuclear DNA damage signalling, giving particular attention to interactions between these nuclear events and apoptotic processes in other intracellular compartments.