Showing papers by "University of Erlangen-Nuremberg published in 2010"

Sarcopenia: European consensus on definition and diagnosis Report of the European Working Group on Sarcopenia in Older People

Abstract: The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics-European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document. The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity? For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as 'presarcopenia', 'sarcopenia' and 'severe sarcopenia'. EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research. Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.

Treating rheumatoid arthritis to target: recommendations of an international task force

Abstract: Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA).

The Virtual Family—development of surface-based anatomical models of two adults and two children for dosimetric simulations

Abstract: The objective of this study was to develop anatomically correct whole body human models of an adult male (34 years old), an adult female (26 years old) and two children (an 11-year-old girl and a six-year-old boy) for the optimized evaluation of electromagnetic exposure. These four models are referred to as the Virtual Family. They are based on high resolution magnetic resonance (MR) images of healthy volunteers. More than 80 different tissue types were distinguished during the segmentation. To improve the accuracy and the effectiveness of the segmentation, a novel semi-automated tool was used to analyze and segment the data. All tissues and organs were reconstructed as three-dimensional (3D) unstructured triangulated surface objects, yielding high precision images of individual features of the body. This greatly enhances the meshing flexibility and the accuracy with respect to thin tissue layers and small organs in comparison with the traditional voxel-based representation of anatomical models. Conformal computational techniques were also applied. The techniques and tools developed in this study can be used to more effectively develop future models and further improve the accuracy of the models for various applications. For research purposes, the four models are provided for free to the scientific community.

Halogen bonding: an electrostatically-driven highly directional noncovalent interaction

Abstract: A halogen bond is a highly directional, electrostatically-driven noncovalent interaction between a region of positive electrostatic potential on the outer side of the halogen X in a molecule R–X and a negative site B, such as a lone pair of a Lewis base or the π-electrons of an unsaturated system. The positive region on X corresponds to the electronically-depleted outer lobe of the half-filled p-type orbital of X that is involved in forming the covalent bond to R. This depletion is labeled a σ-hole. The resulting positive electrostatic potential is along the extension of the R–X bond, which accounts for the directionality of halogen bonding. Positive σ-holes can also be found on covalently-bonded Group IV–VI atoms, which can similarly interact electrostatically with negative sites. Since positive σ-holes often exist in conjunction with negative potentials on other portions of the atom's surface, such atoms can interact electrostatically with both nucleophiles and electrophiles, as has been observed in surveys of crystallographic structures. Experimental as well as computational studies indicate that halogen and other σ-hole interactions can be competitive with hydrogen bonding, which itself can be viewed as a subset of σ-hole bonding.

The Chicxulub Asteroid Impact and Mass Extinction at the Cretaceous-Paleogene Boundary

Abstract: The Cretaceous-Paleogene boundary similar to 65.5 million years ago marks one of the three largest mass extinctions in the past 500 million years. The extinction event coincided with a large asteroid impact at Chicxulub, Mexico, and occurred within the time of Deccan flood basalt volcanism in India. Here, we synthesize records of the global stratigraphy across this boundary to assess the proposed causes of the mass extinction. Notably, a single ejecta-rich deposit compositionally linked to the Chicxulub impact is globally distributed at the Cretaceous-Paleogene boundary. The temporal match between the ejecta layer and the onset of the extinctions and the agreement of ecological patterns in the fossil record with modeled environmental perturbations (for example, darkness and cooling) lead us to conclude that the Chicxulub impact triggered the mass extinction.

Hacking commercial quantum cryptography systems by tailored bright illumination

Abstract: By using bright pulses of light to ‘blind’ the avalanche photodiode detectors used in quantum cryptography equipment, scientists in Europe have shown that it is possible to tracelessly steal the secret encryption key generated by such systems and thus compromise their security.

A Genome-Wide Association Study Identifies New Psoriasis Susceptibility Loci and an Interaction Between HLA-C and ERAP1

Abstract: To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

Validation of proposed diagnostic criteria (the "budapest Criteria") for Complex Regional Pain Syndrome

Abstract: Current IASP diagnostic criteria for CRPS have low specificity, potentially leading to overdiagnosis. This validation study compared current IASP diagnostic criteria for CRPS to proposed new diagnostic criteria (the "Budapest Criteria") regarding diagnostic accuracy. Structured evaluations of CRPS-related signs and symptoms were conducted in 113 CRPS-I and 47 non-CRPS neuropathic pain patients. Discriminating between diagnostic groups based on presence of signs or symptoms meeting IASP criteria showed high diagnostic sensitivity (1.00), but poor specificity (0.41), replicating prior work. In comparison, the Budapest clinical criteria retained the exceptional sensitivity of the IASP criteria (0.99), but greatly improved upon the specificity (0.68). As designed, the Budapest research criteria resulted in the highest specificity (0.79), again replicating prior work. Analyses indicated that inclusion of four distinct CRPS components in the Budapest Criteria contributed to enhanced specificity. Overall, results corroborate the validity of the Budapest Criteria and suggest they improve upon existing IASP diagnostic criteria for CRPS.

The era of carbon allotropes

Abstract: Twenty-five years on from the discovery of C60, the outstanding properties and potential applications of the synthetic carbon allotropes — fullerenes, nanotubes and graphene — overwhelmingly illustrate their unique scientific and technological importance.

Bioactive Glass and Glass-Ceramic Scaffolds for Bone Tissue Engineering

Abstract: Traditionally, bioactive glasses have been used to fill and restore bone defects. More recently, this category of biomaterials has become an emerging research field for bone tissue engineering applications. Here, we review and discuss current knowledge on porous bone tissue engineering scaffolds on the basis of melt-derived bioactive silicate glass compositions and relevant composite structures. Starting with an excerpt on the history of bioactive glasses, as well as on fundamental requirements for bone tissue engineering scaffolds, a detailed overview on recent developments of bioactive glass and glass-ceramic scaffolds will be given, including a summary of common fabrication methods and a discussion on the microstructural-mechanical properties of scaffolds in relation to human bone (structure-property and structure-function relationship). In addition, ion release effects of bioactive glasses concerning osteogenic and angiogenic responses are addressed. Finally, areas of future research are highlighted in this review.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

Abstract: Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible.

Frequency of malnutrition in older adults:a multinational perspective using the Mini Nutritional Assessment

Abstract: OBJECTIVES: To provide pooled data on the prevalence of malnutrition in elderly people as evaluated using the Mini Nutritional Assessment (MNA). DESIGN: Retrospective pooled analysis of previously published datasets. SETTING: Hospital, rehabilitation, nursing home, community. PARTICIPANTS: Four thousand five hundred seven people (75.2% female) with a mean age of 82.3. MEASUREMENTS: The prevalence of malnutrition in the combined database and in the four settings was examined. RESULTS: Twenty-four data sets with information on full MNA classification from researchers from 12 countries were submitted. In the combined database, the prevalence of malnutrition was 22.8%, with considerable differences between the settings (rehabilitation, 50.5%; hospital, 38.7%; nursing home, 13.8%; community, 5.8%). In the combined database, the "at risk" group had a prevalence of 46.2%. Consequently, approximately two-thirds of study participants were at nutritional risk or malnourished. CONCLUSION: The MNA has gained worldwide acceptance and shows a high prevalence of malnutrition in different settings, except for the community. Because of its specific geriatric focus, the MNA should be recommended as the basis for nutritional evaluation in older people.

Interface materials for organic solar cells

Abstract: The progress in the development and understanding of interfacial materials for organic photovoltaics (OPV) is reviewed. The proper choice of interface materials is a must for highly efficient and stable OPV devices and has become a significant part of the OPV research today. Interface materials are either non-conducting, semiconducting or conducting layers which not only provide selective contacts for carriers of one sort, but can also determine the polarity of OPV devices, affect the open-circuit voltage, and act as optical spacers or protective layers. In this review both inorganic and organic interface materials are discussed with respect to their function in the OPV device.

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

Abstract: Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

The role of prenucleation clusters in surface-induced calcium phosphate crystallization

Abstract: Unravelling the processes of calcium phosphate formation is important in our understanding of both bone and tooth formation, and also of pathological mineralization, for example in cardiovascular disease. Serum is a metastable solution from which calcium phosphate precipitates in the presence of calcifiable templates such as collagen, elastin and cell debris. A pathological deficiency of inhibitors leads to the uncontrolled deposition of calcium phosphate. In bone and teeth the formation of apatite crystals is preceded by an amorphous calcium phosphate (ACP) precursor phase. ACP formation is thought to proceed through prenucleation clusters--stable clusters that are present in solution already before nucleation--as was recently demonstrated for CaCO(3) (refs 15,16). However, the role of such nanometre-sized clusters as building blocks for ACP has been debated for many years. Here we demonstrate that the surface-induced formation of apatite from simulated body fluid starts with the aggregation of prenucleation clusters leading to the nucleation of ACP before the development of oriented apatite crystals.

Electrophoretic deposition of biomaterials

Abstract: Electrophoretic deposition (EPD) is attracting increasing attention as an effective technique for the processing of biomaterials, specifically bioactive coatings and biomedical nanostructures. The well-known advantages of EPD for the production of a wide range of microstructures and nanostructures as well as unique and complex material combinations are being exploited, starting from well-dispersed suspensions of biomaterials in particulate form (microsized and nanoscale particles, nanotubes, nanoplatelets). EPD of biological entities such as enzymes, bacteria and cells is also being investigated. The review presents a comprehensive summary and discussion of relevant recent work on EPD describing the specific application of the technique in the processing of several biomaterials, focusing on (i) conventional bioactive (inorganic) coatings, e.g. hydroxyapatite or bioactive glass coatings on orthopaedic implants, and (ii) biomedical nanostructures, including biopolymer–ceramic nanocomposites, carbon nanotube coatings, tissue engineering scaffolds, deposition of proteins and other biological entities for sensors and advanced functional coatings. It is the intention to inform the reader on how EPD has become an important tool in advanced biomaterials processing, as a convenient alternative to conventional methods, and to present the potential of the technique to manipulate and control the deposition of a range of nanomaterials of interest in the biomedical and biotechnology fields.

Coronary computed tomography angiography with a consistent dose below 1 mSv using prospectively electrocardiogram-triggered high-pitch spiral acquisition

Abstract: Aims We evaluated the feasibility and image quality of a new scan mode for coronary computed tomography angiography (CTA) with an effective dose of less than 1 mSv. Methods and results In 50 consecutive patients (body weight ≤ 100 kg, sinus rhythm ≤60 b.p.m. after pre-medication, coronary CTA was performed using a dual-source CT system with 2 × 128 × 0.6 mm collimation, 0.28 s rotation time, a pitch of 3.2 or 3.4, 100 kV tube voltage and current of 320 mA s. Data acquisition was prospectively triggered at 60% of the R–R interval and completed within one cardiac cycle. Image quality was evaluated using a four-point scale (1 = absence of any artefacts to 4 = uninterpretable). In all 50 patients, imaging was successful. Mean duration of data acquisition was 258 ± 20 ms. Mean dose-length product was 62 ± 5 mGy cm, the effective dose was 0.87 ± 0.07 mSv (0.78–0.99 mSv). Of the 742 coronary artery segments, 94% had an image quality score of 1, 5.0% a score of 2, 0.9% a score of 3, and 4 segments (0.5%) were ‘uninterpretable’. Conclusion In non-obese patients with a low and stable heart rate, prospectively ECG-triggered high-pitch spiral coronary CTA provides excellent image quality at a consistent dose below 1.0 mSv.

TiO2 nanotubes and their application in dye-sensitized solar cells

Abstract: The present article reviews the current status of using TiO2 nanotubes in Gratzel-type, dye-sensitized solar cells and extends the overview with the latest results and findings. Critical factors in tube geometry (length, diameter, top morphology), crystal structure (amorphous, anatase, rutile) as well as factors affecting dye loading or electron mobility are addressed. The highest solar cell efficiencies today for pure nanotube systems reach approximately 4% while for some mixed systems, around 7% has been reported. For both systems significant room for enhancement is anticipated and some key points and strategies for improvement are outlined.

The role of defective clearance of apoptotic cells in systemic autoimmunity

Abstract: The accumulation of postapoptotic cell remnants resulting from inefficient phagocytic clearance might lead to the initiation and maintenance of systemic autoimmune reactions and chronic inflammation—hallmarks of systemic lupus erythematosus (SLE). The consequences of apoptotic cell accumulation for the etiology, pathogenesis and pathophysiology of SLE are summarized in this Review. The inefficient clearance of dying cells can result in the accumulation of apoptotic cell remnants. This occurrence is considered an intrinsic defect that can cause the permanent presence of cellular debris responsible for the initiation of systemic autoimmunity in diseases such as systemic lupus erythematosus (SLE). If postapoptotic debris accumulates in germinal centers, activates complement and functions as a survival signal for B cells that have become autoreactive by somatic hypermutation, autoimmunity could arise (etiology). The accumulation of postapoptotic remnants and fragments derived from secondary necrotic cells in the presence of autoantibodies against apoptotic cells or adaptor molecules obliges their pathological elimination and maintains autoinflammation. The autoimmunity that occurs in patients with SLE involves complex antigens that contain nucleic acids, which can function as virus mimetics. Complexes of autoantibodies, proteins and nucleic acids are likely to be mistaken by the immune system for opsonized viruses, resulting in the production of type I interferons, a hallmark of SLE (pathogenesis). The pathogenicity of autoantibodies is thought to strongly increase if autoantigens are accessible for immune-complex formation. The immune complex could be considered a binary pyrogen formed from less proinflammatory components. The accessibility of cognate autoantigens, in turn, is likely to be related to impaired or delayed clearance of apoptotic cells.

The INTERSPEECH 2010 Paralinguistic Challenge

Abstract: Most paralinguistic analysis tasks are lacking agreed-uponevaluation procedures and comparability, in contrast to more‘traditional’ disciplines in speech analysis. The INTERSPEECH2010 Paralinguistic Challenge shall help overcome the usuallylow compatibility of results, by addressing three selected sub-challenges. In the Age Sub-Challenge, the age of speakers hasto be determined in four groups. In the Gender Sub-Challenge,a three-class classification task has to be solved and finally, theAffect Sub-Challenge asks for speakers’ interest in ordinal rep-resentation. This paper introduces the conditions, the Challengecorpora “aGender” and “TUM AVIC” and standard feature setsthat may be used. Further, baseline results are given.Index Terms: Paralinguistic Challenge, Age, Gender, Affect 1. Introduction Most paralinguistic analysis tasks resemble each other not onlyby means of processing and ever-present data sparseness, but bylacking agreed-upon evaluation procedures and comparability,in contrast to more traditional disciplines in speech analysis. Atthe same time, this is a rapidly emerging field of research, dueto the constantly growing interest on applications in the fieldsof Human-Machine Communication, Human-Robot Communi-cation, and Multimedia Retrieval. In these respects, the INTER-SPEECH 2010 Paralinguistic Challenge shall help bridging thegap between excellent research on paralinguistic information inspoken language and low compatibility of results, by address-ing three selected tasks. The “aGender” and the “TUM AVIC”corpora are provided by the organizers. The first consists of 46hours of telephone speech, stemming from 954 speakers, andserves to evaluate features and algorithms for the detection ofspeaker age and gender. The second features 2 hours of humanconversational speech recording (21 subjects), annotated in 5differentlevelsofinterest. Thecorpusfurtherfeaturesauniquelydetailed transcription of spoken content with word boundaries byforced alignment, non-linguistic vocalizations, single annotatortracks, and the sequence of (sub-)speaker-turns. Both are given

Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer.

Abstract: Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. Two teams working independently have now found a mechanistic basis for this association. Schramek et al. show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing the osteoclast differentiation factor RANKL, which acts on mammary epithelial cells through the RANKL receptor RANK. Gonzalez-Suarez et al. find that inhibition of RANKL reduces tumorigenesis in hormone-induced as well as in other mouse mammary gland tumour models, suggesting a new therapeutic approach. One RANKL inhibitor (denosumab) is in clinical trials as a treatment for bone loss in post-menopausal osteoporosis and for the treatment of skeletal-related symptoms in metastatic bone disease. Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. These authors provide a mechanistic basis for this association. They show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing RANKL (receptor activator of NF-KB ligand), which acts on mammary epithelial cells through the RANKL receptor RANK. Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe1. The Women’s Health Initiative and the Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer2,3. In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-κB ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49fhi stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.

Normalized metal artifact reduction (NMAR) in computed tomography

Abstract: Purpose: While modern clinical CT scanners under normal circumstances produce high quality images, severe artifacts degrade the image quality and the diagnostic value if metal prostheses or other metal objects are present in the field of measurement. Standard methods for metal artifact reduction (MAR) replace those parts of the projection data that are affected by metal (the so-called metal trace or metal shadow) by interpolation. However, while sinogram interpolation methods efficiently remove metal artifacts, new artifacts are often introduced, as interpolation cannot completely recover the information from the metal trace. The purpose of this work is to introduce a generalized normalization technique for MAR, allowing for efficient reduction of metal artifacts while adding almost no new ones. The method presented is compared to a standard MAR method, as well as MAR using simple length normalization. Methods: In the first step, metal is segmented in the image domain by thresholding. A 3D forward projection identifies the metal trace in the original projections. Before interpolation, the projections are normalized based on a 3D forward projection of a prior image. This prior image is obtained, for example, by a multithreshold segmentation of the initial image. The original rawdata are divided by the projection data of the prior image and, after interpolation, denormalized again. Simulations and measurements are performed to compare normalized metal artifact reduction (NMAR) to standard MAR with linear interpolation and MAR based on simple length normalization. Results: Promising results for clinical spiral cone-beam data are presented in this work. Included are patients with hip prostheses, dental fillings, and spine fixation, which were scanned at pitch values ranging from 0.9 to 3.2. Image quality is improved considerably, particularly for metal implants within bone structures or in their proximity. The improvements are evaluated by comparing profiles through images and sinograms for the different methods and by inspecting ROIs. NMAR outperforms both other methods in all cases. It reduces metal artifacts to a minimum, even close to metal regions. Even for patients with dental fillings, which cause most severe artifacts, satisfactory results are obtained with NMAR. In contrast to other methods, NMAR prevents the usual blurring of structures close to metal implants if the metal artifacts are moderate. Conclusions: NMAR clearly outperforms the other methods for both moderate and severe artifacts. The proposed method reliably reduces metal artifacts from simulated as well as from clinical CT data. Computationally efficient and inexpensive compared to iterative methods, NMAR can be used as an additional step in any conventional sinogram inpainting-based MAR method.

MicroRNA-29, a key regulator of collagen expression in systemic sclerosis.

Abstract: Objective To investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc). Methods MicroRNA, which target collagens, were identified by in silico analysis. Expression of miRNA-29 (miR-29) was determined by TaqMan real-time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycin-induced skin fibrosis. Cells were transfected with precursor miRNA (pre-miRNA)/anti-miRNA of miR-29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor beta (TGFbeta), platelet-derived growth factor B (PDGF-B), or interleukin-4 (IL-4) was used. The effects of inhibiting PDGF-B and TGFbeta signaling on the levels of miR-29 were studied in vitro and in the bleomycin model. Results We found that miR-29a was strongly down-regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre-miR-29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR-29a. TGFbeta, PDGF-B, or IL-4 reduced the levels of miR-29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR-29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF-B and TGFbeta pathways by treatment with imatinib restored the levels of miR-29a in vitro and in the bleomycin model in vivo. Conclusion These data add the posttranscriptional regulation of collagens by miR-29a as a novel aspect to the fibrogenesis of SSc and suggest miR-29a as a potential therapeutic target.

COSMO-RS: An Alternative to Simulation for Calculating Thermodynamic Properties of Liquid Mixtures

Abstract: The conductor-like screening model for realistic solvation (COSMO-RS) method has been established as a novel way to predict thermophysical data for liquid systems and has become a frequently used alternative to force field-based molecular simulation methods on one side and group contribution methods on the other. Through its unique combination of a quantum chemical treatment of solutes and solvents with an efficient statistical thermodynamics procedure for the molecular surface interactions, it enables the efficient calculation of many properties that other methods can barely predict. This review presents a short delineation of the theory, the application potential and limitations of COSMO-RS, and its most important application areas.

Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.

Abstract: N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.