Biomedical subjects
Publications and source records attributed to M van der Linden.
Globicatella sanguinis is a very rare isolate in clinical samples. We present a case of meningitis in a 69-year-old female patient after implantation of an external left ventricular drainage due to a hydrocephalus. She recovered after antibiotic treatment with ceftriaxone.
A population-based survey of invasive pneumococcal disease (IPD) was conducted among adults in North-Rhine Westphalia, Germany. The study included 202 of the 386 hospitals in the region, together with the 27 microbiological laboratories that submitted reports of IPD in these hospitals to the National Reference Centre for Streptococci. The reports of 16 laboratories were comprehensively reviewed. Most (95.8%) IPD isolates were susceptible to penicillin G, but 14.5% were resistant to clarithromycin. Serotypes 14 (15.6%), 3 (9.3%), 4 (7.1%) and 7F (7.9%) were the most common. The serotype coverage of the 23-valent pneumococcal polysaccharide vaccine was 80.8%. During 2001-2003, the annual incidence of IPD, after correcting for laboratory and hospital under-reporting, was 16.2/100 000 in individuals aged >or= 65 years. In three university hospitals, blood cultures were obtained for only 37% of patients with community-acquired pneumonia, and fewer than one-third of such cultures were obtained in one hospital before antibiotics were prescribed, suggesting that the true incidence of IPD was closer to 50/100 000.
SUMMARY: The Helmholtz Network for Bioinformatics (HNB) is a joint venture of eleven German bioinformatics research groups that offers convenient access to numerous bioinformatics resources through a single web portal. The 'Guided Solution Finder' which is available through the HNB portal helps users to locate the appropriate resources to answer their queries by employing a detailed, tree-like questionnaire. Furthermore, automated complex tool cascades ('tasks'), involving resources located on different servers, have been implemented, allowing users to perform comprehensive data analyses without the requirement of further manual intervention for data transfer and re-formatting. Currently, automated cascades for the analysis of regulatory DNA segments as well as for the prediction of protein functional properties are provided. AVAILABILITY: The HNB portal is available at http://www.hnbioinfo.de
Abstract Although phonological processing is generally considered to be a proficiency in Williams syndrome (WS), there are very few studies which have extensively explored phonological processing abilities in WS. In this study, we re-assessed phonological processing in WS by exploring verbal STM and phonological awareness abilities in 4 children with WS (CA: 10-12 years) and two control groups, one matched for chronological age (CA) and the other matched for verbal mental age (VA). Our results confirm and extend previous claims of preserved phonological STM in WS by showing specifically preserved STM performance for non-words, compared to both VA and CA control groups. However, we observed that this was the case only for non-words where support of phonological and lexico-semantic knowledge was minimized, with reduced phonological and lexico-semantic effects on STM performance. Furthermore, a more direct assessment of phonological processing abilities through phonological awareness tasks showed impaired performance for the 4 WS children. Our data confirm that STM for non-words represents a real strength in WS but they do not support previous assumptions of a more general preservation of phonological processing abilities in WS. Implications for impaired and preserved cognitive processes underlying verbal STM and phonological awareness abilities in WS are discussed.
The human transcription factor Oct-1 can stimulate transcription from a variety of promoters by interacting with the coactivators OBF-1/OCA-B/BOB-1, SNAP190 and VP16. These proteins contact Oct-1 regions different from the DNA binding surface. Oct-1 also stimulates the DNA replication of adenovirus through its DNA binding site in the origin. The Oct-1 POU homeodomain (POUhd) binds the adenovirus precursor terminal protein pTP, which serves as the protein primer of DNA replication and recruits pTP to the origin. To map the interaction with pTP at the POUhd surface, we screened a library of randomly mutated POU domains and identified mutations that interfered with pTP interaction and DNA replication stimulation. These mutants clustered at a surface different from those recognized by OBF-1, SNAP190 and VP16. Unexpectedly, the pTP binding region largely overlapped with the DNA binding surface of POUhd. In agreement with this, pTP binding and DNA binding were mutually exclusive. We propose a model to reconcile pTP recruitment and DNA binding by Oct-1.
Colorectal cancer is the second most frequent cancer in Western countries. Exogenous factors play a major role in the aetiology of sporadic colorectal cancer representing about 90% of all cases, hereditary cancers accounting for about 10% of patients. Thus, in the large majority of cases, cell dysfunction in CRC results from multiple rather than single, gene interactions. Numerous cellular events and environmental influences modify gene expression or post-translational protein modifications. Changes like glycosylation of proteins and lipids which are a common feature in colorectal cancer and influence cancer cell behaviour, cannot be directly detected by genetic studies. Better than genomics studies, functional proteomics studies allow the investigation of environmental factors over time, allowing the monitoring of metabolic responses to various stimuli. However, proteomics studies also have several drawbacks: a) current tools only allow narrow-range analyses, b) identification of proteins of interest remains cumbersome, c) protein studies address multiple compounds of high complexity, d) large amount of proteins are necessary to allow analysis, e) protein research require specific tools, e.g. tagged antibodies, that first have to be developed. Some protein tests are already in application for CRC: a classical prognostic test in colorectal cancer is based on the detection and quantification of a single protein (CEA) in body fluids. Recently, a screening assay based on APC protein truncation test has also been proposed. However, studies linking large protein expression patterns with clinical outcome in colorectal cancer are still in their infancy. To be able to predict occurrence of disease, and treatment outcome, more studies on genotype-phenotype correlations are needed both in sporadic and in hereditary colorectal cancer.
Although many epidemiological studies have shown an association between hyperfibrinogenemia and atherosclerosis, it is not established whether elevated fibrinogen has an etiological role in the pathogenesis or is only a reflection of the ongoing disease. We have studied the contribution of fibrinogen to the development of atherosclerosis in atherosclerosis-prone ApoE*3-Leiden mice that have been cross-bred with transgenic mice overexpressing fibrinogen. Genetic compound offspring were used to evaluate the progression of atherosclerotic lesions after being fed an atherogenic diet for 7 weeks. It was observed that the lesion area of the plaques as well as the severity of the lesions in the aortic valve was comparable in control single transgenic ApoE*3-Leiden mice and in double transgenic apoE*3-Leiden mice overexpressing fibrinogen. No thrombus or fibrin deposition was observed in atherosclerotic lesions in either group of mice. These results indicate that elevated plasma fibrinogen concentrations in ApoE*3-Leiden transgenic mice do not affect the progression of diet-induced atherosclerotic lesions.
One function of sleep is hypothesized to be the reprocessing and consolidation of memory traces (Smith, 1995; Gais et al., 2000; McGaugh, 2000; Stickgold et al., 2000). At the cellular level, neuronal reactivations during post-training sleep in animals have been observed in hippocampal (Wilson and McNaughton, 1994) and cortical (Amzica et al., 1997) neuronal populations. At the systems level, using positron emission tomography, we have recently shown that some brain areas reactivated during rapid-eye-movement sleep in human subjects previously trained on an implicit learning task (a serial reaction time task) (Maquet et al., 2000). These cortical reactivations, located in the left premotor area and bilateral cuneus, were thought to reflect the reprocessing--possibly the consolidation--of memory traces during post-training rapid-eye-movement sleep. Here, the experience-dependent functional connectivity of these brain regions is examined. It is shown that the left premotor cortex is functionally more correlated with the left posterior parietal cortex and bilateral pre-supplementary motor area during rapid-eye-movement sleep of subjects previously trained to the reaction time task compared to rapid-eye-movement sleep of untrained subjects. The increase in functional connectivity during post-training rapid-eye-movement sleep suggests that the brain areas reactivated during post-training rapid-eye-movement sleep participate in the optimization of the network that subtends subject's visuo-motor response. The optimization of this visuo-motor network during sleep could explain the gain in performance observed during the following day.
Tumor cells may display a multidrug resistance phenotype by overexpression of ATP binding cassette transporter genes such as multidrug resistance (MDR) 1 P-glycoprotein (P-gp) or the multidrug resistance protein 1 (MRP1). MDR3 P-gp is a close homologue of MDR1 P-gp, but its role in MDR is probably minor and remains to be established. The MRP1 protein belongs to a family of at least six members. Three of these, i.e., MRP1, MRP2, and MRP3, can transport MDR drugs and could be involved in MDR. The substrate specificity of the other family members remains to be defined. Specific monoclonal antibodies are required for wide-scale studies on the putative contribution of these closely related transporter proteins to MDR. In this report, we describe the extensive characterization of a panel of monoclonal antibodies (Mabs) detecting several MDR-related transporter proteins in both human and animal tissues. The panel consists of P3II-1 and P3II-26 for MDR3 P-gp; MRPr1, MRPm6, MRPm5, and MIB6 for MRP1; M2I-4, M2II-12, M2III-5 and M2III-6 for MRP2; M3II-9 and M3II-21 for MRP3; and M5I-1 and M5II-54 for MRP5. All Mabs in the panel appeared to be fully specific for their cognate antigens, both in Western blots and cytospin preparations, as revealed by lack of cross-reactivity with any of the other family members. Indeed, all Mabs were very effective in detecting their respective antigens in cytospins of transfected cell lines, whereas in flow cytometric and immunohistochemical analyses, distinct differences in reactivity and suitability were noted. These Mabs should become valuable tools in studying the physiological functions of these transporter proteins, in screening procedures for the absence of these proteins in hereditary metabolic (liver) diseases, and in studying the possible contributions of these molecules to MDR in cancer patients.
Humans, like numerous other species, strongly rely on the observation of gestures of other individuals in their everyday life. It is hypothesized that the visual processing of human gestures is sustained by a specific functional architecture, even at an early prelexical cognitive stage, different from that required for the processing of other visual entities. In the present PET study, the neural basis of visual gesture analysis was investigated with functional neuroimaging of brain activity during naming and orientation tasks performed on pictures of either static gestures (upper-limb postures) or tridimensional objects. To prevent automatic object-related cerebral activation during the visual processing of postures, only intransitive postures were selected, i. e., symbolic or meaningless postures which do not imply the handling of objects. Conversely, only intransitive objects which cannot be handled were selected to prevent gesture-related activation during their visual processing. Results clearly demonstrate a significant functional segregation between the processing of static intransitive postures and the processing of intransitive tridimensional objects. Visual processing of objects elicited mainly occipital and fusiform gyrus activity, while visual processing of postures strongly activated the lateral occipitotemporal junction, encroaching upon area MT/V5, involved in motion analysis. These findings suggest that the lateral occipitotemporal junction, working in association with area MT/V5, plays a prominent role in the high-level perceptual analysis of gesture, namely the construction of its visual representation, available for subsequent recognition or imitation.
The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding the canalicular multispecific organic anion transporter; and four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2. In Madin-Darby canine kidney II cells, MRP3 routes to the basolateral membrane and mediates transport of the organic anion S-(2,4-dinitrophenyl-)glutathione toward the basolateral side of the monolayer. In ovarian carcinoma cells (2008), expression of MRP3 results in low-level resistance to the epipodophyllotoxins etoposide and teniposide. In short-term drug exposure experiments, MRP3 also confers high-level resistance to methotrexate. Neither 2008 cells nor Madin-Darby canine kidney II cells overexpressing MRP3 showed an increase in glutathione export or a decrease in the level of intracellular glutathione, in contrast to cells overexpressing MRP1 or MRP2. We discuss the possible function of MRP3 in (hepatic) physiology and its potential contribution to drug resistance of cancer cells.
The human multidrug resistance protein (MRP) family contains at least six members: MRP1, the gene encoding the multidrug resistance protein; cMOAT or MRP2, encoding the canalicular multispecific organic anion transporter; and four homologues, called MRP3, MRP4, MRP5, and MRP6. The most recently discovered member of the family, MRP6, is analyzed in this report. The MRP6 gene is located on chromosome 16, immediately next to MRP1, and encodes a protein of 1503 amino acids with a predicted molecular weight of Mr 165,000. The 3' end of the MRP6 protein was found to be almost identical with the anthracycline resistance associated (ARA) protein identified previously in epirubicin-selected leukemia cells. Using both 3'- and 5'-derived MRP6 probes, we found that MRP6 is highly expressed in liver and kidney and to a low or very low extent in a few other tissues. No evidence was obtained for an independent expression of the ARA part of the MRP6 gene in normal tissues. To assess a possible role for MRP6 in multidrug resistance, we examined a large panel of resistant cell lines for the (over)expression of MRP6. We found overexpression of the complete MRP6 gene or part of it only in those cell lines with high overexpression and amplification of the MRP1 gene. DNA blot (Southern) analysis showed that MRP6 or a part of it is also amplified in these cell lines. Our results suggest that MRP6 does not play a role in the resistance of the resistant cells analyzed, and that MRP6/ARA is only coamplified with MRP1 because of its location immediately next to it on the same chromosome.
When pantomiming gestures to verbal command, the overall production of body-part-as-object (BPO) errors is differentially affected by age and educational level in normal subjects. The higher overall frequency of BPO with age may be related to difficulties in the inhibition of the automatic activation of tool emblems (i.e., the BPO) instead of the appropriate hand posture to hold the tool. However, all subjects are equally able to correct errors in BPO on subsequent trials, which suggests the integrity of these gestural representations. In a clinical perspective, BPO data have therefore to be considered carefully when one wants to include this error type as an indicator of limb apraxia.
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The DNA sequences of two related plasmids pPR1 and pPR3 described previously in Streptococcus pneumoniae isolates from Germany and Spain were now determined. Both plasmids belong to a family of rolling circle (RC) plasmids found in a variety of bacteria. Their GC content with 32% is lower than that of the S. pneumoniae chromosomal DNA. The plasmid pPR3 has a molecular size of 3160 bp with four putative open reading frames, whereas pPR1 contained a deletion of 313 bp that included the 5'-part of ORF2 and upstream regions and differed by three bp from pPR3. The predicted protein of ORF1 showed high similarity to replication proteins of RC plasmids with 74% identical amino acids to RepA of Streptococcus thermophilus plasmids. Sequences similar to the plus origin of replication of ssDNA plasmids were present in both plasmids. They also contained a 152-bp region with over 83% identity to the minus origin of replication of the Streptococcus agalacticae plasmid pMV158.
Penicillin-resistant isolates of Streptococcus pneumoniae generally contain mosaic genes encoding the low-affinity penicillin-binding proteins (PBPs) PBP2x, PBP2b, and PBP1a. We now present evidence that PBP2a and PBP1b also appear to be low-affinity variants and are encoded by distinct alleles in beta-lactam-resistant transformants of S. pneumoniae obtained with chromosomal donor DNA from a Streptococcus mitis isolate. Different lineages of beta-lactam-resistant pneumococcal transformants were analyzed, and transformants with low-affinity variants of all high-molecular-mass PBPs, PBP2x, -2a, -2b, -1a, and -1b, were isolated. The MICs of benzyl-penicillin, oxacillin, and cefotaxime for these transformants were up to 40, 100, and 50 microg/ml, respectively, close to the MICs for the S. mitis donor strain. Recruitment of low-affinity PBPs was accompanied by a decrease in cross-linked muropeptides as revealed by high-performance liquid chromatography of muramidase-digested cell walls, but no qualitative changes in muropeptide chemistry were detected. The growth rates of all transformants were identical to that of the parental S. pneumoniae strain. The results stress the potential for the acquisition by S. pneumoniae of high-level beta-lactam resistance by interspecies gene transfer.
Flashbulb memories (FBMs) are detailed recollections of the context in which people first heard about important events. The present study investigates three models of the formation and maintenance of FBM. Two models have previously been proposed in the literature (Brown & Kulik, 1977; Conway et al., 1994). A third model of FBM that integrates theories of FBM and recent developments in the field of emotions is proposed. The present study compares these three competing models by investigating the FBMs that Belgian citizens developed upon learning of the unexpected death of their king Baudouin. Structural equation modeling revealed that, as compared to the two previously proposed models, the third model, which takes into account emotional processes, better explains FBM.
This study assesses the incidence of sudden death and classifies the causes of death following radiofrequency ablation of the atrioventricular (AV) junction. We studied 220 patients with paroxysmal (n = 105) or chronic (n = 115) atrial fibrillation (AF) and a mean age of 64 +/- 12 years. These patients were followed 31 +/- 15 months after radiofrequency ablation of the AV junction and pacemaker implantation. In 86 patients, structural heart disease was identified before the procedure. All patients were traced via the Swedish National Civic Registry and Cause of Death Registry. The cause-of-death was classified according to data from death certificates, autopsy protocols, and medical records. Thirty-one patients (mean age 69 +/- 11 years, 16 men) died 15 +/- 15 months (range 0.2 to 60) after the procedure. There were 6 sudden unexplained deaths, 14 cardiovascular deaths, and 11 deaths from noncardiovascular causes. Eleven patients, all with structural heart disease, died suddenly out of hospital 16 +/- 16 months (range 0.2 to 42) after the procedure. In 6 of these there was no obvious cause of death. Three of these 6 patients underwent autopsy, which showed extensive coronary artery disease (n = 1), severe heart failure (n = 1) and cardiac hypertrophy and dilation (n = 1). The remaining 3 all had depressed left ventricular systolic function and a history of congestive heart failure. Five of the patients who died suddenly from cardiovascular causes had autopsies that revealed acute myocardial infarction (n = 4) and massive pulmonary embolism (n = 1).