Showing papers by "University of Bonn published in 2008"

Second consensus statement on the diagnosis of multiple system atrophy

Abstract: Background: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here.Methods: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology.Results: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality.Conclusions: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

Large recurrent microdeletions associated with schizophrenia

Abstract: Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Identification of loci associated with schizophrenia by genome-wide association and follow-up

Abstract: We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).

Debris clearance by microglia: an essential link between degeneration and regeneration

Abstract: Microglia are cells of myeloid origin that populate the CNS during early development and form the brain's innate immune cell type. They perform homoeostatic activity in the normal CNS, a function associated with high motility of their ramified processes and their constant phagocytic clearance of cell debris. This debris clearance role is amplified in CNS injury, where there is frank loss of tissue and recruitment of microglia to the injured area. Recent evidence suggests that this phagocytic clearance following injury is more than simply tidying up, but instead plays a fundamental role in facilitating the reorganization of neuronal circuits and triggering repair. Insufficient clearance by microglia, prevalent in several neurodegenerative diseases and declining with ageing, is associated with an inadequate regenerative response. Thus, understanding the mechanism and functional significance of microglial-mediated clearance of tissue debris following injury may open up exciting new therapeutic avenues.

Unit Roots and Cointegration in Panels

Abstract: This paper provides a review of the literature on unit roots and cointegration in panels where the time dimension (T), and the cross section dimension (N) are relatively large. It distinguishes between the first generation tests developed on the assumption of the cross section independence, and the second generation tests that allow, in a variety of forms and degrees, the dependence that might prevail across the different units in the panel. In the analysis of cointegration, the hypothesis testing and estimation problems are further complicated by the possibility of cross section cointegration which could arise if the unit roots in the different cross section units are due to common random walk components.

European Society of Hypertension guidelines for blood pressure monitoring at home: a summary report of the Second International Consensus Conference on Home Blood Pressure Monitoring.

Abstract: This document summarizes the available evidence and provides recommendations on the use of home blood pressure monitoring in clinical practice and in research. It updates the previous recommendations on the same topic issued in year 2000. The main topics addressed include the methodology of home blood pressure monitoring, its diagnostic and therapeutic thresholds, its clinical applications in hypertension, with specific reference to special populations, and its applications in research. The final section deals with the problems related to the implementation of these recommendations in clinical practice.

Astroglial metabolic networks sustain hippocampal synaptic transmission.

Abstract: Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.

Analysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells

Abstract: Analysis of mitochondrial function is central to the study of intracellular energy metabolism, mechanisms of cell death and pathophysiology of a variety of human diseases, including myopathies, neurodegenerative diseases and cancer. However, important properties of mitochondria differ in vivo and in vitro. Here, we describe a protocol for the analysis of functional mitochondria in situ, without the isolation of organelles, in selectively permeabilized cells or muscle fibers using digitonin or saponin. A specially designed substrate/inhibitor titration approach allows the step-by-step analysis of several mitochondrial complexes. This protocol allows the detailed characterization of functional mitochondria in their normal intracellular position and assembly, preserving essential interactions with other organelles. As only a small amount of tissue is required for analysis, the protocol can be used in diagnostic settings in clinical studies. The permeabilization procedure and specific titration analysis can be completed in 2 h.

ATLAS pixel detector electronics and sensors

Abstract: The silicon pixel tracking system for the ATLAS experiment at the Large Hadron Collider is described and the performance requirements are summarized. Detailed descriptions of the pixel detector electronics and the silicon sensors are given. The design, fabrication, assembly and performance of the pixel detector modules are presented. Data obtained from test beams as well as studies using cosmic rays are also discussed.

Breast MRI: guidelines from the European Society of Breast Imaging

Abstract: The aim of breast MRI is to obtain a reliable evaluation of any lesion within the breast. It is currently always used as an adjunct to the standard diagnostic procedures of the breast, i.e., clinical examination, mammography and ultrasound. Whereas the sensitivity of breast MRI is usually very high, specificity—as in all breast imaging modalities—depends on many factors such as reader expertise, use of adequate techniques and composition of the patient cohorts. Since breast MRI will always yield MR-only visible questionable lesions that require an MR-guided intervention for clarification, MRI should only be offered by institutions that can also offer a MRI-guided breast biopsy or that are in close contact with a site that can perform this type of biopsy for them. Radiologists involved in breast imaging should ensure that they have a thorough knowledge of the MRI techniques that are necessary for breast imaging, that they know how to evaluate a breast MRI using the ACR BI-RADS MRI lexicon, and most important, when to perform breast MRI. This manuscript provides guidelines on the current best practice for the use of breast MRI, and the methods to be used, from the European Society of Breast Imaging (EUSOBI).

Insights into the Mode of Action of Chitosan as an Antibacterial Compound

Abstract: Chitosan is a polysaccharide biopolymer that combines a unique set of versatile physicochemical and biological characteristics which allow for a wide range of applications. Although its antimicrobial activity is well documented, its mode of action has hitherto remained only vaguely defined. In this work we investigated the antimicrobial mode of action of chitosan using a combination of approaches, including in vitro assays, killing kinetics, cellular leakage measurements, membrane potential estimations, and electron microscopy, in addition to transcriptional response analysis. Chitosan, whose antimicrobial activity was influenced by several factors, exhibited a dose-dependent growth-inhibitory effect. A simultaneous permeabilization of the cell membrane to small cellular components, coupled to a significant membrane depolarization, was detected. A concomitant interference with cell wall biosynthesis was not observed. Chitosan treatment of Staphylococcus simulans 22 cells did not give rise to cell wall lysis; the cell membrane also remained intact. Analysis of transcriptional response data revealed that chitosan treatment leads to multiple changes in the expression profiles of Staphylococcus aureus SG511 genes involved in the regulation of stress and autolysis, as well as genes associated with energy metabolism. Finally, a possible mechanism for chitosan's activity is postulated. Although we contend that there might not be a single classical target that would explain chitosan's antimicrobial action, we speculate that binding of chitosan to teichoic acids, coupled with a potential extraction of membrane lipids (predominantly lipoteichoic acid) results in a sequence of events, ultimately leading to bacterial death.

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder.

Abstract: The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550 000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 × 10−8, experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.

Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection

Abstract: Results In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detect ed in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. Conclusions In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

Abstract: Background: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. Methods and Findings: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in β-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. Conclusions: The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.

MAMBO Mapping Of Spitzer c2d Small Clouds And Cores

Abstract: Aims. To study the structure of nearby (<500 pc) dense starless and star-forming cores with the particular goal to identify and understand evolutionary trends in core properties, and to explore the nature of Very Low Luminosity Objects (<0.1 L ⊙ ; VeLLOs). Methods. Using the MAMBO bolometer array, we create maps unusually sensitive to faint (few mJy per beam) extended (≈5') thermal dust continuum emission at 1.2 mm wavelength. Complementary information on embedded stars is obtained from Spitzer, IRAS, and 2MASS. Results. Our maps are very rich in structure, and we characterize extended emission features ("subcores") and compact intensity peaks in our data separately to pay attention to this complexity. We derive, e.g., sizes, masses, and aspect ratios for the subcores, as well as column densities and related properties for the peaks. Combination with archival infrared data then enables the derivation of bolometric luminosities and temperatures, as well as envelope masses, for the young embedded stars. Conclusions. Starless and star-forming cores occupy the same parameter space in many core properties; a picture of dense core evolution in which any dense core begins to actively form stars once it exceeds some fixed limit in, e.g., mass, density, or both, is inconsistent with our data. A concept of necessary conditions for star formation appears to provide a better description: dense cores fulfilling certain conditions can form stars, but they do not need to, respectively have not done so yet. Comparison of various evolutionary indicators for young stellar objects in our sample (e.g., bolometric temperatures) reveals inconsistencies between some of them, possibly suggesting a revision of some of these indicators. Finally, we challenge the notion that VeLLOs form in cores not expected to actively form stars, and we present a first systematic study revealing evidence for structural differences between starless and candidate VeLLO cores.

Guidelines for the clinical management of familial adenomatous polyposis (FAP)

Abstract: BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

How relevant is recalcitrance for the stabilization of organic matter in soils

Abstract: Traditionally, the selective preservation of certain recalcitrant organic compounds and the formation of recalcitrant humic substances have been regarded as an important mechanism for soil organic matter (SOM) stabilization. Based on a critical overview of available methods and on results from a cooperative research program, this paper evaluates how relevant recalcitrance is for the long-term stabilization of SOM or its fractions. Methodologically, recalcitrance is difficult to assess, since the persistence of certain SOM fractions or specific compounds may also be caused by other stabilization mechanisms, such as physical protection or chemical interactions with mineral surfaces. If only free particulate SOM obtained from density fractionation is considered, it rarely reaches ages exceeding 50 y. Older light particles have often been identified as charred plant residues or as fossil C. The degradability of the readily bioavailable dissolved or water-extractable OM fraction is often negatively correlated with its content in aromatic compounds, which therefore has been associated with recalcitrance. But in subsoils, dissolved organic matter aromaticity and biodegradability both are very low, indicating that other factors or compounds limit its degradation. Among the investigated specific compounds, lignin, lipids, and their derivatives have mean turnover times faster or similar as that of bulk SOM. Only a small fraction of the lignin inputs seems to persist in soils and is mainly found in the fine textural size fraction ( 40–50 y, unless fossil C was present in substantial amounts, as at a site exposed to lignite inputs in the past. Here, turnover of pyrolysis products seemed to be much longer, even for those attributed to carbohydrates or proteins. Apparently, fossil C from lignite coal is also utilized by soil organisms, which is further evidenced by low 14C concentrations in microbial phospholipid fatty acids from this site. Also, black C from charred plant materials was susceptible to microbial degradation in a short-term (60 d) and a long-term (2 y) incubation experiment. This degradation was enhanced, when glucose was supplied as an easily available microbial substrate. Similarly, SOM mineralization in many soils generally increased after addition of carbohydrates, amino acids, or simple organic acids, thus indicating that stability may also be caused by substrate limitations. It is concluded that the presented results do not provide much evidence that the selective preservation of recalcitrant primary biogenic compounds is a major SOM-stabilization mechanism. Old SOM fractions with slow turnover rates were generally only found in association with soil minerals. The only not mineral-associated SOM components that may be persistent in soils appear to be black and fossil C.

Diversity of structure, morphology and wetting of plant surfaces

Abstract: This review paper presents the diversity of plant surface structures from a single cell to multi-cellular surface sculptures There is still no comprehensive book which provides an overview of the diversity of plant surface structures This article presents a guide for the description of cellular and sub-cellular plant surface structures, which include hairs, wax crystals and surface folding Biological surfaces are multifunctional boundary layers to their environment Functionally optimized surfaces are one of the key innovations in the more than 400 million years of evolution of land plants In the plant surface, micro- and nanostructures play a special role, and a large diversity of surface structures exists at different size levels Well known functional aspects of plant surface structures are the reduction of particle adhesion, the sliding structures of carnivorous plants for insect catching, and the self-cleaning properties of the superhydrophobic Lotus (Nelumbo nucifera) leaves Their structures and functions might be useful models for the development of functional materials The surface properties of plants are based on physico-chemical principles and can be transferred to technical “biomimetic” materials, as successfully done for the self-cleaning properties of the Lotus leaves This article is designed as an introduction for biologists and non biologists and should stimulate the reader to initiate or intensify the study of biological surfaces

Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.

Abstract: Background We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. Methods We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. Results Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. Conclusions When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Modeling the Price Dynamics of Co2 Emission Allowances

Abstract: In this paper we analyze the short-term spot price behavior of carbon dioxide (CO2) emission allowances of the new EU-wide CO2 emissions trading system (EU-ETS). After reviewing the stylized facts of this new class of assets we investigate several approaches for modeling the returns of emission allowances. Due to the different phases of price and volatility behavior in the returns, we suggest the use of Markov switching and AR-GARCH models for stochastic modeling. We examine the approaches by conducting an in-sample and out-of-sample forecasting analysis and by comparing the results to alternative approaches. Our findings strongly support the adequacy of the models capturing characteristics like skewness, excess kurtosis and in particular different phases of volatility behavior in the returns.

Symbolic transfer entropy.

Abstract: We propose to estimate transfer entropy using a technique of symbolization. We demonstrate numerically that symbolic transfer entropy is a robust and computationally fast method to quantify the dominating direction of information flow between time series from structurally identical and nonidentical coupled systems. Analyzing multiday, multichannel electroencephalographic recordings from 15 epilepsy patients our approach allowed us to reliably identify the hemisphere containing the epileptic focus without observing actual seizure activity.

Fundus autofluorescence imaging: review and perspectives.

Abstract: Fundus autofluorescence (FAF) imaging is a novel imaging method that allows topographic mapping of lipofuscin distribution in the retinal pigment epithelium cell monolayer as well as of other fluorophores that may occur with disease in the outer retina and the subneurosensory space. Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases, including age-related macular degeneration. FAF imaging has been shown to be useful with regard to understanding of pathophysiologic mechanisms, diagnostics, phenotype-genotype correlation, identification of predictive markers for disease progression, and monitoring of novel therapies. FAF imaging gives information above and beyond that obtained by conventional imaging methods, such as fundus photography, fluorescein angiography, and optical coherence tomography. Its clinical value coupled with its simple, efficient, and noninvasive nature is increasingly appreciated. This review summarizes basic principles and FAF findings in various retinal diseases.

Size exclusion limits and lateral heterogeneity of the stomatal foliar uptake pathway for aqueous solutes and water-suspended nanoparticles

Abstract: Penetration rates of foliar-applied polar solutes are highly variable and the underlying mechanisms are not yet fully understood. The contribution of stomata especially, is still a matter of debate. Thus, the size exclusion limits of the stomatal foliar uptake pathway, its variability and its transport capacity have been investigated. The size exclusion limits were analyzed by studying the penetration of water-suspended hydrophilic particles of two different sizes (43 nm or 1.1 microm diameter) into leaves of Vicia faba (L.). To avoid agglutination of the particles, plants were kept in water-saturated atmosphere. Penetration of the larger particles was never detected, whereas after 2 to 9 days, the smaller particles occasionally penetrated the leaf interior through stomatal pores. Permeability of stomata to Na(2)-fluorescein along the leaf blade of Allium porrum (L.) was highly variable and not correlated with the position on the leaf. When evaporated residues of the foliar-applied solutions were rewetted repeatedly, approximately 60% of the previously penetrated stomata were penetrated again. The average rate constant of penetration of an individual stoma was in the same order of magnitude as typical rate constants reported for the cuticular pathway. The observed sparseness of stomatal penetration together with its high lateral variability but local and temporal persistency was taken as evidence that stomata contributing to uptake differ from non-penetrated ones in the wettability of their guard cell cuticle. These results show that the stomatal pathway is highly capacitive because of its large size exclusion limit above 10 nm and its high transport velocity, but at the same time the high variability renders this pathway largely unpredictable.

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

Abstract: The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.

Sirt1 contributes critically to the redox-dependent fate of neural progenitors

Abstract: Repair processes that are activated in response to neuronal injury, be it inflammatory, ischaemic, metabolic, traumatic or other cause, are characterized by a failure to replenish neurons and by astrogliosis. The underlying molecular pathways, however, are poorly understood. Here, we show that subtle alterations of the redox state, found in different brain pathologies, regulate the fate of mouse neural progenitor cells (NPCs) through the histone deacetylase (HDAC) Sirt1. Mild oxidation or direct activation of Sirt1 suppressed proliferation of NPCs and directed their differentiation towards the astroglial lineage at the expense of the neuronal lineage, whereas reducing conditions had the opposite effect. Under oxidative conditions in vitro and in vivo, Sirt1 was upregulated in NPCs, bound to the transcription factor Hes1 and subsequently inhibited pro-neuronal Mash1. In utero shRNA-mediated knockdown of Sirt1 in NPCs prevented oxidation-mediated suppression of neurogenesis and caused upregulation of Mash1 in vivo. Our results provide evidence for an as yet unknown metabolic master switch that determines the fate of neural progenitors.