Showing papers by "University of Hamburg published in 2009"

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Abstract: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 10-157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 10-9) and 5' to the PICALM gene (rs3851179, P = 1.9 10-8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10-10, odds ratio = 0.86; rs3851179, P = 1.3 10-9, odds ratio = 0.86).

Temporal and Spatial Dynamics of Cerebral Immune Cell Accumulation in Stroke

Abstract: Background and Purpose— Ischemic stroke leads to significant morbidity and mortality in the Western world Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage The understanding of postischemic inflammation is very limited The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia–reperfusion injury model Methods— Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets Results— Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells DCs exhi

Strict blood-pressure control and progression of renal failure in children.

Abstract: Background Although inhibition of the renin–angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting–enzyme (ACE) inhibitor. Methods After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m 2 of body-surface area) received ramipril at a dose of 6 mg per square meter of bodysurface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin–angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. Results A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan– Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P = 0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. Conclusions Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination.

Abstract: Background The prevalence of thyroid nodules in a healthy population is high: in the German Papillon study, nationwide ultrasound screening of more than 90 000 people using 7·5 MHz scanners revealed the presence of thyroid nodules in 33% of the normal population. A study employing more sensitive 13 MHz scanners has not been conducted so far. Materials and methods Six hundred and thirty-five consecutive patients (33% female, 67% male, mean 56·7 years) presenting for a preventive health check up underwent ultrasound screening of the thyroid gland (Siemens Acuson Antares, 13 MHz-linear scanner, B-mode and Power mode) and measurement of the basal TSH (thyroid stimulating hormone) value. Size and degree of vascularization of the thyroid gland and of nodules were determined and analysed retrospectively. Results In 432 of 635 patients, thyroid nodules could be detected with an increasing incidence with age, in 338 without goiter. Mean thyroid size was 12·3 mL for women and 20·5 mL for men correlating strongly with body weight. Fifty-three percentage of the nodules were smaller than 5 mm. Incidence of thyroid dysfunction was only 4%. No cancerous lesions could be found. Conclusions Using the 13 MHz technology, we found a substantially higher prevalence of thyroid nodules (68%) than the Papillon study (33%). Even if our population is older than in Papillon, the difference remains in comparable age groups. This is due to the higher sensitivity of 13 MHz scanning. Our study underlines the clinical significance of iodine deficiency and should renew the discussion on routine iodine supplementation.

Resolving the effect of climate change on fish populations

Abstract: This paper develops a framework for the study of climate on fish populations based on first principles of physiology, ecology, and available observations. Environmental variables and oceanographic features that are relevant to fish and that are likely to be affected by climate change are reviewed. Working hypotheses are derived from the differences in the expected response of different species groups. A review of published data on Northeast Atlantic fish species representing different biogeographic affinities, habitats, and body size lends support to the hypothesis that global warming results in a shift in abundance and distribution (in patterns of occurrence with latitude and depth) of fish species. Pelagic species exhibit clear changes in seasonal migration patterns related to climateinduced changes in zooplankton productivity. Lusitanian species have increased in recent decades (sprat, anchovy, and horse mackerel), especially at the northern limit of their distribution areas, while Boreal species decreased at the southern limit of their distribution range (cod and plaice), but increased at the northern limit (cod). Although the underlying mechanisms remain uncertain, available evidence suggests climate-related changes in recruitment success to be the key process, stemming from either higher production or survival in the pelagic egg or larval stage, or owing to changes in the quality/quantity of nursery habitats.

Single domain antibodies: promising experimental and therapeutic tools in infection and immunity.

Abstract: Antibodies are important tools for experimental research and medical applications. Most antibodies are composed of two heavy and two light chains. Both chains contribute to the antigen-binding site which is usually flat or concave. In addition to these conventional antibodies, llamas, other camelids, and sharks also produce antibodies composed only of heavy chains. The antigen-binding site of these unusual heavy chain antibodies (hcAbs) is formed only by a single domain, designated VHH in camelid hcAbs and VNAR in shark hcAbs. VHH and VNAR are easily produced as recombinant proteins, designated single domain antibodies (sdAbs) or nanobodies. The CDR3 region of these sdAbs possesses the extraordinary capacity to form long fingerlike extensions that can extend into cavities on antigens, e.g., the active site crevice of enzymes. Other advantageous features of nanobodies include their small size, high solubility, thermal stability, refolding capacity, and good tissue penetration in vivo. Here we review the results of several recent proof-of-principle studies that open the exciting perspective of using sdAbs for modulating immune functions and for targeting toxins and microbes.

Fast Mapping of Short Sequences with Mismatches, Insertions and Deletions Using Index Structures

Abstract: With few exceptions, current methods for short read mapping make use of simple seed heuristics to speed up the search. Most of the underlying matching models neglect the necessity to allow not only mismatches, but also insertions and deletions. Current evaluations indicate, however, that very different error models apply to the novel high-throughput sequencing methods. While the most frequent error-type in Illumina reads are mismatches, reads produced by 454's GS FLX predominantly contain insertions and deletions (indels). Even though 454 sequencers are able to produce longer reads, the method is frequently applied to small RNA (miRNA and siRNA) sequencing. Fast and accurate matching in particular of short reads with diverse errors is therefore a pressing practical problem. We introduce a matching model for short reads that can, besides mismatches, also cope with indels. It addresses different error models. For example, it can handle the problem of leading and trailing contaminations caused by primers and poly-A tails in transcriptomics or the length-dependent increase of error rates. In these contexts, it thus simplifies the tedious and error-prone trimming step. For efficient searches, our method utilizes index structures in the form of enhanced suffix arrays. In a comparison with current methods for short read mapping, the presented approach shows significantly increased performance not only for 454 reads, but also for Illumina reads. Our approach is implemented in the software segemehl available at http://www.bioinf.uni-leipzig.de/Software/segemehl/.

Probing the ATIC peak in the cosmic-ray electron spectrum with H.E.S.S.

Abstract: The measurement of an excess in the cosmic-ray electron spectrum between 300 and 800 GeV by the ATIC experiment has - together with the PAMELA detection of a rise in the positron fraction up to 100 GeV - motivated many interpretations in terms of dark matter scenarios; alternative explanations assume a nearby electron source like a pulsar or supernova remnant. Here we present a measurement of the cosmic-ray electron spectrum with H.E.S.S. starting at 340 GeV. The H.E.S.S. data with their lower statistical errors show no indication of a structure in the electron spectrum, but rather a power-law spectrum with spectral index of 3.0 +- 0.1 (stat.) +- 0.3 (syst.) which steepens at about 1 TeV.

Exact Spectrum of Anomalous Dimensions of Planar N = 4 Supersymmetric Yang-Mills Theory

Abstract: We present a set of functional equations defining the anomalous dimensions of arbitrary local single trace operators in planar $\mathcal{N}=4$ supersymmetric Yang-Mills theory. It takes the form of a $Y$ system based on the integrability of the dual superstring $\ensuremath{\sigma}$ model on the five-dimensional anti--de Sitter space (${\mathrm{AdS}}_{5}\ifmmode\times\else\texttimes\fi{}{\mathrm{S}}^{5}$) background. This $Y$ system passes some very important tests: it incorporates the full asymptotic Bethe ansatz at large length of operator $L$, including the dressing factor, and it confirms all recently found wrapping corrections. The recently proposed ${\mathrm{AdS}}_{4}/\mathrm{\text{three-dimensional}}$ conformal field theory duality is also treated in a similar fashion.

A cultural task analysis of implicit independence: comparing North America, Western Europe, and East Asia.

Abstract: Informed by a new theoretical framework that assigns a key role to cultural tasks (culturally prescribed means to achieve cultural mandates such as independence and interdependence) in mediating the mutual influences between culture and psychological processes, the authors predicted and found that North Americans are more likely than Western Europeans (British and Germans) to (a) exhibit focused (vs. holistic) attention, (b) experience emotions associated with independence (vs. interdependence), (c) associate happiness with personal achievement (vs. communal harmony), and (d) show an inflated symbolic self. In no cases were the 2 Western European groups significantly different from one another. All Western groups showed (e) an equally strong dispositional bias in attribution. Across all of the implicit indicators of independence, Japanese were substantially less independent (or more interdependent) than the three Western groups. An explicit self-belief measure of independence and interdependence showed an anomalous pattern. These data were interpreted to suggest that the contemporary American ethos has a significant root in both Western cultural heritage and a history of voluntary settlement. Further analysis offered unique support for the cultural task analysis.

Randomized Study of the Crush Technique Versus Provisional Side-Branch Stenting in True Coronary Bifurcations: The CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) Study

Abstract: Background— Sirolimus-eluting stents have been reported to be effective in the treatment of coronary bifurcations. Still, it has not been fully clarified which strategy would provide the best results with true bifurcation lesions. Methods and Results— The CACTUS trial (Coronary bifurcations: Application of the Crushing Technique Using Sirolimus-eluting stents) is a prospective, randomized, multicenter study comparing 2 different techniques of stenting, with mandatory final kissing-balloon inflation, in true bifurcations: (1) elective “crush” stenting and (2) stenting of only the main branch, with provisional side-branch T-stenting. From August 2004 to June 2007, 350 patients were enrolled in 12 European centers. The primary angiographic end point was the in-segment restenosis rate, and the primary clinical end point was the occurrence of major adverse cardiac events (cardiac death, myocardial infarction, or target-vessel revascularization) at 6 months. At 6 months, angiographic restenosis rates were not d...

Threshold resummation for squark-antisquark and gluino-pair production at the LHC.

Abstract: We study the effect of soft gluon emission in the hadroproduction of squark-antisquark and gluino-gluino pairs at the next-to-leading logarithmic (NLL) accuracy within the framework of the minimal supersymmetric model. The one-loop soft anomalous dimension matrices controlling the color evolution of the underlying hard-scattering processes are calculated. We present the resummed total cross sections and show numerical results for proton-proton collisions at 14 TeV. For the gluino-pair production, the theoretical uncertainty due to scale variation is reduced to the few-percent level.

Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.

Abstract: Recently, local morphologic alterations of the brain in areas ascribable to the transmission of pain were reported in patients suffering from chronic pain. Although some authors discussed these findings as damage or loss of brain gray matter, one of the key questions is whether these structural alterations in the cerebral pain-transmitting network precede or succeed the chronicity of pain. We investigated 32 patients with chronic pain due to primary hip osteoarthritis and found a characteristic gray matter decrease in patients compared with controls in the anterior cingulate cortex (ACC), right insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC), amygdala, and brainstem. We then investigated a subgroup of these patients (n = 10) 6 weeks and 4 months after total hip replacement surgery, monitoring whole brain structure. After surgery, all 10 patients were completely pain free and we observed a gray matter increase in the DLPFC, ACC, amygdala, and brainstem. As gray matter decrease is at least partly reversible when pain is successfully treated, we suggest that the gray matter abnormalities found in chronic pain do not reflect brain damage but rather are a reversible consequence of chronic nociceptive transmission, which normalizes when the pain is adequately treated.

Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells

Abstract: The reprogramming of somatic cells into induced pluripotent stem (iPS) cells upon overexpression of the transcription factors Oct4, Sox2, Klf4 and cMyc is inefficient. It has been assumed that the somatic differentiation state provides a barrier for efficient reprogramming; however, direct evidence for this notion is lacking. Here, we tested the potential of mouse hematopoietic cells at different stages of differentiation to be reprogrammed into iPS cells. We show that hematopoietic stem and progenitor cells give rise to iPS cells up to 300 times more efficiently than terminally differentiated B and T cells do, yielding reprogramming efficiencies of up to 28%. Our data provide evidence that the differentiation stage of the starting cell has a critical influence on the efficiency of reprogramming into iPS cells. Moreover, we identify hematopoietic progenitors as an attractive cell type for applications of iPS cell technology in research and therapy.

Assessing the Quality of Decision Support Technologies Using the International Patient Decision Aid Standards instrument (IPDASi)

Abstract: Objectives To describe the development, validation and inter-rater reliability of an instrument to measure the quality of patient decision support technologies (decision aids). Design Scale development study, involving construct, item and scale development, validation and reliability testing. Setting There has been increasing use of decision support technologies – adjuncts to the discussions clinicians have with patients about difficult decisions. A global interest in developing these interventions exists among both for-profit and not-for-profit organisations. It is therefore essential to have internationally accepted standards to assess the quality of their development, process, content, potential bias and method of field testing and evaluation. Methods Scale development study, involving construct, item and scale development, validation and reliability testing. Participants Twenty-five researcher-members of the International Patient Decision Aid Standards Collaboration worked together to develop the instrument (IPDASi). In the fourth Stage (reliability study), eight raters assessed thirty randomly selected decision support technologies. Results IPDASi measures quality in 10 dimensions, using 47 items, and provides an overall quality score (scaled from 0 to 100) for each intervention. Overall IPDASi scores ranged from 33 to 82 across the decision support technologies sampled (n = 30), enabling discrimination. The inter-rater intraclass correlation for the overall quality score was 0.80. Correlations of dimension scores with the overall score were all positive (0.31 to 0.68). Cronbach's alpha values for the 8 raters ranged from 0.72 to 0.93. Cronbach's alphas based on the dimension means ranged from 0.50 to 0.81, indicating that the dimensions, although well correlated, measure different aspects of decision support technology quality. A short version (19 items) was also developed that had very similar mean scores to IPDASi and high correlation between short score and overall score 0.87 (CI 0.79 to 0.92). Conclusions This work demonstrates that IPDASi has the ability to assess the quality of decision support technologies. The existing IPDASi provides an assessment of the quality of a DST's components and will be used as a tool to provide formative advice to DSTs developers and summative assessments for those who want to compare their tools against an existing benchmark.

Direct Evidence for Spinal Cord Involvement in Placebo Analgesia

Abstract: Placebo analgesia is a prime example of the impact that psychological factors have on pain perception. We used functional magnetic resonance imaging of the human spinal cord to test the hypothesis that placebo analgesia results in a reduction of nociceptive processing in the spinal cord. In line with behavioral data that show decreased pain responses under placebo, pain-related activity in the spinal cord is strongly reduced under placebo. These results provide direct evidence for spinal inhibition as one mechanism of placebo analgesia and highlight that psychological factors can act on the earliest stages of pain processing in the central nervous system.