A Review of Human Carcinogens--Part E: Tobacco, Areca Nut, Alcohol, Coal Smoke, and Salted Fish

The Lancet Oncology. Nov, 2009  |  Pubmed ID: 19891056

A Review of Human Carcinogens--Part F: Chemical Agents and Related Occupations

The Lancet Oncology. Dec, 2009  |  Pubmed ID: 19998521

Ethylglucuronide As a Potential Marker for Alcohol-induced Elevation of Urinary Testosterone/epitestosterone Ratios

Drug Testing and Analysis. Nov, 2009  |  Pubmed ID: 20355168

The potential influence of alcohol consumption on endogenous steroids has already been described in the literature. In those studies the ethanol level after ingestion was monitored using its concentration in blood, urine or saliva. Corresponding methods are not commonly used in anti-doping laboratories. Ethylglucuronide (EtG), which can be easily detected by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), appears to be a more suitable parameter for this purpose. It is slowly excreted into the urine and indicates alcohol intake for a much longer period than blood or urinary alcohol and it is therefore routinely used for legal purposes as an alcohol consumption marker. In pharmacokinetic studies that aimed to establish calculation models after ethanol intake, the formation of EtG was observed to coincide with elevated urinary testosterone/epitestosterone (T/E) ratios. Similarly, large amounts of EtG were correlated with abnormal steroid profiles found in routine doping samples. In this pilot study, several cases with significantly elevated T/E ratios were associated with urinary EtG concentrations higher than 50 microg/mL. These findings confirmed recent intake of ethanol in considerable amounts and suggest a connection to changes in specific steroid profile parameters. Owing to the ease with which procedures to determine EtG can be carried out, and the potential for such procedures to be introduced into screening schemes, the inclusion of this marker in the final evaluation of suspicious outliers in T/E ratio longitudinal studies would seem to be very useful.

WNT5a in Tongue and Fungiform Papilla Development

Annals of the New York Academy of Sciences. Jul, 2009  |  Pubmed ID: 19686099

Fungiform papillae are complex taste organs that develop in a pattern on anterior tongue in rodent embryos. Several intrinsic secreted molecules are important for papilla development and patterning, including sonic hedgehog, bone morphogenetic proteins, Noggin, epidermal growth factor, and WNTs. Recent data about roles of WNTs in regulation of tongue and fungiform papilla development lead to new insights about the importance of tissue and timing contexts when studying the effects of morphogenetic proteins. WNT/beta-catenin signaling is required for formation of fungiform papillae, but not for determining tongue size and shape. In contrast, WNT5a apparently is important for tongue outgrowth, but not papilla development. Preliminary data from WNT5a mutant mice separate genetic programs for papilla number from those for tongue shape and size.

Evidence and Evolutionary Analysis of Ancient Whole-genome Duplication in Barley Predating the Divergence from Rice

BMC Evolutionary Biology. 2009  |  Pubmed ID: 19698139

Well preserved genomic colinearity among agronomically important grass species such as rice, maize, Sorghum, wheat and barley provides access to whole-genome structure information even in species lacking a reference genome sequence. We investigated footprints of whole-genome duplication (WGD) in barley that shaped the cereal ancestor genome by analyzing shared synteny with rice using a approximately 2000 gene-based barley genetic map and the rice genome reference sequence.

The Prolyl Cis/trans Isomerase Cyclophilin 18 Interacts with the Tumor Suppressor P53 and Modifies Its Functions in Cell Cycle Regulation and Apoptosis

Oncogene. Nov, 2009  |  Pubmed ID: 19718045

The functional diversity of the tumor suppressor protein p53 is mainly regulated by protein interactions. In this study, we describe a new interaction with the peptidyl-prolyl cis/trans isomerase cyclophilin 18 (Cyp18). The interaction reduced the sequence-specific DNA binding of p53 in vitro, whereas the inhibition of the interaction increased p53-reporter gene activity in vivo. The active site of the folding helper enzyme Cyp18 was directly involved in binding. The proline-rich region (amino acids 64-91) of p53 was most likely responsible for the observed binding because a synthetic peptide comprising amino acids 68-81 of p53 inhibited this interaction, and a p53 variant containing a proline residue at position 72 (p53(P72)) interacted with Cyp18 more effectively than the corresponding p53(R72) variant. Impairment of the Cyp18-p53 interaction induced an accumulation of cells in the G2/M phase of the cell cycle, which was more pronounced when p53(P72) was expressed compared with p53(R72) in an otherwise isogenic cellular background. Moreover, p53-dependent apoptosis was elevated in Cyp18 knockout cells, suggesting an antiapoptotic potential of Cyp18-p53 complexes. Functional in vivo data hint to a possible clinical relevance of the p53-Cyp18 interaction observed.

[How to Prepare a Patient for Upcoming Surgery]

MMW Fortschritte Der Medizin. May, 2009  |  Pubmed ID: 19728665

Congenital Lung Malformation: Evaluation of Prenatal and Postnatal Radiological Findings

Respirology (Carlton, Vic.). Sep, 2009  |  Pubmed ID: 19740261

Background and objective: This study evaluated the accuracy of prenatal MRI and postnatal CT imaging in the identification of congenital cystic adenomatoid malformation and bronchopulmonary sequestration by comparison with histological analysis. Methods: Over a 3-year period, 15 patients with lung malformations diagnosed prenatally by ultrasound were referred for prenatal MRI, and all were investigated postnatally by chest CT. All asymptomatic newborns with unresolved lesions underwent elective surgery by thoracoscopy. All surgical specimens were analysed histologically. Results: Among the 15 patients with an abnormality diagnosed by ultrasound, prenatal MRI findings differed from the final histological diagnosis with respect to extent (n = 3), type of lesion (n = 1) and aberrant vessel identification (n = 4). Postnatal chest CT failed to visualize the aberrant vessel in one patient. Complete regression of the lesion was noted in two patients with bronchopulmonary sequestration, and in one patient with congenital cystic adenomatoid malformation and was confirmed by CT. Elective thoracoscopic lobectomy of the affected lobe was performed for 12 patients. Two conversions to thoracotomy were required. All operated patients had an uneventful hospital course. Conclusions: Prenatal MRI is less accurate than postnatal CT scan, which remains the most reliable diagnostic modality to specify the location and extent and kind of lesions.

[Evaluation of a Multimodal Pain Therapy at the University Pain Centre Dresden]

Schmerz (Berlin, Germany). Dec, 2009  |  Pubmed ID: 19756770

Data of a multimodal pain management program of the multidisciplinary pain management centre at the University Hospital of Dresden is presented. Over a period of 4 weeks, supplemented by an additional week 3 months later (booster week), patients with chronic pain of different origins are being treated in groups of 12. Based on the principles of the biopsychosocial pain model and the idea of functional restoration, the program is dedicated for pain patients where outpatient treatment was insufficient.

Healthcare Expenditures for Privately Insured People with Cystic Fibrosis

Pediatric Pulmonology. Oct, 2009  |  Pubmed ID: 19768806

With improved survival and new therapies for people with cystic fibrosis (CF), updated information on medical care expenditures for those individuals is needed. We estimated medical care expenditures, including both insurance reimbursements and patient out-of-pocket expenses, for privately insured people with CF and investigated how those expenditures varied with certain complications of CF. From a private insurance claims database of people covered by health plans associated with large corporate employers, we identified people with CF who were currently receiving medical care for the disorder and characterized their medical expenditures during the period 2004-2006. We selected a matching group of people who did not have CF based on age, sex, and geographic area, and calculated incremental expenditures associated with CF. We also examined the effect of age and certain complications of CF on these expenditures. The annual medical care expenditure for a person with actively managed CF averaged $48,098 in 2006 dollars, which was 22 times higher than for a person without CF. This ratio is high relative to other chronic disorders. Outpatient prescription medications made up the largest component of total expenditures for people with CF (39%). Those who were recorded in claims data as having a liver or lung transplant, malnutrition, diabetes, or a chronic Pseudomonas aeruginosa pulmonary infection incurred much higher expenditures than people without these conditions. People with CF will incur high medical expenditures throughout their lifespan. These findings will assist in the development of economic evaluations of future CF screening and management initiatives.

Newborn Screening for Congenital Cytomegalovirus: Options for Hospital-based and Public Health Programs

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Dec, 2009  |  Pubmed ID: 19783205

Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) and developmental disability in children. Early identification of infected children through screening could allow for early intervention and improvement in functional outcomes among the subset who develop sequelae.

Oligonuclear Homoleptic Copper(I) Pyrazolates with Multinucleating Ligand Scaffolds: High Structural Diversity in Solid-state and Solution

Inorganic Chemistry. Nov, 2009  |  Pubmed ID: 19803532

The synthesis of three pyrazole-based, potentially binucleating ligands 3,5-bis(R(1)N(CH(3))CH(2))-4-R(2)pyrazole (L(1)H: R(1) = pyridyl-2-methyl-, R(2) = Ph; L(2)H: R(1) = 8-quinolyl-, R(2) = H; L(3)H: R(1) = 8-quinolyl-, R(2) = Ph) is described. Reaction of L(1-3)H with 1 equiv. of mesitylcopper affords oligonuclear homoleptic complexes of the type [CuL](n) (1-3). The single crystal X-ray structure of 2 shows a tetranuclear assembly of linear coordinated copper(I)-centers bridged by pyrazolato ligands that alternate above and below the Cu(4) plane, with additional weak interactions from some of the ligand side arms. As the single crystal X-ray structure of 3 reveals, phenyl substitution at the 4-position of the pyrazolato framework leads to significant structural modification of the Cu(4) array, giving a rhombical tetranuclear complex with two linear coordinated copper(I) centers that exhibit a short intramolecular Cu...Cu contact (2.8212(10) A) and two peripheral copper(I) centers in a distorted tetrahedral coordination mode. Thus, 3 represents a very rare example of an inorganic pyrazolato cuprate which can also be viewed as a partly rearranged structural isomer of 2. Furthermore, the crystal lattice of 3 shows an extended network of intra- and intermolecular pi-pi stacking interactions between the aromatic rings. In solution, 1-3 each form two types of oligomers a and b that slowly (<1 s(-1)) equilibrate at room temperature. Using Diffusion Ordered Spectroscopy (DOSY) and variable temperature (1)H NMR spectroscopy it can be shown that a and b correspond to a tetrameric and a (planar) trimeric species. Coordination of the pyridyl/quinolyl side arms that is observed in the solid state seems to be only transient in solution.

Mechanisms of Gold Biomineralization in the Bacterium Cupriavidus Metallidurans

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2009  |  Pubmed ID: 19815503

While the role of microorganisms as main drivers of metal mobility and mineral formation under Earth surface conditions is now widely accepted, the formation of secondary gold (Au) is commonly attributed to abiotic processes. Here we report that the biomineralization of Au nanoparticles in the metallophillic bacterium Cupriavidus metallidurans CH34 is the result of Au-regulated gene expression leading to the energy-dependent reductive precipitation of toxic Au(III)-complexes. C. metallidurans, which forms biofilms on Au grains, rapidly accumulates Au(III)-complexes from solution. Bulk and microbeam synchrotron X-ray analyses revealed that cellular Au accumulation is coupled to the formation of Au(I)-S complexes. This process promotes Au toxicity and C. metallidurans reacts by inducing oxidative stress and metal resistances gene clusters (including a Au-specific operon) to promote cellular defense. As a result, Au detoxification is mediated by a combination of efflux, reduction, and possibly methylation of Au-complexes, leading to the formation of Au(I)-C-compounds and nanoparticulate Au(0). Similar particles were observed in bacterial biofilms on Au grains, suggesting that bacteria actively contribute to the formation of Au grains in surface environments. The recognition of specific genetic responses to Au opens the way for the development of bioexploration and bioprocessing tools.

Hospital Use and Associated Costs of Children Aged Zero-to-two Years with Craniofacial Malformations in Massachusetts

Birth Defects Research. Part A, Clinical and Molecular Teratology. Nov, 2009  |  Pubmed ID: 19830851

Craniofacial malformations (CFMs) are among the most common and correctable birth defects in the United States, often requiring multiple medical and surgical treatments. However, population-based data on hospital utilization and costs are sparse.

Interdisciplinary Expert Consultation Via a Teleradiology Platform--influence on Therapeutic Decision-making and Patient Referral Rates to an Academic Tertiary Care Center

RöFo : Fortschritte Auf Dem Gebiete Der Röntgenstrahlen Und Der Nuklearmedizin. Dec, 2009  |  Pubmed ID: 19859862

In addition to teleradiological reporting as a nighthawking or a regular service, teleradiological communication can be used for interdisciplinary expert consultation. We intended to evaluate an interdisciplinary consultation system based on a teleradiology platform with regard to its impact on therapeutic decision-making, directed patient referrals to an academic tertiary care center and the economic benefit for the hospital providing the service. Therefore, consultations from five secondary care centers and consecutive admissions to an academic tertiary care center were prospectively evaluated over a time period of six months. A total of 69 interdisciplinary expert consultations were performed. In 54 % of the cases the patients were consecutively referred to the university hospital for further treatment. In all acutely life-threatening emergencies (n = 9), fast and focused treatment by referral to the academic tertiary care center was achieved (average time to treat 130 min). The admissions to the academic tertiary care center led to improved utilization of its facilities with additional revenue of more than 1,000000 euro p. a. An interdisciplinary expert consultation via a teleradiology platform enables fast and efficient expert care with improved and accelerated patient management and improved utilization of the service providing hospital.

Clinical Evaluation of the New BMU 40 In-line Blood Analysis Monitor

Perfusion. Jul, 2009  |  Pubmed ID: 19880664

Accurate information about different blood parameters is essential in maintaining haemodynamics, perfusion and gas exchange during cardiopulmonary bypass (CPB). For this purpose, precise, accurate and continuous measurement and monitoring, preferably visually available, is needed.The objective of this clinical study was to compare the newly developed continuous in-line blood parameter monitoring system (CIBPMS) BMU 40 with a reference laboratory analyser with regards to the precision and accuracy of blood parameter measurement.

Left Superior Vena Cava Conduction to the Left Atrium Unmasked by Adenosine in a Patient with Paroxysmal Atrial Fibrillation During Pulmonary Vein Isolation

Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. Jan, 2010  |  Pubmed ID: 19880849

The use of adenosine in unmasking potential 'trigger' activity in a patient with paroxysmal atrial fibrillation (AF) and persistent left superior vena cava (LSVC) has never been reported. In a 75-year-old woman with paroxysmal AF and LSVC anomaly, pulmonary vein isolation (PVI) procedure was performed. After successful PVI, repeated bolus adenosine infusions were given. Adenosine response originating from the LSVC was observed: it was reproducible, brief, and exhibited decremental atrial-to-LSVC conduction properties until cessation. Pacing from the LSVC resulted in atrial capture (confirming vein-to-atrium conduction). Disconnection of the LSVC from the coronary sinus (CS) was obtained by successfully ablating within the distal CS. Adenosine challenge may be important to identify AF triggers in non-PVI foci.

Distribution of Cardiac Iron Measured by Magnetic Resonance Imaging (MRI)-R*2

Journal of Magnetic Resonance Imaging : JMRI. Nov, 2010  |  Pubmed ID: 21031515

To assess regional iron distribution by magnetic resonance imaging (MRI)-R(2)* within the heart of patients with β-thalassemia major (TM) and other iron overload diseases.

Attention-deficit/hyperactivity Disorder, Conduct Disorder, and Young Adult Intimate Partner Violence

Archives of General Psychiatry. Nov, 2010  |  Pubmed ID: 21041619

Studies based on clinical samples suggest a connection between childhood attention-deficit/hyperactivity disorder (ADHD) and later intimate partner violence (IPV) perpetration.

[Guidelines for Diagnosis and Treatment of Secondary Iron Overload in Patients with Congenital Anemia]

Klinische Pädiatrie. Nov, 2010  |  Pubmed ID: 20862634

In Germany and Central Europe, congenital disorders leading to secondary hemochromatosis are rare. The majority of these patients are treated in peripheral medical institutions. As a consequence, the experience of each institution in the treatment of secondary hemochromatosis in patients with congenital anemia is limited. Recent developments concerning new chelating agents, their combination for intensified chelation and new possibilities to diagnose and monitor iron overload have important consequences for the management of patients with secondary hemochromatosis and increase its complexity enormously. Therefore, the development of a guideline for rational and efficient diagnostics and treatment was necessary. The new guideline was developed within a formal consensus process and finally approved by a consensus conference with participants from both the pediatric and adult German hematology societies (GPOH and DGHO). Apart from general information and recommendations, the guideline contains 9 consensus statements on diagnostics (iron status, siderotic complications, chelator side-effects), the start of chelation, indications for intensified chelation, iron elimination in specific disorders, and iron elimination after stem cell transplantation. Here, these consensus statements are presented and discussed in detail. For the complete text of the guideline, please visit the AWMF homepage at http://www.leitlinien.net .

Infants Communicate in Order to Be Understood

Developmental Psychology. Nov, 2010  |  Pubmed ID: 20873924

Infants intentionally communicate with others from before their 1st birthday. But there is some question about how they understand the communicative process. Do they understand that for their request to work the recipient must both understand the request and be cooperatively disposed to fulfill it? On the basis of the study by Shwe and Markman (1997), we developed a new paradigm that tested whether and how 18-, 24-, and 30-month-old children repair a failed request. Children at all ages repaired their requests in the case of a misunderstanding even if they had obtained the requested object already. They also repaired differently depending on the precise reason for the communicative failure (e.g., misunderstanding the referent versus the communicative intent) and did not repair in the case of correct understanding, even if they did not get the requested object. Thus, from very early in their communicative careers, young children operate with a basic understanding of the mental and cooperative nature of human communication.

Structural Characterization of a Beta-turn Mimic Within a Protein-protein Interface

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2010  |  Pubmed ID: 20937907

β-Turns are secondary structure elements not only exposed on protein surfaces, but also frequently found to be buried in protein-protein interfaces. Protein engineering so far considered mainly the backbone-constraining properties of synthetic β-turn mimics as parts of surface-exposed loops. A β-turn mimic, Hot═Tap, that is available in gram amounts, provides two hydroxyl groups that enhance its turn-inducing properties besides being able to form side-chain-like interactions. NMR studies on cyclic hexapeptides harboring the Hot═Tap dipeptide proved its strong β-turn-inducing capability. Crystallographic analyses of the trimeric fibritin-foldon/Hot═Tap hybrid reveal at atomic resolution how Hot═Tap replaces a βI'-turn by a βII'-type structure. Furthermore, Hot═Tap adapts to the complex protein environment by participating in several direct and water-bridged interactions across the foldon trimer interface. As building blocks, β-turn mimics capable of both backbone and side-chain mimicry may simplify the design of synthetic proteins.

Prevalence of Venous Thromboembolism Among Privately Insured US Adults

Archives of Internal Medicine. Oct, 2010  |  Pubmed ID: 20975028

Regulation of Endobiotics Glucuronidation by Ligand-activated Transcription Factors: Physiological Function and Therapeutic Potential

Drug Metabolism Reviews. Feb, 2010  |  Pubmed ID: 19831728

Recent progresses in molecular pharmacology approaches have allowed the identification and characterization of a series of nuclear receptors (NR) which efficiently control the level UDP-glucuronosyltransferase (UGT) genes expression. These regulatory processes ensure optimized UGT expression in response to specific endogenous and/or exogenous stimuli. Interestingly, numerous endogenous activators of these NRs are conjugated by the UGT enzymes they regulate. In such a case, the NR-dependent regulation of UGT genes corresponds to a feedforward/feedback mechanism by which a bioactive molecule controls its own concentrations. In the present review, we will discuss i) how bilirubin reduces its circulating levels by activating AhR in the liver; ii) how bile acids modulate their hepatic glucuronidation via PXR- and FXR-dependent processes in enterohepatic tissues; and iii) how androgens inhibit their cellular metabolism in prostate cancer cells through an AR-dependent mechanism. Subsequently, with further discussion of the same examples (bilirubin and bile acids), we will illustrate how NR-dependent regulation of UGT enzymes may contribute to the beneficial effects of pharmacological activators of nuclear receptors, such as CAR and PPARa.

MiRGen 2.0: a Database of MicroRNA Genomic Information and Regulation

Nucleic Acids Research. Jan, 2010  |  Pubmed ID: 19850714

MicroRNAs are small, non-protein coding RNA molecules known to regulate the expression of genes by binding to the 3'UTR region of mRNAs. MicroRNAs are produced from longer transcripts which can code for more than one mature miRNAs. miRGen 2.0 is a database that aims to provide comprehensive information about the position of human and mouse microRNA coding transcripts and their regulation by transcription factors, including a unique compilation of both predicted and experimentally supported data. Expression profiles of microRNAs in several tissues and cell lines, single nucleotide polymorphism locations, microRNA target prediction on protein coding genes and mapping of miRNA targets of co-regulated miRNAs on biological pathways are also integrated into the database and user interface. The miRGen database will be continuously maintained and freely available at http://www.microrna.gr/mirgen/.

S3 Guidelines for Intensive Care in Cardiac Surgery Patients: Hemodynamic Monitoring and Cardiocirculary System

German Medical Science : GMS E-journal. 2010  |  Pubmed ID: 20577643

Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment. Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography. The German Society for Thoracic and Cardiovascular Surgery (Deutsche Gesellschaft für Thorax-, Herz- und Gefässchirurgie, DGTHG) and the German Society for Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin, DGAI) made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines. Goal of this guideline is to assess the available monitoring methods with regard to indication, procedures, predication, limits, contraindications and risks for use. The differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilatators, inodilatators and calcium sensitizers and the use of intra-aortic balloon pumps will also be addressed. The guideline has been developed following the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF).

SnapShot: Formins

Cell. Jul, 2010  |  Pubmed ID: 20603022

Natural Variation of Transcriptional Auxin Response Networks in Arabidopsis Thaliana

The Plant Cell. Jul, 2010  |  Pubmed ID: 20622145

Natural variation has been observed for various traits in Arabidopsis thaliana. Here, we investigated natural variation in the context of physiological and transcriptional responses to the phytohormone auxin, a key regulator of plant development. A survey of the general extent of natural variation to auxin stimuli revealed significant physiological variation among 20 genetically diverse natural accessions. Moreover, we observed dramatic variation on the global transcriptome level after induction of auxin responses in seven accessions. Although we detect isolated cases of major-effect polymorphisms, sequencing of signaling genes revealed sequence conservation, making selective pressures that favor functionally different protein variants among accessions unlikely. However, coexpression analyses of a priori defined auxin signaling networks identified variations in the transcriptional equilibrium of signaling components. In agreement with this, cluster analyses of genome-wide expression profiles followed by analyses of a posteriori defined gene networks revealed accession-specific auxin responses. We hypothesize that quantitative distortions in the ratios of interacting signaling components contribute to the detected transcriptional variation, resulting in physiological variation of auxin responses among accessions.

The Global Impact of Sutures Assessed in a Finite Element Model of a Macaque Cranium

Anatomical Record (Hoboken, N.J. : 2007). Sep, 2010  |  Pubmed ID: 20652940

The biomechanical significance of cranial sutures in primates is an open question because their global impact is unclear, and their material properties are difficult to measure. In this study, eight suture-bone functional units representing eight facial sutures were created in a finite element model of a monkey cranium. All the sutures were assumed to have identical isotropic linear elastic material behavior that varied in different modeling experiments, representing either fused or unfused sutures. The values of elastic moduli employed in these trials ranged over several orders of magnitude. Each model was evaluated under incisor, premolar, and molar biting conditions. Results demonstrate that skulls with unfused sutures permitted more deformations and experienced higher total strain energy. However, strain patterns remained relatively unaffected away from the suture sites, and bite reaction force was likewise barely affected. These findings suggest that suture elasticity does not substantially alter load paths through the macaque skull or its underlying rigid body kinematics. An implication is that, for the purposes of finite element analysis, omitting or fusing sutures is a reasonable modeling approximation for skulls with small suture volume fraction if the research objective is to observe general patterns of craniofacial biomechanics under static loading conditions. The manner in which suture morphology and ossification affect the mechanical integrity of skulls and their ontogeny and evolution awaits further investigation, and their viscoelastic properties call for dynamic simulations.

Two Distinct Mechanisms Regulate Recruitment of Murine Leukemia Virus Envelope Protein to Retroviral Assembly Sites

Virology. Sep, 2010  |  Pubmed ID: 20655565

The cytoplasmic tail domain (CTD) of retroviral envelope (Env) proteins has been implicated in modulating Env incorporation into viral particles. We generated a panel of murine leukemia virus (MLV) Env mutants and analyzed their ability to be recruited to human immunodeficiency virus-1 (HIV-1) assembly sites. Surprisingly, the entire CTD was dispensable for recruitment to assembly sites, but a mutation that disrupted the furin cleavage site in Env abolished recruitment. To determine if MLV Env can show selectivity for homologous assembly sites, cells were co-transfected with both HIV-1 and MLV assembly components along with each MLV Env construct and assayed for infectious particle production. MLV Env selectively formed infectious particles with the MLV components at the expense of infectious HIV-1 infectious particle production, but truncation of the CTD progressively reduced this selectivity. Collectively these data suggest that there are two separable mechanisms that govern MLV Env recruitment to viral assembly sites.

Human DHX9 Helicase Unwinds Triple-helical DNA Structures

Biochemistry. Aug, 2010  |  Pubmed ID: 20669935

Naturally occurring poly(purine.pyrimidine) rich regions in the human genome are prone to adopting non-canonical DNA structures such as intramolecular triplexes (i.e., H-DNA). Such structure-forming sequences are abundant and can regulate the expression of several disease-linked genes. In addition, the use of triplex-forming oligonucleotides (TFOs) to modulate gene structure and function has potential as an approach to targeted gene therapy. Previously, we found that endogenous H-DNA structures can induce DNA double-strand breaks and promote genomic rearrangements. Herein, we find that the DHX9 helicase co-immunoprecipitates with triplex DNA structures in mammalian cells, suggesting a role in the maintenance of genome stability. We tested this postulate by assessing the helicase activity of purified human DHX9 on various duplex and triplex DNA substrates in vitro. DHX9 displaced the third strand from a specific triplex DNA structure and catalyzed the unwinding with a 3' --> 5' polarity with respect to the displaced third strand. Helicase activity required a 3'-single-stranded overhang on the third strand and was dependent on ATP hydrolysis. The reaction kinetics consisted of a pre-steady-state burst phase followed by a linear, steady-state pseudo-zero-order reaction. In contrast, very little if any helicase activity was detected on blunt triplexes, triplexes with 5'-overhangs, blunt duplexes, duplexes with overhangs, or forked duplex substrates. Thus, triplex structures containing a 3'-overhang represent preferred substrates for DHX9, where it removes the strand with Hoogsteen hydrogen-bonded bases. Our results suggest the involvement of DHX9 in maintaining genome integrity by unwinding mutagenic triplex DNA structures.

Efficient Directional Coupling Between Silicon and Copper Plasmonic Nanoslot Waveguides: Toward Metal-oxide-silicon Nanophotonics

Nano Letters. Aug, 2010  |  Pubmed ID: 20698605

Coupling plasmonics and silicon photonics is the best way to bridge the size gap between macroscopic optics and nanodevices in general and especially nanoelectronic devices. We report on the realization of key blocks for future plasmonic planar integrated optics, nano-optical couplers, and nanoslot waveguides that are compatible both with the silicon photonics and the CMOS microelectronics. Copper-based devices provide for very efficient optical coupling, unexpectedly low propagation losses and a broadband sub-50 nm optical confinement. The fabrication in a standard frontline microelectronic facilities hints broad possibilities of hybrid opto-electronic very large scale integration.

[The Example of Cystic Fibrosis to Highlight the Complexity of Genetic Screening]

Revue Médicale Suisse. Jul, 2010  |  Pubmed ID: 20701015

Various institutions and countries often reach different conclusions about the utility of introducing a newborn screening test in the general population. This paper highlights the complexity of population screening including genetic tests. Using the example of cystic fibrosis genetic screening, for which a Swiss Working Group for Cystic Fibrosis is currently evaluating the pertinence, we outline that screening recommendations are often based more on expert opinion and emerging new technologies rather than on evidence. We also present some ethical and economic issues related to cystic fibrosis genetic screening.

Autaptic Cultures of Single Hippocampal Granule Cells of Mice and Rats

The European Journal of Neuroscience. Sep, 2010  |  Pubmed ID: 20726880

When a single neuron is grown on a small island of glial cells, the neuron forms synapses onto itself. The so-called autaptic culture systems have proven extremely valuable in elucidating basic mechanisms of synaptic transmission, as they allow application of technical approaches that cannot be used in slice preparations. However, this method has been almost exclusively used for pyramidal cells and interneurons. In this study, we generated autaptic cultures from granule cells isolated from the dentate gyrus of rodent hippocampi. Our subsequent morphological and functional characterisation of these cells confirms that this culture model is suitable for investigating basic mechanisms of granule cell synaptic transmission. Importantly, the autosynaptic connectivity allows recordings of pure mossy fibre miniature EPSCs, which are not possible in slice preparations. Further, by fast application of hypertonic sucrose solutions it is possible to directly measure the readily releasable pool and to calculate the probability of vesicular release.

Employment Impact and Financial Burden for Families of Children with Fragile X Syndrome: Findings from the National Fragile X Survey

Journal of Intellectual Disability Research : JIDR. Oct, 2010  |  Pubmed ID: 20796162

The employment impact and financial burden experienced by families of children with fragile X syndrome (FXS) has not been quantified in the USA.

Relapsing Features of Bile Salt Export Pump Deficiency After Liver Transplantation in Two Patients with Progressive Familial Intrahepatic Cholestasis Type 2

Journal of Hepatology. Nov, 2010  |  Pubmed ID: 20800306

PFIC2 is caused by mutations in ABCB11 encoding BSEP. In most cases affected children need liver transplantation that is thought to be curative. We report on two patients who developed recurrent normal GGT cholestasis mimicking primary BSEP disease, after liver transplantation.

Evaluation of the Validity and Utility of Genetic Testing for Rare Diseases

Advances in Experimental Medicine and Biology. 2010  |  Pubmed ID: 20824443

The conventional criteria for evaluating genetic tests include analytic validity, clinical validity, and clinical utility. Analytical validity refers to a test's ability to measure the genotype of interest accurately and reliably. Clinical validity refers to a test's ability to detect or predict the clinical disorder or phenotype associated with the genotype. Clinical utility of a test is a measure of its usefulness in the clinic and resulting changes in clinical endpoints. In addition, the utility to individuals and families of genomic information, or personal utility, should be considered. This chapter identifies methodological and data issues involved in assessing each type of validity or utility. The validity and utility of a test must be considered in a specific context, which include diagnostic testing, newborn screening, prenatal carrier screening, and family or cascade screening. Specific rare disorders addressed include cystic fibrosis, fragile X syndrome, Duchenne and Becker muscular dystrophy, spinal muscular atrophy, Huntington disease, as well as cancer associated with BRCA mutations.

Probabilistic Approaches to Transcription Factor Binding Site Prediction

Methods in Molecular Biology (Clifton, N.J.). 2010  |  Pubmed ID: 20827588

Many different computer programs for the prediction of transcription factor binding sites have been developed over the last decades. These programs differ from each other by pursuing different objectives and by taking into account different sources of information. For methods based on statistical approaches, these programs differ at an elementary level from each other by the statistical models used for individual binding sites and flanking sequences and by the learning principles employed for estimating the model parameters. According to our experience, both the models and the learning principles should be chosen with great care, depending on the specific task at hand, but many existing programs do not allow the user to choose them freely. Hence, we developed Jstacs, an object-oriented Java framework for sequence analysis, which allows the user to combine different statistical models and different learning principles in a modular manner with little effort. In this chapter we explain how Jstacs can be used for the recognition of transcription factor binding sites.

Extension of a Classic Theory of the Low Frequency Dielectric Dispersion of Colloidal Suspensions to the High Frequency Domain

The Journal of Physical Chemistry. B. Oct, 2010  |  Pubmed ID: 20831225

The classic Shilov-Dukhin theory of the low frequency dielectric dispersion of colloidal suspensions in binary electrolyte solutions [ Shilov , V. N. ; Dukhin , S. S. , Colloid J. 1970 , 32 , 245. ; Dukhin , S. S. ; Shilov , V. N. Dielectric Phenomena and the Double Layer in Disperse Systems and Polyelectrolytes ; Wiley : New York , 1974 ] was developed for the frequency range corresponding to the concentration polarization phenomenon: up to a few megahertz. While a few extensions to a broad frequency range including the Maxwell-Wagner-O'Konski dispersion exist, they all consist of modifications of the final results of the theory rather than modifications of its hypothesis, extending their validity to high frequencies. In this work we avoid this artificial process by providing a high frequency extension fully from within the theory.

Structural and Functional Characterization of a Synthetically Modified OmpG

Bioorganic & Medicinal Chemistry. Nov, 2010  |  Pubmed ID: 20378361

Chemical modification of ion channels has recently attracted attention due to their potential use in stochastic sensing and neurobiology. Among the available channel templates stable β-barrel proteins have shown their potential for large scale chemical modifications due to their wide pore lumen. Ion-channel hybrids using the outer membrane protein OmpG were generated by S-alkylation with a synthetic modulator and functionally as well as structurally characterized. The dansyl moiety of the used modulator resulted in partial blockage of current though the OmpG channel with its gating characteristics mainly unaffected. The crystal structure of an OmpG-dansyl hybrid at 2.4Å resolution correlates this finding by showing that the modulator lines the inner walling of the OmpG pore. These results underline the suitability of OmpG as a structural base for the construction of stochastic sensors.

WRN Helicase Unwinds Okazaki Fragment-like Hybrids in a Reaction Stimulated by the Human DHX9 Helicase

Nucleic Acids Research. Aug, 2010  |  Pubmed ID: 20385589

Mutations in the Werner gene promote the segmental progeroid Werner syndrome (WS) with increased genomic instability and cancer. The Werner gene encodes a DNA helicase (WRN) that can engage in direct protein-protein interactions with DHX9, also known as RNA helicase A or nuclear DNA helicase II, which represents an essential enzyme involved in transcription and DNA repair. By using several synthetic nucleic acid substrates we demonstrate that WRN preferably unwinds RNA-containing Okazaki fragment-like substrates suggesting a role in lagging strand maturation of DNA replication. In contrast, DHX9 preferably unwinds RNA-RNA and RNA-DNA substrates, but fails to unwind Okazaki fragment-like hybrids. We further show that the preferential unwinding of RNA-containing substrates by WRN is stimulated by DHX9 in vitro, both on Okazaki fragment-like hybrids and on RNA-containing 'chicken-foot' structures. Collectively, our results suggest that WRN and DHX9 may also cooperate in vivo, e.g. at ongoing and stalled replication forks. In the latter case, the cooperation between both helicases may serve to form and to dissolve Holliday junction-like intermediates of regressed replication forks.

A Novel Detection Method for Alaria Alata Mesocercariae in Meat

Parasitology Research. Jun, 2010  |  Pubmed ID: 20405145

Distomum musculorum suis (DMS), the mesocercarial stage of the trematode Alaria alata, can cause severe damages within their hosts, and since several reports about cases of human larval alariosis have been published, it became apparent that infected game animals and in particular wild boars are a potential source of infection for both humans and animals. A final statement concerning the health risks for consumers could not be given due to the lack of information about both the prevalence of DMS and the suitability of Trichinella inspection methods to detect this parasite in wild boar meat. Our studies concentrate on (1) the verification of suitability of the official digestion methods for Trichinella spp. for DMS detection in wild boars, (2) development, optimization, and validation of methods, and (3) the distribution of the parasites within their paratenic hosts. A total of 868 individual samples/digests from 48 wild boars were analyzed by the reference method for Trichinella detection in meat samples according to regulation (EC) No. 2075/2005. In addition to the official protocol, a method modification with Pankreatin(c) and bile acid was applied for analysis of adipose tissue samples (n = 89). On the basis of our results, a new detection method based on a larvae migration technique was developed and used for detection of DMS in 574 single samples. Furthermore, the distribution patterns of DMS in wild boars in a total of 1377 single sample migrations/digestions from 35 positive animals were analyzed by application of all three methods. The official digestion method for Trichinella spp. in wild boars meat is inapplicable for the detection of A. alata mesocercariae as it shows shortcomings in both digestion and sampling. A direct comparison between the newly developed A. alata mesocercariae migration technique and the official digestion method for Trichinella spp. based on 574 single samples from 18 animals clearly shows that the sensitivity to detect A. alata developmental stages in tissues of wild boars of the new method is nearly 60% higher compared with the magnetic stirrer method for pooled sample digestion as laid down in regulation (EC) No. 2075/2005. Among other advantages, this method offers a simple, highly applicable, fast, and cost effective way to detect DMS in wild boars which is already applicable in routine veterinary inspection.

C3 Peptide Enhances Recovery from Spinal Cord Injury by Improved Regenerative Growth of Descending Fiber Tracts

Journal of Cell Science. May, 2010  |  Pubmed ID: 20406886

Functional recovery and regeneration of corticospinal tract (CST) fibers following spinal cord injury by compression or dorsal hemisection in mice was monitored after application of the enzyme-deficient Clostridium botulinum C3-protein-derived 29-amino-acid fragment C3bot(154-182). This peptide significantly improved locomotor restoration in both injury models as assessed by the open-field Basso Mouse Scale for locomotion test and Rotarod treadmill experiments. These data were supported by tracing studies showing an enhanced regenerative growth of CST fibers in treated animals as visualized by anterograde tracing. Additionally, C3bot(154-182) stimulated regenerative growth of raphespinal fibers and improved serotonergic input to lumbar alpha-motoneurons. These in vivo data were confirmed by in vitro data, showing an enhanced axon outgrowth of alpha-motoneurons and hippocampal neurons cultivated on normal or growth-inhibitory substrates after application of C3bot(154-182). The observed effects were probably caused by a non-enzymatic downregulation of active RhoA by the C3 peptide as indicated by pull-down experiments. By contrast, C3bot(154-182) did not induce neurite outgrowth in primary cultures of dorsal root ganglion cells. In conclusion, C3bot(154-182) represents a novel, promising tool to foster axonal protection and/or repair, as well as functional recovery after traumatic CNS injury.

Voltage Mapping and Pacing to Assess the Level of Pulmonary Venous Isolation Achieved with a Novel Circular Multielectrode Ablation Catheter

Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. Jul, 2010  |  Pubmed ID: 20410044

The aim of the study was to determine the level of pulmonary vein (PV) isolation achieved with the use of a novel radiofrequency circular multielectrode ablation catheter [pulmonary vein ablation catheter (PVAC)] in patients with paroxysmal atrial fibrillation. Although some efficacy data have been presented, the level of PV isolation, which is crucial both for efficacy and safety of the ablation, has not been defined with this new ablation catheter.

3D Shape Measurement of Macroscopic Objects in Digital Off-axis Holography Using Structured Illumination

Optics Letters. Apr, 2010  |  Pubmed ID: 20410977

We propose what we believe to be a novel approach to measure the 3D shape of arbitrary diffuse-reflecting macroscopic objects in holographic setups. Using a standard holographic setup, a second CCD and a liquid-crystal-on-silicon spatial light modulator to modulate the object wave, the method yields a dense 3D point cloud of an object or a scene. The calibration process is presented, and first quantitative results of a shape measurement are shown and discussed. Furthermore, a shape measurement of a complex object is displayed to demonstrate its universal use.

Embryonated Eggs As an Alternative Infection Model to Investigate Aspergillus Fumigatus Virulence

Infection and Immunity. Jul, 2010  |  Pubmed ID: 20421382

Infection models are essential tools for studying microbial pathogenesis. Murine models are considered the "gold standard" for studying in vivo infections caused by Aspergillus species, such as A. fumigatus. Recently developed molecular protocols allow rapid construction of high numbers of fungal deletion mutants, and alternative infection models based on cell culture or invertebrates are widely used for screening such mutants to reduce the number of rodents in animal experiments. To bridge the gap between invertebrate models and mice, we have developed an alternative, low-cost, and easy-to-use infection model for Aspergillus species based on embryonated eggs. The outcome of infections in the egg model is dose and age dependent and highly reproducible. We show that the age of the embryos affects the susceptibility to A. fumigatus and that increased resistance coincides with altered chemokine production after infection. The progress of disease in the model can be monitored by using egg survival and histology. Based on pathological analyses, we hypothesize that invasion of embryonic membranes and blood vessels leads to embryonic death. Defined deletion mutant strains previously shown to be fully virulent or partially or strongly attenuated in a mouse model of bronchopulmonary aspergillosis showed comparable degrees of attenuation in the egg model. Addition of nutrients restored the reduced virulence of a mutant lacking a biosynthetic gene, and variations of the infectious route can be used to further analyze the role of distinct genes in our model. Our results suggest that embryonated eggs can be a very useful alternative infection model to study A. fumigatus virulence and pathogenicity.

Prevalence of Congenital Hypothyroidism--current Trends and Future Directions: Workshop Summary

Pediatrics. May, 2010  |  Pubmed ID: 20435715

In response to published newborn-screening data that have shown an increase in the incidence (birth prevalence) rate of primary congenital hypothyroidism (CH) in the United States, a workshop was held in Atlanta, Georgia, on February 27 and 28, 2008, to examine this issue. Topics of the meeting included pathophysiology, medical management, and follow-up of CH; transient hypothyroidism (etiology, clinical implications, management, and changes in prevalence); risk factors for CH; laboratory approaches to newborn screening for CH; state-specific evaluations of trends in incidence rates of CH; and concluding discussions on future directions to resolve outstanding issues. Through presentations and discussion, gaps in knowledge were identified, such as the lack of consistent definitions for CH and transient hypothyroidism and the effects of preventable risk factors on incidence rates of CH. One outcome of the meeting was a series of accompanying articles that examined (1) trends in the incidence rates of CH in individual states and nationally, (2) effects of newborn-screening practices on CH-incidence rates, (3) the contribution of transient hypothyroidism to CH-incidence rates, and (4) future research directions. In this summary, we briefly touch on the topics of these articles and examine highlights of other presentations from the workshop that illuminated the secular trends in reported CH-incidence rates in the United States.

The Impact of Transient Hypothyroidism on the Increasing Rate of Congenital Hypothyroidism in the United States

Pediatrics. May, 2010  |  Pubmed ID: 20435718

The reported incidence rate of primary congenital hypothyroidism (CH) has been increasing in the United States over the past 2 decades. We have considered the possibility that the inclusion of cases of transient hypothyroidism has inflated the reported incidence rate of CH. Assessing the effects of cases of transient hypothyroidism on the incidence rate is problematic, because the definitions, diagnostic criteria, and differentiation from transient hyperthyrotropinemia vary widely among state newborn screening programs. Among the 4 etiologies for transient hypothyroidism (maternal thyrotropin receptor-blocking antibodies, exposure to maternal antithyroid medications, iodine deficiency, and iodine excess), there is little evidence of increases in the incidence rate from thyrotropin receptor-blocking antibodies. Exposure to antithyroid drugs could contribute significantly to the incidence rate of transient CH, given the high estimated incidence of active maternal hyperthyroidism. Iodine deficiency or excess in the United States seems unlikely to have contributed significantly to the incidence rate of CH, because the secular trend toward lower iodine intake among women of reproductive age in the 1980s and 1990s seems to have plateaued, and perinatal iodine exposure has presumably declined as a result of recommendations to discontinue using iodine-containing disinfectants. Although the female-to-male sex ratio among newborns with thyroid agenesis or dysgenesis (the most common causes of CH) is typically 2:1, analysis of the sex ratio of newborns diagnosed with presumed CH in the United States suggests that a substantial proportion might have transient hypothyroidism or hyperthyrotropinemia, because the sex ratio has been well below the expected 2:1 ratio. Combined ultrasonography and (123)I scintigraphy of the thyroid gland are effective tools for identifying cases of thyroid agenesis and dysgenesis and can help to differentiate cases of transient hypothyroidism from true CH. Imaging is also a vital component in evaluating children who, at 3 years of age, undergo a trial of discontinuation of levothyroxine treatment to test for persistence of hypothyroidism. Ultimately, thyroid gland imaging, in conjunction with long-term follow-up studies that appropriately assess and report whether there was permanence of hypothyroidism, will be necessary to address the true incidence rate of CH and any contribution to the observed rate by transient cases of hypothyroidism or hyperthyrotropinemia.

In Vitro Comparison of the New In-line Monitor BMU 40 Versus a Conventional Laboratory Analyzer

The Journal of Extra-corporeal Technology. Mar, 2010  |  Pubmed ID: 20437794

Reliable information about different blood parameters is essential in maintaining hemodynamics, perfusion, and gas exchange during cardiopulmonary bypass (CPB). For this purpose, a precise and continuous monitoring is needed. The objective of this in vitro study was to compare a novel continuous in-line blood parameter monitoring system versus a reference laboratory analyzer. The study was conducted as an in vitro prospective experimental study during a CPB simulation. The reliability of BMU 40 was tested in monitoring the pO2, oxygen saturation (SO2), and hematocrit (Hct) under physiological and extreme conditions with regards to temperature, oxygenation, and blood concentration. Four different tests were performed and conducted with five sensors each. Correlation analyses and Bland-Altman analyses were performed. A total of 350 measurement points were compared. All monitored values of blood parameters correlated highly with laboratory values (all r values >.90). Test 1: Biases of pO2 (act) varied from -3.24 mmHg (+/- 6.86 mmHg) up to 6.0 mmHg (+/- 17.89 mmHg). The biases of pO2 (37 degrees C) ranged from -3.52 mmHg (+/- 6.01 mmHg) up to 68.8 mmHg (+/- 67.82 mmHg). Test 2: The biases standard deviations (SD) for Hct ranged from -0.35% (+/- .79%) up to 2.35% (+/- .91%). The biases (SD) for SO2 varied from -.45% (+/- .86%) up to .85% (+/- 1.01%). Test 3: The biases (SD) of Hct ranged from -1.00% (+/- 1.84%) up to -.67% (+/- 1.49%). Test 4: The biases (SD) for SO2 varied from -.36% (+/- 1.60%) up to .48% (+/- .90%).The BMU 40 is a reliable device in measuring the partial oxygen pressure (pO2), SO2, and Hct under normal physiological and extreme conditions with regards to temperature, oxygenation, and blood concentration in simulation of CPB. The algorithm to calculate pO2 (37 degrees C) under hypothermic conditions needs to be adjusted. (Before the official market launch a new software version of the BMU 40 has been developed. The algorithm to calculate pO2 (37 degrees C) under hypothermic conditions has been improved and the miscalculation eliminated.)

Predicting Bite Force in Mammals: Two-dimensional Versus Three-dimensional Lever Models

The Journal of Experimental Biology. Jun, 2010  |  Pubmed ID: 20472771

Bite force is a measure of whole-organism performance that is often used to investigate the relationships between performance, morphology and fitness. When in vivo measurements of bite force are unavailable, researchers often turn to lever models to predict bite forces. This study demonstrates that bite force predictions based on two-dimensional (2-D) lever models can be improved by including three-dimensional (3-D) geometry and realistic physiological cross-sectional areas derived from dissections. Widely used, the 2-D method does a reasonable job of predicting bite force. However, it does so by over predicting physiological cross-sectional areas for the masseter and pterygoid muscles and under predicting physiological cross-sectional areas for the temporalis muscle. We found that lever models that include the three dimensional structure of the skull and mandible and physiological cross-sectional areas calculated from dissected muscles provide the best predictions of bite force. Models that accurately represent the biting mechanics strengthen our understanding of which variables are functionally relevant and how they are relevant to feeding performance.

Equilibrium Electric Double Layer of Charged Spherical Colloidal Particles: Effect of Different Distances of Minimum Ion Approach to the Particle Surface

The Journal of Physical Chemistry. B. Jun, 2010  |  Pubmed ID: 20476777

A study of the equilibrium double layer surrounding charged spherical particles is presented, considering that ions in the suspending medium have a finite size. It is assumed that each ionic species has a different minimum approach distance to the particle surface, while the distance of minimum approach between ions in the bulk has the same value for all ion species. Numerical calculations made using the network simulation method and including all the features of the considered model are presented, together with rigorous analytical results valid for a flat interface and point ions in the bulk electrolyte solution. It is shown that the double-layer parameters are very sensitive to the difference between the minimum approach distances of co-ions and counterions. For negative particles and greater approach distances for co-ions than for counterions, the potential always increases with this difference and, under appropriate circumstances, attains positive values leading to charge reversal. This phenomenon is favored by a high electrolyte concentration, high counterion valences, and low surface charge (in modulus). An analytical expression relating these parameters to the threshold value of the difference between the minimum approach distances of co-ions and counterions to the particle surface is presented.

Analysis of Prototype Foamy Virus Particle-host Cell Interaction with Autofluorescent Retroviral Particles

Retrovirology. 2010  |  Pubmed ID: 20478027

The foamy virus (FV) replication cycle displays several unique features, which set them apart from orthoretroviruses. First, like other B/D type orthoretroviruses, FV capsids preassemble at the centrosome, but more similar to hepadnaviruses, FV budding is strictly dependent on cognate viral glycoprotein coexpression. Second, the unusually broad host range of FV is thought to be due to use of a very common entry receptor present on host cell plasma membranes, because all cell lines tested in vitro so far are permissive.

A Novel Stress Distribution Organ in the Arthropod Exoskeleton

Arthropod Structure & Development. Sep, 2010  |  Pubmed ID: 20478397

The vertebrate endoskeleton possesses a massive internal network of load-distributing trabeculae that in most locations accounts for the vast majority of bone cross sectional area. In contrast, arthropods rely on the external cuticle and its intermittent outpocketings to distribute the daily stresses of physiological loading. One of the constraints of the arthropod exoskeleton is the necessity to house the musculature involved in locomotion, feeding and etc. Because of this lack of an extensive internal load-distributing trabecular network, any load-distributing mechanism in arthropods would necessarily have to incorporate the exoskeleton. Several authors have identified structural apophysi whose functions presumably have mechanical significance, but few have been identified using quantitative analyses. This study investigates a novel stress-reducing structure arising from the articulation sites in the exoskeleton of the blue crab, Callinectes sapidus. During dissection of the merus-carpus joint and leg cuticle of the blue crab, an unique system of internal strut-like members was found radiating, both longitudinally and laterally, from the articular surface of the proximal merus segment, tapering into the diaphyseal region. This strut system, an internal outpocketing of the exoskeleton and semi-circular in cross section, mirrors the trabecular pattern seen radiating from vertebrate joint surfaces. Earlier reports of this structural system described it as a muscle attachment site and made little or no reference to potential load distribution properties. Finite element analysis (FEA) models confirm the efficacy of stress distributing properties of this articular strut system in the blue crab leg. In the models, the struts significantly reduce stress concentrations, reduce localized strains and minimize the risk of failure via buckling. Models lacking this strut system generate 94.7% larger peak von Mises stress at the articulation site, 37% higher peak displacement and 4% greater equivalent strain. The model with the struts is capable of withstanding an applied physiological load of up to 16.6 N prior to buckling, more than twice that of the model without struts (7.8 N). We suggest that this novel arthropod strut system is likely utilized at many joint surfaces at locations of high skeletal stress concentrations, is an adaptation for minimizing skeletal failure via localized buckling, and may be present in other arthropod taxa.

Aesthetically Pleasant Umbilicoplasty

Annals of Plastic Surgery. Jun, 2010  |  Pubmed ID: 20489399

The umbilicus is an important aesthetic feature of the abdomen and thus calls for an optimized reinsertation technique. Localization and characteristics of the umbilicus were assessed in 137 adults. In addition, age, height, weight, pregnancy, and gender were recorded. Each participant reviewed his own photographs while the authors reviewed all of them. The categorization included a rating and an evaluation of the silhouette. A vertical-configured umbilicus was the most frequently observed. Nevertheless, the score for oval shape was superior. Following a pregnancy, the navel became shorter and wider. Furthermore, the distances measured between the fixed bony points were larger in males and as BMI increased. The height of a person had no impact on the position or height of the umbilicus. An oval-shaped umbilicus that is positioned at 2/3 of the distance from the pubis to the xiphisternum may lead to the most aesthetic results. Thus, the goal in umbilicoplasty is to obtain this configuration.

A Label-free Assay of Exonuclease Activity Using a Pyrosequencing Technique

Analytical Biochemistry. Oct, 2010  |  Pubmed ID: 20522331

Enzymes with 3'-5' exonuclease activities are important in promoting the accuracy of DNA replication and DNA repair by proofreading. The alteration of the function of these enzymes by endogenous or exogenous effectors could, therefore, have a considerable impact on DNA replication and ultimately on genome integrity. We have developed a label-free high-throughput screening method for quantifying the effects of different reagents on exonuclease activity. The assay is based on a hairpin-forming biotinylated oligonucleotide substrate that contains one or more exonuclease-resistant phosphorothioate nucleotides. The activity and specificity of the selected 3'-5' exonuclease is determined indirectly using a sensitive pyrosequencing reaction after cleanup of the samples. In this pyrosequencing step, the amount of nucleotides filled into each position of the exonucleolytically degraded 3' end of the substrate can be recorded quantitatively and equals the amount of the nucleotides removed by the exonuclease. This system allows the estimation of both processivity and efficiency of the exonuclease activity. We have employed compounds reported in the literature to inhibit the exonuclease activities of either exonuclease III or the large fragment of polymerase I (Klenow fragment) to evaluate the assay.

The Justy Mutation Identifies Gon4-like As a Gene That is Essential for B Lymphopoiesis

The Journal of Experimental Medicine. Jul, 2010  |  Pubmed ID: 20530203

A recessive mutation named Justy was found that abolishes B lymphopoiesis but does not impair other major aspects of hematopoiesis. Transplantation experiments showed that homozygosity for Justy prevented hematopoietic progenitors from generating B cells but did not affect the ability of bone marrow stroma to support B lymphopoiesis. In bone marrow from mutant mice, common lymphoid progenitors and pre-pro-B cells appeared normal, but cells at subsequent stages of B lymphopoiesis were dramatically reduced in number. Under culture conditions that promoted B lymphopoiesis, mutant pre-pro-B cells remained alive and began expressing the B cell marker CD19 but failed to proliferate. In contrast, these cells were able to generate myeloid or T/NK precursors. Genetic and molecular analysis demonstrated that Justy is a point mutation within the Gon4-like (Gon4l) gene, which encodes a protein with homology to transcriptional regulators. This mutation was found to disrupt Gon4l pre-mRNA splicing and dramatically reduce expression of wild-type Gon4l RNA and protein. Consistent with a role for Gon4l in transcriptional regulation, the levels of RNA encoding C/EBPalpha and PU.1 were abnormally high in mutant B cell progenitors. Our findings indicate that the Gon4l protein is required for B lymphopoiesis and may function to regulate gene expression during this process.

Public Health and Laboratory Considerations Regarding Newborn Screening for Congenital Cytomegalovirus

Journal of Inherited Metabolic Disease. Oct, 2010  |  Pubmed ID: 20532822

Congenital cytomegalovirus (CMV) infection is the most common infection in newborns worldwide and causes hearing loss and other neurological disability in 15-20% of infected infants. Only about half of the hearing loss resulting from congenital CMV infection is currently detected by universal newborn hearing screening because of late-onset hearing loss. Thus, much of the hearing loss and the majority of other CMV-associated disabilities remain undetected for years after birth and are never connected to CMV infection. Congenital CMV may be appropriate to include in national newborn screening (NBS) programs because it is more common than other disorders tested for by NBS programs and is a major cause of disability. Significant obstacles to the implementation of screening for congenital CMV include the lack of a standardized, high-throughput screening test and a protocol for follow-up of CMV-infected children. Nonetheless, screening newborns for congenital CMV infection merits further consideration.

QALY Weights for Neurosensory Impairments in Pediatric Economic Evaluations: Case Studies and a Critique

Expert Review of Pharmacoeconomics & Outcomes Research. Jun, 2010  |  Pubmed ID: 20545594

The use of utility weights for the calculation of quality-adjusted life years is particularly problematic for pediatric health states. This article reviews variability in utility weights for intellectual disability and permanent hearing loss in economic evaluations of newborn screening and childhood immunizations. Utility weights for severe intellectual disability ranged from 0.06 to 0.74. Most studies either did not vary these utility weights in sensitivity analyses or assumed low variability; consequently, the robustness of cost-effectiveness estimates was not fully assessed. Two recently published catalogs of utility weights for pediatric health states also show wide divergences in estimates. More work is needed to establish measures of health utilities for childhood health states in order to allow for comparable assessments of pediatric interventions.

Pure-tone Auditory Thresholds Are Decreased in Depressed People with Post-traumatic Stress Disorder

Journal of Affective Disorders. Dec, 2010  |  Pubmed ID: 20547422

Depression has been related to sensory modulation and notably to auditory modifications such as alterations in auditory event-related potentials, abnormal patterns of auditory habituation, increased activation of primary and secondary auditory cortex, and higher bilateral auditory thresholds. However, few experiments have considered the exploration of the auditory system in depression. The aim of the experiment is to further explore auditory thresholds across a higher number of frequencies than has previously been undertaken in depressed subjects, to determine whether thresholds are modified as compared to controls, and if so, at which frequencies.

High-speed Pattern Projection for Three-dimensional Shape Measurement Using Laser Speckles

Applied Optics. Jun, 2010  |  Pubmed ID: 20563218

We propose a high-speed projection system that is able to project statistical speckle patterns at a rate of 500Hz. Its purpose is to generate structured light for a real-time photogrammetry stereo vision setup. As conventional digital light projector (DLP) projection setups are limited in their maximum projection rate to 250Hz for gray-value patterns, stripe projection systems are usually applied for real-time three-dimensional (3D) measurements. However, these techniques can only be used on steady surfaces as phase unwrapping has to be done. In contrast, the proposed setup is able to measure the shape of multiple spatially separated objects at once. We compare the speckle setup with a system using a DLP projector and with other fast 3D shape measurement setups, like the widely used stripe projection methods, qualitatively and quantitatively.

Endogenous Purinergic Signaling is Required for Osmotic Volume Regulation of Retinal Glial Cells

Journal of Neurochemistry. Mar, 2010  |  Pubmed ID: 20002522

Intense neuronal activity in the sensory retina is associated with a volume increase of neuronal cells (Uckermann et al., J. Neurosci. 2004, 24:10149) and a decrease in the osmolarity of the extracellular space fluid (Dmitriev et al., Vis. Neurosci. 1999, 16:1157). Here, we show the existence of an endogenous purinergic mechanism that prevents hypoosmotic swelling of retinal glial (Müller) cells in mice. In contrast to the cells from wild-type mice, hypoosmotic stress induced rapid swelling of glial cell somata in retinal slices from mice deficient in P2Y(1), adenosine A(1) receptors, or ecto-5'-nucleotidase (CD73). Consistently, glial cell bodies in retinal slices from wild-type mice displayed osmotic swelling when P2Y(1) or A(1) receptors, or CD73, were pharmacologically blocked. Exogenous ATP, UTP, and UDP inhibited glial swelling in retinal slices, while the swelling of isolated glial cells was prevented by ATP but not by UTP or UDP, suggesting that uracil nucleotides indirectly regulate the glial cell volume via activation of neuronal P2Y(4/6) and neuron-to-glia signaling. It is suggested that autocrine/paracrine activation of purinergic receptors and enzymes is crucially involved in the regulation of the glial cell volume.

The Initiation Step of Eukaryotic DNA Replication

Sub-cellular Biochemistry. 2010  |  Pubmed ID: 20012578

Eukaryotic initiation of DNA replication is a tightly regulated process. In the yeasts, S-phase-specific cyclin Cdk1 complex as well as Dfb4-Cdc7 kinase phosphorylate the initiation factors Sld2 and Sld3. These factors form a ternary complex with another initiation factor Dbp11 in their phosphorylated state, and associate with the origin of replication. This complex mediates the loading of Cdc45. A second complex called GINS and consisting of Sld5 and Psf1, 2 and 3 is also loaded onto the origin during the initiation process, in an interdependent manner with the Sld2/Sld3/Dpb11 complex. Both complexes cooperate in the recruitment of the replicative DNA polymerases, thus executing the initiation and subsequent establishment of the replication fork. Cdc45 and GINS are essential, well-conserved factors that are retained at the elongating replication fork. They form a stable helicase complex with MCM2-7 and mediate its contact to the replicative DNA polymerases. In contrast, the Sld2/Sld3/Dpb11 complex critical for the initiation is not retained by the elongating replication fork. Sld2 displays limited homology to the amino-terminal region of RecQL4 helicase, which may represent its metazoan orthologue, whereas Sld3 homologues have been identified only in fungi. Dbp11 and its fission yeast homologue Cut5 are members of a large family of BRCT-containing proteins including human TopBP1 and fruit fly Mus101. Similar principles of regulation apply also to human initiation of DNA replication, despite obvious differences in the detailed mechanisms. The regulatory initiation cascade is intimately intertwined with the cell cycle apparatus as well as the checkpoint control.

Age-dependent Axonal Expression of Potassium Channel Proteins During Development in Mouse Hippocampus

Histochemistry and Cell Biology. Mar, 2010  |  Pubmed ID: 20012645

The development of the hippocampal network requires neuronal activity, which is shaped by the differential expression and sorting of a variety of potassium channels. Parallel to their maturation, hippocampal neurons undergo a distinct development of their ion channel profile. The age-dependent dimension of ion channel occurrence is of utmost importance as it is interdependently linked to network formation. However, data regarding the exact temporal expression of potassium channels during postnatal hippocampal development are scarce. We therefore studied the expression of several voltage-gated potassium channel proteins during hippocampal development in vivo and in primary cultures, focusing on channels that were sorted to the axonal compartment. The Kv1.1, Kv1.2, Kv1.4, and Kv3.4 proteins showed a considerable temporal variation of axonal localization among neuronal subpopulations. It is possible, therefore, that hippocampal neurons possess cell type-specific mechanisms for channel compartmentalization. Thus, age-dependent axonal sorting of the potassium channel proteins offers a new approach to functionally distinguish classes of hippocampal neurons and may extend our understanding of hippocampal circuitry and memory processing.

Nandrolone: a Multi-faceted Doping Agent

Handbook of Experimental Pharmacology. 2010  |  Pubmed ID: 20020363

Nandrolone or nortestosterone, an anabolic-androgenic steroid, has been prohibited by doping control regulations for more than 30 years. Although its main metabolism in the human body was already known at that time, and detection of its misuse by gas or liquid chromatographic separation with mass spectrometric detection is straightforward, many interesting aspects regarding this doping agent have appeared since.Over the years, nandrolone preparations have kept their position among the prohibited substances that are most frequently detected in WADA-accredited laboratories. Their forms of application range from injectable fatty acid esters to orally administered nandrolone prohormones. The long detection window for nandrolone ester preparations and the appearance of orally available nandrolone precursors have changed the pattern of misuse.At the same time, more refined analytical methods with lowered detection limits led to new insights into the pharmacology of nandrolone and revelation of its natural production in the body.Possible contamination of nutritional supplements with nandrolone precursors, interference of nandrolone metabolism by other drugs and rarely occurring critical changes during storage of urine samples have to be taken into consideration when interpreting an analytical finding.A set of strict identification criteria, including a threshold limit, is applied to judge correctly an analytical finding of nandrolone metabolites. The possible influence of interfering drugs, urine storage or natural production is taken into account by applying appropriate rules and regulations.

Application of Free-flow IEF to Identify Protein Candidates Changing Under Microgravity Conditions

Proteomics. Mar, 2010  |  Pubmed ID: 20049858

Using antibody-related methods, we recently found that human thyroid cells express various proteins differently depending on whether they are cultured under normal gravity (1g) or simulated microgravity (s-microg). In this study, we performed proteome analysis in order to identify more gravity-sensitive thyroid proteins. Cells cultured under 1g or s-microg conditions were sonicated. Proteins released into the supernatant and those remaining in the cell fragments were fractionated by free-flow IEF. The fractions obtained were further separated by SDS-gel electrophoresis. Selected gel pieces were excised and their proteins were determined by MS. A total of 235 different proteins were found. Out of 235 proteins, 37 appeared to be first identifications in human thyroid cells. Comparing SDS gel lanes of equally numbered free-flow IEF fractions revealed similar patterns with a number of identical bands if proteins of a distinct cell line had been applied, irrespective of whether the cells had been cultured under 1g or s-microg. Most of the identical band pairs contained identical proteins. However, the concentrations of some types of proteins were different within the two pieces of gel. Proteins that concentrated differently in such pieces of gel are considered as candidates for further investigations of gravitational sensitivity.

The Cost-effectiveness of Genetic Testing Strategies for Lynch Syndrome Among Newly Diagnosed Patients with Colorectal Cancer

Genetics in Medicine : Official Journal of the American College of Medical Genetics. Feb, 2010  |  Pubmed ID: 20084010

To estimate the cost-effectiveness of genetic testing strategies to identify Lynch syndrome among newly diagnosed patients with colorectal cancer and to offer targeted testing to relatives of patients with Lynch syndrome.

Personalized Medicine and Genomics: Challenges and Opportunities in Assessing Effectiveness, Cost-effectiveness, and Future Research Priorities

Medical Decision Making : an International Journal of the Society for Medical Decision Making. May-Jun, 2010  |  Pubmed ID: 20086232

Personalized medicine is health care that tailors interventions to individual variation in risk and treatment response. Although medicine has long strived to achieve this goal, advances in genomics promise to facilitate this process. Relevant to present-day practice is the use of genomic information to classify individuals according to disease susceptibility or expected responsiveness to a pharmacologic treatment and to provide targeted interventions. A symposium at the annual meeting of the Society for Medical Decision Making on 23 October 2007 highlighted the challenges and opportunities posed in translating advances in molecular medicine into clinical practice. A panel of US experts in medical practice, regulatory policy, technology assessment, and the financing and organization of medical innovation was asked to discuss the current state of practice and research on personalized medicine as it relates to their own field. This article reports on the issues raised, discusses potential approaches to meet these challenges, and proposes directions for future work. The case of genetic testing to inform dosing with warfarin, an anticoagulant, is used to illustrate differing perspectives on evidence and decision making for personalized medicine.

Formin-like 2 Drives Amoeboid Invasive Cell Motility Downstream of RhoC

Oncogene. Apr, 2010  |  Pubmed ID: 20101212

Invasive cell migration is a key step for cancer metastasis and involves Rho GTPase-controlled reorganization of the actin cytoskeleton. Altered Rho GTPase expression is found in various malignancies. Particularly, the closely related GTPases RhoA and RhoC are upregulated in many aggressive tumours, but specific effectors that distinguish between these two GTPases to explain mechanistic differences have not been identified. The formins are by far the largest family of Rho GTPase effectors and are characterized by the actin-nucleating formin homology 2 domain. Using siRNA-based screening against all 15 human formins, we systematically analysed their functions in 3D cell motility using three different cancer cell lines. These results reveal distinct requirements for specific formins in amoeboid versus mesenchymal invasive cell migration. Importantly, by knocking down all Rho proteins, we identified formin-like 2 (FMNL2) as a specific RhoC effector, showing selective interaction of FMNL2 with active RhoC, but not RhoA or RhoB. Functional analysis shows that RhoC regulates autoinhibition of FMNL2, whereas suppression of FMNL2 inhibits RhoC-, but not RhoA-dependent, rounded invasive cell migration. Thus, our data uncover a novel regulatory and functional interaction between RhoC and FMNL2 for modulating cell shape and invasiveness and provide mechanistic insight into RhoC-specific signalling events.

Thermostable Feruloyl Esterase for the Bioproduction of Ferulic Acid from Triticale Bran

Applied Microbiology and Biotechnology. Jun, 2010  |  Pubmed ID: 20127235

A putative alpha/beta hydrolase fold-encoding gene (locus tag TTE1809) from the genome of Thermoanaerobacter tengcongensis was cloned and expressed in Escherichia coli as a possible source of thermostable feruloyl esterase (FAE) for the production of antioxidant phenolic acids from biomass. Designated as TtFAE, the 33-kDa protein was purified to apparent homogeneity. The lipase-like sequence characteristics of TtFAE and its substrate specificity towards methyl ferulate, methyl sinapate, and methyl p-coumarate classify it as a new member of the type A FAEs. At 75 degrees C, the enzyme retained at least 95% of its original activity for over 80 min; at 80 degrees C, its half-life was found to be 50 min, rendering TtFAE a highly thermostable protein. Under different hydrolytic conditions, ferulic acid (FA) was shown to be released from feruloylated oligosaccharides prepared from triticale bran. An estimated recovery of 68 mg FA/100 g triticale bran was demonstrated by a 30% release of the total FA from triticale bran within a 5-h incubation period. Both the oxygen radical absorbing capacity values of the feruloylated oligosaccharides and free FA were also determined. Overall, this work introduces a new bacterial member to the growing family of plant cell wall degrading FAEs that at present is largely of fungal origin, and it benchmarks the bioproduction of FA from triticale bran.

Changes of Apoptosis, P53, and Bcl-2 by Irradiation in Poorly Differentiated Thyroid Carcinoma Cell Lines: a Prognostic Marker for the Prospect of Therapeutic Success?

Thyroid : Official Journal of the American Thyroid Association. Feb, 2010  |  Pubmed ID: 20151823

Poorly differentiated thyroid carcinoma (PDTC) has an unfavorable prognosis. Surgical management is the principal treatment approach. In addition, radioiodine treatment and external beam radiotherapy (EBRT) are given to reduce the risk of local relapse. Despite aggressive therapy, the response to treatment tends to become increasingly poorer over time. The objective of this study was to investigate the induction of apoptosis by EBRT as a function of p53 and bcl-2 protein levels in PDTC. The predictive value of these molecules with respect to treatment efficacy was evaluated.

Discontinuation of Thyroid Hormone Treatment Among Children in the United States with Congenital Hypothyroidism: Findings from Health Insurance Claims Data

BMC Pediatrics. 2010  |  Pubmed ID: 20156344

Thyroid hormone treatment in children with congenital hypothyroidism can prevent intellectual disability. Guidelines recommend that children diagnosed with congenital hypothyroidism through newborn screening remain on treatment to at least 3 years of age, after which a trial off therapy can determine which children have transient hypothyroidism. The purpose of this study was to describe the rate at which children with congenital hypothyroidism in the United States discontinue thyroid hormone treatment in early childhood.

Unifying Generative and Discriminative Learning Principles

BMC Bioinformatics. 2010  |  Pubmed ID: 20175896

The recognition of functional binding sites in genomic DNA remains one of the fundamental challenges of genome research. During the last decades, a plethora of different and well-adapted models has been developed, but only little attention has been payed to the development of different and similarly well-adapted learning principles. Only recently it was noticed that discriminative learning principles can be superior over generative ones in diverse bioinformatics applications, too.

Tumor-specific Gene Transfer with Receptor-mediated Nanocomplexes Modified by Polyethylene Glycol Shielding and Endosomally Cleavable Lipid and Peptide Linkers

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Jul, 2010  |  Pubmed ID: 20203088

Synthetic nanoparticle formulations have the potential for tumor-targeted gene delivery. Receptor-targeted nanocomplex (RTN) formulations comprise mixtures of cationic liposomes and targeting peptides that self-assemble on mixing with nucleic acids. RTN formulations were prepared containing different polyethylene glycol (PEG)ylated lipids with esterase-cleavable linkers (e.g., ME42) to promote intracellular PEG detachment and nanoparticle disassembly. In addition, integrin-targeting peptides (peptide ME27) were tested with endosomal furin- and cathepsin B-cleavable peptide linkers located between the integrin-binding ligand and the K(16) nucleic acid-binding domain to promote intracellular disengagement from the receptor. ME42/ME27 RTNs formed stable particles of <200 nm in isotonic salt buffers, compared with 4-microm particles formed by un-PEGylated RTNs. Transfection efficiency by PEG-modified, cleavable RTNs improved approximately 2-fold in 4 different cell lines, with 80% efficiency in murine neuroblastoma cells. In an in vivo model of neuroblastoma, ME42/ME27 RTNs delivering luciferase genes were tumor specific, with little expression in other organs tested. PEGylation of the RTNs enhanced luciferase transfection 5-fold over non-PEG formulations, whereas the cleavability of the peptide ME27 enhanced transfection 4-fold over that of RTNs with noncleavable peptides. Cleavability of the lipid for in vivo transfections had no effect. PEGylated, cleavable RTN formulations offer prospects for tumor-specific therapeutic gene transfer.

What is the Value for Money of Prenatal Carrier Screening for Spinal Muscular Atrophy? Too Soon to Say

American Journal of Obstetrics and Gynecology. Mar, 2010  |  Pubmed ID: 20207235

Molecular Characterization of Nuclear DNA Helicase II (RNA Helicase A)

Methods in Molecular Biology (Clifton, N.J.). 2010  |  Pubmed ID: 20225158

Nuclear DNA helicase II (NDH II) was first isolated from calf thymus using a DNA-unwinding assay. Subsequently it has been shown to be a homologue of human RNA helicase A (RHA) and the maleless protein (MLE) from Drosophila. Accordingly, the protein possesses both DNA and RNA unwinding activities. Also, it can use all four NTPs or dNTPs to fuel the reaction. At its N-terminus it possesses two double-strand RNA binding domains (dsRBD I and II), while the C-terminus comprises an imperfect glycine (G)- and arginine (R)-rich repeat, a so-called RGG-box that preferably binds to ssDNA or ssRNA. Many proteins interact with NDH II both at its N- and C-terminus and thereby mediate transcriptional regulation, RNA processing, and transport, the DNA damage response and genome surveillance. The latter includes the histone variant gamma-H2AX and the Werner syndrome helicase (WRN). Here we describe experimental approaches to obtain mechanistic information about this important nuclear helicase.

The Structural Rigidity of the Cranium of Australopithecus Africanus: Implications for Diet, Dietary Adaptations, and the Allometry of Feeding Biomechanics

Anatomical Record (Hoboken, N.J. : 2007). Apr, 2010  |  Pubmed ID: 20235314

Australopithecus africanus is an early hominin (i.e., human relative) believed to exhibit stress-reducing adaptations in its craniofacial skeleton that may be related to the consumption of resistant food items using its premolar teeth. Finite element analyses simulating molar and premolar biting were used to test the hypothesis that the cranium of A. africanus is structurally more rigid than that of Macaca fascicularis, an Old World monkey that lacks derived australopith facial features. Previously generated finite element models of crania of these species were subjected to isometrically scaled loads, permitting a direct comparison of strain magnitudes. Moreover, strain energy (SE) in the models was compared after results were scaled to account for differences in bone volume and muscle forces. Results indicate that strains in certain skeletal regions below the orbits are higher in M. fascicularis than in A. africanus. Moreover, although premolar bites produce von Mises strains in the rostrum that are elevated relative to those produced by molar biting in both species, rostral strains are much higher in the macaque than in the australopith. These data suggest that at least the midface of A. africanus is more rigid than that of M. fascicularis. Comparisons of SE reveal that the A. africanus cranium is, overall, more rigid than that of M. fascicularis during premolar biting. This is consistent with the hypothesis that this hominin may have periodically consumed large, hard food items. However, the SE data suggest that the A. africanus cranium is marginally less rigid than that of the macaque during molar biting. It is hypothesized that the SE results are being influenced by the allometric scaling of cranial cortical bone thickness.

The Effect of Early Hominin Occlusal Morphology on the Fracturing of Hard Food Items

Anatomical Record (Hoboken, N.J. : 2007). Apr, 2010  |  Pubmed ID: 20235316

Tooth profile plays an important role in interpretations of the functional morphology of extinct species. We tested hypotheses that australopith occlusal morphology influences the fracture force required to crack large, hard food items using a combination of physical testing and finite element analysis (FEA). We performed mechanical experiments simulating both molar and premolar biting using metal replicas of four hominin specimens representing species that differ in occlusal relief (Praeanthropus afarensis, Australopithecus africanus, Paranthropus robustus, and P. boisei). The replicas were inserted into an Instron machine and used to fracture hollow acrylic hemispheres with known material properties. These hemispheres simulate a hard and brittle food item but exhibit far less variability in size and strength than actual nuts or seeds, thereby facilitating interpretations of tooth function. Fracture forces and fracture displacements were measured, and analysis of variance revealed significant differences in fracture force and energy between specimens and tooth types. Complementing the physical testing, a nonlinear contact finite element model was developed to simulate each physical test. Experimental and FEA results showed good correspondence in most cases, and FEA identified stress concentrations consistent with mechanical models predicting that radial/median fractures are important factors in the failure of nut and seed shells. The fracture force data revealed functional similarities between relatively unworn Pr. afarensis and P. robustus teeth, and between relatively unworn A. africanus and heavily worn P. boisei teeth. These results are inconsistent with functional hypotheses, and raise the possibility that the tooth morphology of early hominins and other hard object feeders may not represent adaptations for inducing fractures in large, hard food items, but rather for resisting fractures in the tooth crown.

A Dexter Exo Within P53

Cell Cycle (Georgetown, Tex.). Mar, 2010  |  Pubmed ID: 20237417

[Cooperation with a Psychotherapist is Important for Chronic Pain Patients]

MMW Fortschritte Der Medizin. Jan, 2010  |  Pubmed ID: 20302162

Apples and Oranges: Avoiding Different Priors in Bayesian DNA Sequence Analysis

BMC Bioinformatics. 2010  |  Pubmed ID: 20307305

One of the challenges of bioinformatics remains the recognition of short signal sequences in genomic DNA such as donor or acceptor splice sites, splicing enhancers or silencers, translation initiation sites, transcription start sites, transcription factor binding sites, nucleosome binding sites, miRNA binding sites, or insulator binding sites. During the last decade, a wealth of algorithms for the recognition of such DNA sequences has been developed and compared with the goal of improving their performance and to deepen our understanding of the underlying cellular processes. Most of these algorithms are based on statistical models belonging to the family of Markov random fields such as position weight matrix models, weight array matrix models, Markov models of higher order, or moral Bayesian networks. While in many comparative studies different learning principles or different statistical models have been compared, the influence of choosing different prior distributions for the model parameters when using different learning principles has been overlooked, and possibly lead to questionable conclusions.

Late-treated Phenylketonuria and Partial Reversibility of Intellectual Impairment

Child Development. Jan-Feb, 2010  |  Pubmed ID: 20331662

Individuals with late-treated phenylketonuria (PKU) not detected by newborn screening but who followed dietary treatment for at least 12 months before 7 years of age have intelligence quotient (IQ) scores that range from severe impairment to the low-normal range. Among adults with late-treated PKU in California, 85% of those who were born from 1961 to 1978 had IQ scores of 70 or above. Longitudinal studies with repeated cognitive assessments often show average changes in cognitive test scores as high as 20-45 points. Although the severe cognitive impairment associated with untreated PKU can in many cases be partially reversed with dietary treatment, prompt initiation of treatment following newborn metabolic screening is essential for optimal development and the prevention of disability.

Emergency Department Visits Made by Patients with Sickle Cell Disease: a Descriptive Study, 1999-2007

American Journal of Preventive Medicine. Apr, 2010  |  Pubmed ID: 20331955

Patients with sickle cell disease (SCD) often use emergency department services to obtain medical care. Limited information is available about emergency department use among patients with SCD.

Sickle Cell Disease-related Pediatric Medical Expenditures in the U.S

American Journal of Preventive Medicine. Apr, 2010  |  Pubmed ID: 20331957

Although it is known that people with sickle cell disease (SCD) have relatively high utilization of medical care, most previous estimates of SCD-attributable expenditures have been limited to either inpatient care or single-state data.

Administrative Data Sets and Health Services Research on Hemoglobinopathies: a Review of the Literature

American Journal of Preventive Medicine. Apr, 2010  |  Pubmed ID: 20331958

Large administrative healthcare data sets are an important source of data for health services research on sickle cell disease (SCD) and thalassemia. This paper identifies and describes major U.S. healthcare administrative databases and their use in published health services research on hemoglobinopathies.

Characterization of Human Chondrocytes Exposed to Simulated Microgravity

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2010  |  Pubmed ID: 20332636

Tissue engineering is a strategy of cartilage regeneration, but scaffolds, required for 3D growth of chondrocytes, are still a problem.

Containment of Extended Length Polymorphisms in Silk Proteins

Journal of Molecular Evolution. Apr, 2010  |  Pubmed ID: 20349054

The spider silk gene family to the current date has been developed by gene duplication and homogenization events as well as conservation of crucial sequence parts. These evolutionary processes have created an amazing diversity of silk types each associated with specific properties and functions. In addition, they have led to allelic and gene variants within a species as exemplified by the major ampullate spidroin 1 gene of Nephila clavipes. Due to limited numbers of individuals screened to date little is known about the extent of these heterogeneities and how they are finally manifested in the proteins. Using expanded sample sizes, we show that sequence variations expressed as deletions or insertions of tri-nucleotides lead to different sized and structured repetitive units throughout a silk protein. Moreover, major ampullate spidroins 1 can quite dramatically differ in their overall lengths; however, extreme variants do not spread widely in a spider population. This suggests that a certain size range stabilized by purifying selection is important for spidroin 1 gene integrity and protein function. More than one locus for spidroin 1 genes possibly exist within one individual genome, which are homogenized in size, are differentially expressed and give a spider a certain degree of adaptation on silk's composition and properties. Such mechanisms are shared to a lesser extent by the second major ampullate spidroin gene.

CT Findings in Diseases Associated with Pulmonary Hypertension: a Current Review

Radiographics : a Review Publication of the Radiological Society of North America, Inc. Nov, 2010  |  Pubmed ID: 21057119

Pulmonary hypertension may primarily affect either the arterial (precapillary) or the venous (postcapillary) pulmonary circulation. Pulmonary arterial hypertension may be idiopathic or arise in association with chronic pulmonary thromboembolism; pulmonary embolism caused by tumor cells, parasitic material, or foreign material; parenchymal lung disease; liver disease; vasculitis; human immunodeficiency virus infection; or a left-to-right cardiac shunt. Its histologic characteristics include vascular changes-medial hypertrophy, intimal cellular proliferation, intraluminal thrombosis, and the development of plexiform lesions-that manifest primarily in the muscular pulmonary arteries. Features of pulmonary arterial hypertension that may be seen at computed tomography (CT) are central pulmonary artery dilatation, abrupt narrowing or tapering of peripheral pulmonary vessels, right ventricular hypertrophy, right ventricular and atrial enlargement, dilated bronchial arteries, and a mosaic pattern of attenuation due to variable lung perfusion. Pulmonary venous hypertension may result from pulmonary veno-occlusive disease, pulmonary venous compression by extrinsic lesions (eg, mediastinal fibrosis), left-sided cardiac disease, or pulmonary vein stenosis. Its histologic hallmarks include venous intimal cellular proliferation, medial hypertrophy, and thickening of the internal elastic lamina; capillary congestion and proliferation; interlobular septal thickening; lymphatic dilatation; and, sometimes, venous infarction and vascular changes characteristic of pulmonary arterial hypertension. CT scans in patients with pulmonary venous hypertension show pulmonary interstitial and alveolar edema with signs of pulmonary arterial hypertension. High-resolution CT with standard axial and angiographic acquisitions is useful for identifying underlying disorders and differentiating among the various causes of secondary pulmonary hypertension.

Adjuvant Docetaxel for High-risk, Node-negative Breast Cancer

The New England Journal of Medicine. Dec, 2010  |  Pubmed ID: 21121833

A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) is superior to a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) when used as adjuvant therapy in women with node-positive breast cancer. The value of taxanes in the treatment of node-negative disease has not been determined.

The Orphan Adhesion-GPCR GPR126 is Required for Embryonic Development in the Mouse

PloS One. 2010  |  Pubmed ID: 21124978

Adhesion-GPCRs provide essential cell-cell and cell-matrix interactions in development, and have been implicated in inherited human diseases like Usher Syndrome and bilateral frontoparietal polymicrogyria. They are the second largest subfamily of seven-transmembrane spanning proteins in vertebrates, but the function of most of these receptors is still not understood. The orphan Adhesion-GPCR GPR126 has recently been shown to play an essential role in the myelination of peripheral nerves in zebrafish. In parallel, whole-genome association studies have implicated variation at the GPR126 locus as a determinant of body height in the human population. The physiological function of GPR126 in mammals is still unknown. We describe a targeted mutation of GPR126 in the mouse, and show that GPR126 is required for embryonic viability and cardiovascular development.

Nature Versus Nurture in Two Highly Enantioselective Esterases from Bacillus Cereus and Thermoanaerobacter Tengcongensis

Microbial Biotechnology. Jan, 2010  |  Pubmed ID: 21255307

There is an increasing need for the use of biocatalysis to obtain enantiopure compounds as chiral building blocks for drug synthesis such as antibiotics. The principal findings of this study are: (i) the complete sequenced genomes of Bacillus cereus ATCC 14579 and Thermoanaerobacter tengcongensis MB4 contain a hitherto undescribed enantioselective and alkaliphilic esterase (BcEST and TtEST respectively) that is specific for the production of (R)-2-benzyloxy-propionic acid ethyl ester, a key intermediate in the synthesis of levofloxacin, a potent antibiotic; and (ii) directed evolution targeted for increased thermostability of BcEST produced two improved variants, but in either case the 3-5 °C increase in the apparent melting temperature (T(m)) of the mutants over the native BcEST that has a T(m) of 50 °C was outperformed by TtEST, a naturally occurring homologue with a T(m) of 65 °C. Protein modelling of BcEST mapped the S148C and K272R mutations at protein surface and the I88T and Q110L mutations at more buried locations. This work expands the repertoire of characterized members of the α/β-fold hydrolase superfamily. Further, it shows that genome mining is an economical option for new biocatalyst discovery and we provide a rare example of a naturally occurring thermostable biocatalyst that outperforms experimentally evolved homologues that carry out the same hydrolysis.

Outpatient Medical Conditions Among Children and Adults with Spina Bifida in the United States: Frequency and Expenditures

Journal of Pediatric Rehabilitation Medicine. 2010  |  Pubmed ID: 21791849

Objective: To describe the most prevalent conditions and their associated expenditures for the outpatient care of individuals with spina bifida (SB) of varying ages. Design: From a large health insurance claims database of people with private insurance, we examined records on outpatient health care received during 2005-2006 for individuals with SB and a matched comparison group. Chronic conditions from the most frequently recorded 4-digit ICD-9-CM codes for individuals with SB were grouped into four categories: cardiovascular disease risk factors, SB secondary conditions, pain, and other symptoms. Results: Diseases affecting the nervous, genitourinary, and musculoskeletal systems and miscellaneous symptoms (e.g., headache, fever) account for about 70% of outpatient expenditures, excluding those associated with perinatal and congenital conditions. The most common and costly conditions by age group were diseases of the nervous system for children and adults younger than age 30 years and diseases of the musculoskeletal system for adults aged 30-64 years. Individuals with SB had significantly elevated risks for essential hypertension, urinary tract infection, and constipation at young ages and headache, sleep disturbance, and fever throughout the life span. Conclusions: The frequency of health conditions associated with SB varies across the life span. These conditions should be a priority for further investigations to identify risk factors, treatment and prevention strategies for individuals with SB.

Points to Consider in Assessing and Appraising Predictive Genetic Tests

Journal of Community Genetics. Dec, 2010  |  Pubmed ID: 22460301

The use of predictive genetic tests is expanding rapidly. Given limited health care budgets and few national coverage decisions specifically for genetic tests, evidence of benefits and harms is a key requirement in decision making; however, assessing the benefits and harms of genetic tests raises a number of challenging issues. Frequently, evidence of medical benefits and harms is limited due to practical and ethical limitations of conducting meaningful clinical trials. Also, clinical endpoints frequently do not capture the benefit appropriately because the main purpose of many genetic tests is personal utility of knowing the test results, and costs of the tests and counseling can be insufficient indicators of the total costs of care. This study provides an overview of points to consider for the assessment of benefits and harms from genetic tests in an ethically and economically reflected manner. We discuss whether genetic tests are sufficiently exceptional to warrant exceptional methods for assessment and appraisal.

Preventable Exposures Associated with Human Cancers

Journal of the National Cancer Institute. Dec, 2011  |  Pubmed ID: 22158127

Information on the causes of cancer at specific sites is important to cancer control planners, cancer researchers, cancer patients, and the general public. The International Agency for Research on Cancer (IARC) Monograph series, which has classified human carcinogens for more than 40 years, recently completed a review to provide up-to-date information on the cancer sites associated with more than 100 carcinogenic agents. Based on IARC's review, we listed the cancer sites associated with each agent and then rearranged this information to list the known and suspected causes of cancer at each site. We also summarized the rationale for classifications that were based on mechanistic data. This information, based on the forthcoming IARC Monographs Volume 100, offers insights into the current state-of-the-science of carcinogen identification. Use of mechanistic data to identify carcinogens is increasing, and epidemiological research is identifying additional carcinogens and cancer sites or confirming carcinogenic potential under conditions of lower exposure. Nevertheless, some common human cancers still have few (or no) identified causal agents.

Proteomic Identification of PSF and P54(nrb) As TopBP1-interacting Proteins

Journal of Cellular Biochemistry. Dec, 2011  |  Pubmed ID: 22213094

TopBP1 is a BRCT domain-rich protein that is structurally and functionally conserved throughout eukaryotic organisms. It is required for the initiation of DNA replication and for DNA repair and damage signalling. To further dissect its biological functions, we explored TopBP1-interacting proteins by co-immunoprecipitation assays and LC-ESI-MS-analyses. As TopBP1 binding partners we identified p54(nrb) and PSF, and confirmed the physical interactions by GST pull-down assays, co-immunoprecipitations and by yeast two-hybrid experiments. Recent evidence shows an involvement of p54(nrb) and PSF in DNA double-strand break repair (DSB) and radioresistance. To get a first picture of the physiological significance of the interaction of TopBP1 with p54(nrb) and PSF we investigated in real time the spatiotemporal behaviour of the three proteins after laser microirradiation of living cells. Localization of TopBP1 at damage sites was noticed as early as 5 seconds following damage induction, whereas p54(nrb) and PSF localized there after 20 sec. Both p54(nrb) and PSF disappeared after 200 seconds while TopBP1 was retained at damage sites significantly longer suggesting different functions of the proteins during DSB recognition and repair. J. Cell. Biochem. © 2011 Wiley Periodicals, Inc.

Urinary Concentrations of Ethyl Glucuronide and Ethyl Sulfate As Thresholds to Determine Potential Ethanol-induced Alteration of Steroid Profiles

Drug Testing and Analysis. Nov-Dec, 2011  |  Pubmed ID: 22213685

The suppression of steroid biotransformation resulting in a decrease of the major urinary metabolites--androsterone and etiocholanolone--and the elevation of testosterone/epitestosterone (T/E) ratios following ethanol administration is well described. At least the latter parameter T/E represents an important indicator for endogenous steroid abuse in doping control. The quantitative correlation between ethanol consumption markers and steroid profile alteration was evaluated, aiming to differentiate between permitted ethanol administration and potential steroid abuse. Steroid profiles, ethanol, ethyl glucuronide (EtG), and sulfate (EtS) were quantified after administration of ethanol (intended maximum ethanol concentration in blood was 1 mg/g) to 21 male and 15 female volunteers. EtG concentrations in urine (corrected by either specific gravity or creatinine concentration) were found to be most suitable for quantitative evaluations. Gender specific urinary EtG concentrations of 48 ug/ml (men) and 15.5 ug/ml (women) may be considered as useful thresholds for a potential ethanol-induced suppression of steroids biotransformation.

Bitumens and Bitumen Emissions, and Some Heterocyclic Polycyclic Aromatic Hydrocarbons

The Lancet Oncology. Dec, 2011  |  Pubmed ID: 22232803

Ethical Implications and Practical Considerations of Ethnically Targeted Screening for Genetic Disorders: the Case of Hemoglobinopathy Screening

Ethnicity & Health. Aug-Oct, 2011  |  Pubmed ID: 21797724

The prevalence of hemoglobinopathies differs among populations due to genetic differences and due to the protective effects of the heterozygote (carrier) state against malaria. Because of the difference in genetic distribution, public health programs have weighed the ethical versus practical implications of ethnically targeted versus universal newborn, and where applicable, prenatal screening. We examine newborn and prenatal screening for hemoglobinopathies in relation to the use of 'race' and ethnicity to assess risk for genetic conditions. First, categories of race/ethnicity are social constructs, therefore, observed or self-identified broad racial/ethnic categories are correlated but not necessarily reliable indicators of geographic ancestry or genetic risk. Second, targeting based on ethnicity poses serious issues of logistics and equity for public health programs and clinical services. In the past, newborn screening for hemoglobinopathies in the United States and United Kingdom was often selective, targeted to women of certain ethnic groups or areas with large concentrations of ethnic minority groups. Presently, newborn screening for hemoglobinopathies is universal in both countries and programs emphasize that individuals of all ethnic backgrounds are at risk for carrying a hemoglobin genetic variant. Reported race/ethnicity is still used as a criterion for offering prenatal carrier testing in the United States, where it is not a public health responsibility. In the United Kingdom, prenatal screening under the National Health Service is universal in high-prevalence areas and in low-prevalence areas is targeted based on reported ancestry. The continued use of targeted prenatal screening in both countries reflects the different purposes and modes of laboratory testing in newborn and prenatal screening. The ethical imperative to identify as many affected infants with life-threatening conditions as possible in newborn screening programs is not applicable to prenatal carrier testing. Because newborn screening dried blood spot specimens are tested for multiple disorders, targeted screening poses serious logistical challenges which is not the case in prenatal screening.

Visualising the Carboxylate Shift at a Bioinspired Diiron(II) Site in the Solid State

Chemical Communications (Cambridge, England). Oct, 2011  |  Pubmed ID: 21842055

A novel pyrazolate-based diiron(II) complex shows five different binding modes of exogenous carboxylate ligands in a single crystal structure. Temperature dependent X-ray data reveal thermally induced disorder due to carboxylate dynamics that resemble the carboxylate shift, as it is known from various diiron enzyme active sites.

Carcinogenicity of Radiofrequency Electromagnetic Fields

The Lancet Oncology. Jul, 2011  |  Pubmed ID: 21845765

High-speed Three-dimensional Shape Measurements of Objects with Laser Speckles and Acousto-optical Deflection

Optics Letters. Aug, 2011  |  Pubmed ID: 21847172

Many three-dimensional (3D) shape measurement techniques in stereophotogrammetry with temporal coded structured illumination are limited to static scenes because the time for measurement is too long in comparison to the object speed. The measurement of moving objects result in erroneous reconstructions. This is apparent to reduce measurement time to overcome this limitation, which is often done by increasing the projection rate for illumination while shrinking the amount of images taken for reconstruction. The projection rate limits most applications in its speed because digital light processing (DLP) projectors, which are widely used, bring a limited projection rate along. Our approach, in contrast, does not take a DLP. Instead we use laser speckles as projected patterns which are switched using an acousto-optical deflector. The projection rate is 10× higher than what the fastest stripe projection systems to our knowledge achieve. Hence, we present this uncommon but potential approach for highspeed (≈250 3Dfps= [3D measurements per second]), dense, and accurate 3D measurements of spatially separated objects and show the media that emphasizes the ability of accurate measurements while the objects under testing move.

Isolation Strategies of Regulatory T Cells for Clinical Trials: Phenotype, Function, Stability, and Expansion Capacity

Experimental Hematology. Dec, 2011  |  Pubmed ID: 21864487

Recent clinical results demonstrate the highly effective potency of regulatory T cells (Tregs) to control graft-versus-host disease (GvHD). In this presented study, we directly compared different Treg subpopulations in order to define the most promising Treg target cell population for cellular intervention studies with respect to their phenotype, functional properties, stability, and expansion capacity. Different Treg cell populations have been isolated from healthy donors and characterized by fluorescence activated cell sorting (FACS) analysis for their phenotypic marker and purity, functional properties by suppression assay, stability by Treg-specific demethylated region (TSDR) of the Foxp3 promoter and their in vitro expansion capacity. The direct comparison of the respective Treg target cell populations identified CD4(+)CD25(hi)CD127(-) and CD4(+)CD25(hi)ICOS(+) Tregs as the most promising Treg population for fresh cell infusions in clinical trials with respect to cell yield, phenotype, function, and stability. The CD4(+)CD25(hi) Tregs qualified as the best candidate for in vitro expansion combining a highly stable phenotype with strong suppressive potential and attractive cell yield after repetitive stimulation. The suppressive capacity of freshly isolated CD4(+)CD25(hi)CD45RA(+) and CD49d(-)CD127(-) Tregs is comparable to freshly isolated CD4(+)CD25(hi), but inferior to CD4(+)CD25(hi)CD127(-) and CD4(+)CD25(hi)ICOS(+) Tregs. In vitro expansion of CD4(+)CD25(hi)CD45RA(+) and CD49d(-)CD127(-) Tregs resulted in cell populations with less suppressive potency compared with CD4(+)CD25(hi) expanded Tregs correlating well with a higher TSDR demethylation level. In conclusion, future clinical trials should favor CD4(+)CD25(hi)CD127(-) and CD4(+)CD25(hi)ICOS(+) Tregs for direct Treg cell transfer, whereas CD4(+)CD25(hi) Tregs qualify as best candidate for in vitro expansion.

Differential Gene Regulation Under Altered Gravity Conditions in Follicular Thyroid Cancer Cells: Relationship Between the Extracellular Matrix and the Cytoskeleton

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2011  |  Pubmed ID: 21865726

Extracellular matrix proteins, adhesion molecules, and cytoskeletal proteins form a dynamic network interacting with signalling molecules as an adaptive response to altered gravity. An important issue is the exact differentiation between real microgravity responses of the cells or cellular reactions to hypergravity and/or vibrations. To determine the effects of real microgravity on human cells, we used four DLR parabolic flight campaigns and focused on the effects of short-term microgravity (22 s), hypergravity (1.8 g), and vibrations on ML-1 thyroid cancer cells. No signs of apoptosis or necrosis were detectable. Gene array analysis revealed 2,430 significantly changed transcripts. After 22 s microgravity, the F-actin and cytokeratin cytoskeleton was altered, and ACTB and KRT80 mRNAs were significantly upregulated after the first and thirty-first parabolas. The COL4A5 mRNA was downregulated under microgravity, whereas OPN and FN were significantly upregulated. Hypergravity and vibrations did not change ACTB, KRT-80 or COL4A5 mRNA. MTSS1 and LIMA1 mRNAs were downregulated/slightly upregulated under microgravity, upregulated in hypergravity and unchanged by vibrations. These data indicate that the graviresponse of ML-1 cells occurred very early, within the first few seconds. Downregulated MTSS1 and upregulated LIMA1 may be an adaptive mechanism of human cells for stabilizing the cytoskeleton under microgravity conditions.

Health Care Expenditures Associated with Venous Thromboembolism Among Children

Thrombosis Research. Aug, 2011  |  Pubmed ID: 21872297

INTRODUCTION: We used health insurance claims data from large samples of Medicaid-enrolled and privately insured children to identify children with venous thromboembolism (VTE) and to assess their use of health services and associated expenditures during 2009. MATERIALS AND METHODS: Data from the 2009 Thomson Reuters MarketScan® Commercial Database and Multi-State Medicaid database were used to estimate annual expenditures for children 1-17years of age with VTE. Generalized linear models were used to calculate adjusted annual expenditures for Medicaid-enrolled and privately insured children with VTE, controlling for age, sex, type of health plan, VTE classification (deep vein thrombosis and/or pulmonary embolism), and type of VTE event (idiopathic or secondary) and race (Medicaid only) or region (Commercial only). RESULTS: During 2009, Medicaid-enrolled and privately insured children with VTE had an average of 1-2 inpatient admissions and 8-10 non-emergency department visits. Unadjusted mean total expenditures were similar for Medicaid-enrolled and privately insured children with VTE, $105,359 and $87,767, respectively. Adjusted mean expenditures for children with secondary VTE were five times higher than for children with idiopathic VTE. CONCLUSIONS: Given the high frequency of secondary VTE in children, most of the associated expenditures may be due to other health conditions. However, children who develop a VTE incur substantial costs of care, even in the absence of related conditions. Additional research is needed to evaluate the long term outcomes for children with VTE including rates of readmission, complications, and the impact of co-morbid conditions.

Cell Dynamics in Fetal Intestinal Epithelium: Implications for Intestinal Growth and Morphogenesis

Development (Cambridge, England). Oct, 2011  |  Pubmed ID: 21880782

The cellular mechanisms that drive growth and remodeling of the early intestinal epithelium are poorly understood. Current dogma suggests that the murine fetal intestinal epithelium is stratified, that villi are formed by an epithelial remodeling process involving the de novo formation of apical surface at secondary lumina, and that radial intercalation of the stratified cells constitutes a major intestinal lengthening mechanism. Here, we investigate cell polarity, cell cycle dynamics and cell shape in the fetal murine intestine between E12.5 and E14.5. We show that, contrary to previous assumptions, this epithelium is pseudostratified. Furthermore, epithelial nuclei exhibit interkinetic nuclear migration, a process wherein nuclei move in concert with the cell cycle, from the basal side (where DNA is synthesized) to the apical surface (where mitosis takes place); such nuclear movements were previously misinterpreted as the radial intercalation of cells. We further demonstrate that growth of epithelial girth between E12.5 and E14.5 is driven by microtubule- and actinomyosin-dependent apicobasal elongation, rather than by progressive epithelial stratification as was previously thought. Finally, we show that the actin-binding protein Shroom3 is crucial for the maintenance of the single-layered pseudostratified epithelium. In mice lacking Shroom3, the epithelium is disorganized and temporarily stratified during villus emergence. These results favor an alternative model of intestinal morphogenesis in which the epithelium remains single layered and apicobasally polarized throughout early intestinal development.

Chemical Engineering of Mycobacterium Tuberculosis Dodecin Hybrids

Chemical Communications (Cambridge, England). Oct, 2011  |  Pubmed ID: 21897938

The suitability for chemical engineering of the highly symmetrical Mycobacterium tuberculosis dodecin was investigated, its inner cavity providing a large compartment shields introduced compounds from bulk solvent. Hybrids were obtained by S-alkylation of cysteine mutants and characterized by spectroscopic methods, including the crystal structures of wild type and biohybrid dodecins.

Characteristics of Users of Intrauterine Devices and Other Reversible Contraceptive Methods in the United States

Fertility and Sterility. Nov, 2011  |  Pubmed ID: 21917255

To evaluate the determinants of intrauterine device (IUD) use and reasons for choosing IUDs over other reversible contraceptive methods.

New Feruloyl Esterases to Access Phenolic Acids from Grass Biomass

Applied Biochemistry and Biotechnology. Sep, 2011  |  Pubmed ID: 21927859

In the Sorangium cellulosum strain So ce56 genome, two putative esterase-encoding genes (loci sce1896 and sce8927) were cloned, expressed in Escherichia coli, and the resulting enzymes (designated ScFAE1 and ScFAE2) were used to assess the possible release of ferulic acid (FA) from triticale and wheat brans, and an aqueous fraction of steam-exploded wheat straw. The two polypeptides, sharing only 30% sequence identity, exhibit a typical catalytic Ser-Asp-His triad, a characteristic of α/β-hydrolase fold proteins. Both ScFAE1 (35 kDa) and ScFAE2 (34 kDa) were purified to apparent homogeneity and comparison of their kinetic parameters indicated an apparent higher affinity of ScFAE2 than ScFAE1 towards the various feruloyl substrates. This property was reflected by the observation that ScFAE2 was capable of yielding up to 85% of FA from destarched triticale bran. In the steam-exploded wheat sample, more than 85% yield of FA or p-coumaric acid was also effected by ScFAE2 without the decomposition of valuable chemical such as furfural. The two cloned FAEs represent the first of myxobacterial origin to be characterized and they are classified as new members of the type D family of FAEs.

Ten Gbit/s Ring Resonator Silicon Modulator Based on Interdigitated PN Junctions

Optics Express. Jul, 2011  |  Pubmed ID: 21934831

10 Gbit/s silicon modulator based on carrier depletion in interdigitated PN junctions is experimentally demonstrated. The phase-shifter is integrated in a ring resonator, and high extinction ratio larger than 10 dB is obtained in both TE and TM polarizations. VπLπ of about 2.5 V × cm and optical loss lower than 1 dB are estimated. 10 Gbit/s data transmission is demonstrated with an extinction ratio of 4 dB.

A National Profile of Health Care and Family Impacts of Children With Muscular Dystrophy and Special Health Care Needs in the United States

Journal of Child Neurology. Sep, 2011  |  Pubmed ID: 21954427

We used the 2005-2006 National Survey of Children with Special Health Care Needs to compare 3 types of outcomes between children with and those without parental reported muscular dystrophy: (1) functional limitations; (2) health care experiences in terms of the 5 components of a medical home; and (3) family impacts, including financial or out-of-pocket costs and parental employment and time use. We used weighted logistic regression to examine their associations with muscular dystrophy after adjustment for socio-demographic characteristics. Among children with special health care needs, children with reported muscular dystrophy were much more likely to have difficulties with ambulation and self-care. They were more likely to have family members who reported financial problems, reduced or stopped employment, and spent more than 10 hours weekly providing or coordinating care. Muscular dystrophy was not associated with the likelihood of having a medical home after adjustment for socioeconomic status and other socio-demographic characteristics.

Effects of Receptor Modification and Temperature on Dynamics of Sensory Complexes in Escherichia Coli Chemotaxis

BMC Microbiology. 2011  |  Pubmed ID: 21978288

Extracellular stimuli in chemotaxis of Escherichia coli and other bacteria are processed by large clusters of sensory complexes. The stable core of these clusters is formed by transmembrane receptors, a kinase CheA, and an adaptor CheW, whereas adaptation enzymes CheR and CheB dynamically associate with the clusters via interactions with receptors and/or CheA. Several biochemical studies have indicated the dependence of the sensory complex stability on the adaptive modification state of receptors and/or on temperature, which may potentially allow environment-dependent tuning of its signalling properties. However, the extent of such regulation in vivo and its significance for chemotaxis remained unclear.

Magnetization Transfer in Human Achilles Tendon Assessed by a 3D Ultrashort Echo Time Sequence: Quantitative Examinations in Healthy Volunteers at 3T

RöFo : Fortschritte Auf Dem Gebiete Der Röntgenstrahlen Und Der Nuklearmedizin. Nov, 2011  |  Pubmed ID: 21986866

Magnetization transfer contrast (MTC) imaging provides insight into interactions between free and bounded water. Newly developed ultrashort echo time (UTE) sequences implemented on whole-body magnetic resonance (MR) scanners allow MTC imaging in tissues with extremely fast signal decay such as tendons. The aim of this study was to develop a technique for the quantification of the MT effect in healthy Achilles tendons in-vivo at 3 Tesla.

Strategies for Implementing Screening for Critical Congenital Heart Disease

Pediatrics. Nov, 2011  |  Pubmed ID: 21987707

Although newborn screening for critical congenital heart disease (CCHD) was recommended by the US Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children to promote early detection, it was deemed by the Secretary of the HHS as not ready for adoption pending an implementation plan from HHS agencies.

The Role of Health Technology Assessment in Coverage Decisions on Newborn Screening

International Journal of Technology Assessment in Health Care. Oct, 2011  |  Pubmed ID: 22004771

The role and impact of health technology assessment (HTA) in health policy has been widely discussed. Researchers have started to analyze how decisions on coverage of new technologies are made. Although the involvement of HTA may be an indicator of a well established decision process, this hypothesis requires validation. Also, it is not known whether HTA involvement is associated with other characteristics of decision making like participation or transparency. The primary objective of this study was to develop and test statements on the association between the publication of an HTA and coverage decision making for newborn screening tests in European Union countries.

Health Care Expenditures Among Children with and Those Without Spina Bifida Enrolled in Medicaid in North Carolina

Birth Defects Research. Part A, Clinical and Molecular Teratology. Dec, 2011  |  Pubmed ID: 22021073

National data on health care use among children with special needs are limited and do not address children with spina bifida (SB). One recent study examined health care costs during 2003 among privately insured individuals with SB. Our objective was to compare health care use and expenditures among publicly insured children with SB to children without a major birth defect and among children with SB with and without hydrocephalus.

The Effects of Newer Beta-Adrenoceptor Antagonists on Vascular Function in Cardiovascular Disease

Current Vascular Pharmacology. Oct, 2011  |  Pubmed ID: 22022769

This review provides a systematic overview of the influence of the third generation beta-adrenoceptor antagonists on vascular and/or endothelial function at a cellular level as well as of the advantages of their application in hypertension, heart failure and coronary artery disease. Drugs antagonizing the beta-adrenoceptors have been in use for the treatment of hypertension for decades. In systolic heart failure and post-myocardial infarction, beta-adrenoceptor antagonists were proven to be effective in decreasing the number of deaths and improving morbidity. However, beta-adrenoceptor antagonists are a heterogeneous drug group, consisting of agents with different selectivity for adrenoceptors and/or additional effects in heart and peripheral circulation. Beta-adrenoceptor antagonists comprise a multitude of different agents, which may have additional properties exceeding the pure receptor blockade. These features may provide additional benefit in the treatment of hypertension. The third generation drug nebivolol exerts a nitric oxide-mediated vasodilating activity which has positive effects on intima and media thickness and arterial rigidity, a major risk factor in cardiovascular disease. Moreover, anti-proliferative, anti-inflammatory, and anti-oxidative properties have been detected for carvedilol and nebivolol, contributing to their additional value in treatment of hypertension and heart failure.

Attitudes Toward Newborn Screening for Cytomegalovirus Infection

Pediatrics. Dec, 2011  |  Pubmed ID: 22084323

Newborns are not routinely screened for cytomegalovirus (CMV), the leading infectious cause of developmental disability. Congenital CMV satisfies a number of criteria for inclusion in newborn screening, and screening potentially offers benefits. Screening could also introduce harms such as anxiety and unnecessary costs for the families of the substantial proportion of CMV-infected children who never develop CMV-related disabilities. Our objective was to assess attitudes toward newborn screening for CMV.

A Public Health Framework for Rare Blood Disorders

American Journal of Preventive Medicine. Dec, 2011  |  Pubmed ID: 22099353

Disability Among Individuals with Sickle Cell Disease: Literature Review from a Public Health Perspective

American Journal of Preventive Medicine. Dec, 2011  |  Pubmed ID: 22099363

Young people with blood disorders face challenges in maintaining their physical health as they age. Sickle cell disease has well-documented complications in various organ systems. Increasingly, professionals, consumers, and advocates involved in blood disorders are concerned about the cumulative and ongoing effect of organ-specific complications on function and participation.

Sickle Cell Disease in Africa: a Neglected Cause of Early Childhood Mortality

American Journal of Preventive Medicine. Dec, 2011  |  Pubmed ID: 22099364

Sickle cell disease (SCD) is common throughout much of sub-Saharan Africa, affecting up to 3% of births in some parts of the continent. Nevertheless, it remains a low priority for many health ministries. The most common form of SCD is caused by homozygosity for the β-globin S gene mutation (SS disease). It is widely believed that this condition is associated with very high child mortality, but reliable contemporary data are lacking. We have reviewed available African data on mortality associated with SS disease from published and unpublished sources, with an emphasis on two types of studies: cross-sectional population surveys and cohort studies. We have concluded that, although current data are inadequate to support definitive statements, they are consistent with an early-life mortality of 50%-90% among children born in Africa with SS disease. Inclusion of SCD interventions in child survival policies and programs in Africa could benefit from more precise estimates of numbers of deaths among children with SCD. A simple, representative, and affordable approach to estimate SCD child mortality is to test blood specimens already collected through large population surveys targeting conditions such as HIV, malaria, and malnutrition, and covering children of varying ages. Thus, although there is enough evidence to justify investments in screening, prophylaxis, and treatment for African children with SCD, better data are needed to estimate the numbers of child deaths preventable by such interventions and their cost effectiveness.

Iron Overload: What is the Role of Public Health?

American Journal of Preventive Medicine. Dec, 2011  |  Pubmed ID: 22099368

Hereditary hemochromatosis type 1, also known as hereditary hemochromatosis classical (HHC), is an iron overload disorder associated, in most cases, with mutations of the hemochromatosis (HFE) gene. Although suggested algorithms for diagnosing iron overload are available, there are still questions about options for genetic and biochemical screening for hemochromatosis and duration of treatment. This article provides a summary of an expert workgroup meeting convened on September 24-25, 2009, entitled "Iron Overload: What is the Role of Public Health?" The purpose of the meeting was to enable subject matter experts to share their most recent clinical and scientific iron overload information and to facilitate the discussion of future endeavors, with special emphasis on the role of public health in this field. The two main topics were the research priorities of the field, including clinical, genetic, and public health issues, and the concerns about the validity of current screening recommendations for the condition.

Developing Public Health Surveillance for Deep Vein Thrombosis and Pulmonary Embolism

American Journal of Preventive Medicine. Dec, 2011  |  Pubmed ID: 22099369

Deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively known as venous thromboembolism (VTE), are an important and growing public health issue, associated with considerable morbidity and mortality. Presently, there is no national surveillance for DVT and PE. This article provides a summary of an expert workgroup meeting convened January 12, 2010, by the CDC. The purpose of the meeting was to inform CDC on the development of U.S. population-based public health surveillance activities for DVT/PE. Topics discussed included: (1) stakeholders, needs, gaps, and target populations; (2) requirements of surveillance systems; (3) challenges, limitations, and potential barriers to implementation of surveillance activities; and (4) integration of research and education with surveillance activities.

Gender Differences in Haemogregarine Infections in American Alligators (Alligator Mississippiensis) at Savannah River, South Carolina, USA

Journal of Wildlife Diseases. Oct, 2011  |  Pubmed ID: 22102683

We report a host gender bias in haemogregarine infection characteristics in the American alligator (Alligator mississippiensis) at the Savannah River Site, South Carolina, USA. Prevalence and severity in female alligators was higher than it was in males. The reason for this pattern is not clear.

Poisson-Boltzmann Description of the Electrical Double Layer Including Ion Size Effects

Langmuir : the ACS Journal of Surfaces and Colloids. Dec, 2011  |  Pubmed ID: 22035520

The electrical double layer is examined using a generalized Poisson-Boltzmann equation that takes into account the finite ion size by modeling the aqueous electrolyte solution as a suspension of polarizable insulating spheres in water. We find that this model greatly amplifies the steric effects predicted by the usual modified Poisson-Boltzmann equation, which imposes only a restriction on the ability of ions to approach one another. This amplification should allow for an interpretation of the experimental results using reasonable effective ionic radii (close to their well-known hydrated values).

Stereophotogrammetric 3D Shape Measurement by Holographic Methods Using Structured Speckle Illumination Combined with Interferometry

Optics Letters. Dec, 2011  |  Pubmed ID: 22139226

We present a unique combination of the numerical three-dimensional (3D) reconstruction of the shape of an object with interferometric deformation measurements. Two cameras record several holograms of an object that is illuminated by structured illumination. This illumination is realized by speckle patterns. To improve the image quality, an inplace speckle reduction technique is combined with the structured illumination to reduce the effect of disturbing subjective speckles which appear in the reconstructed images. Stereophotogrammetric methods are applied to extract the 3D surface information of the object out of the reconstructed images. Since the recording is done by holography and because stereophotogrammetry enables a pointwise correlation between the two views, it is possible to combine other holographic techniques with the reconstructed 3D shape. This is demonstrated by an interferometric deformation measurement of an object cooling down. The resulting interferometric fringes are mapped onto the reconstructed 3D surface. Hence, the proposed method enables automatic and dense matching of interferometric fringe-maps recorded by spatially separated holograms onto the surface of the object, which has not yet been realized by existing techniques.

Differing and Isoform-specific Roles for the Formin DIAPH3 in Plasma Membrane Blebbing and Filopodia Formation

Cell Research. Dec, 2011  |  Pubmed ID: 22184005

Plasma membrane (PM) blebs are dynamic actin-rich cell protrusions that occur, e.g., during cytokinesis, amoeboid cell motility and cell attachment. Using a targeted siRNA screen against 21 actin nucleation factors, we identify a novel and essential role of the human diaphanous formin DIAPH3 in PM blebbing during cell adhesion. Suppression of DIAPH3 inhibited blebbing to promote rapid cell spreading involving β1-integrin. Multiple isoforms of DIAPH3 were detected on the mRNA and protein level of which isoforms 3 and 7 were the largest and most abundant isoforms that however did not induce formation of actin-rich protrusions. Rather, PM blebbing specifically involved the low abundance isoform 1 of DIAPH3 and activation of isoform 7 by deletion of the diaphanous-autoregulatory domain caused the formation of filopodia. Dimerization and actin assembly activity were essential for induction of specific cell protrusions by DIAPH3 isoforms 1 and 7. Our data suggest that the N-terminal region comprising the GTPase-binding domain determined the subcellular localization of the formin as well as its protrusion activity between blebs and filopodia. We propose that isoform-selective actin assembly by DIAPH3 exerts specific and differentially regulated functions during cell adhesion and motility.Cell Research advance online publication 20 December 2011; doi:10.1038/cr.2011.202.

Integrated Analysis of the Conformation of a Protein-linked Spin Label by Crystallography, EPR and NMR Spectroscopy

Journal of Biomolecular NMR. Feb, 2011  |  Pubmed ID: 21271275

Long-range structural information derived from paramagnetic relaxation enhancement observed in the presence of a paramagnetic nitroxide radical is highly useful for structural characterization of globular, modular and intrinsically disordered proteins, as well as protein-protein and protein-DNA complexes. Here we characterized the conformation of a spin-label attached to the homodimeric protein CylR2 using a combination of X-ray crystallography, electron paramagnetic resonance (EPR) and NMR spectroscopy. Close agreement was found between the conformation of the spin label observed in the crystal structure with interspin distances measured by EPR and signal broadening in NMR spectra, suggesting that the conformation seen in the crystal structure is also preferred in solution. In contrast, conformations of the spin label observed in crystal structures of T4 lysozyme are not in agreement with the paramagnetic relaxation enhancement observed for spin-labeled CylR2 in solution. Our data demonstrate that accurate positioning of the paramagnetic center is essential for high-resolution structure determination.

Electrokinetics of Charged Spherical Colloidal Particles Taking into Account the Effect of Ion Size Constraints

Journal of Colloid and Interface Science. Apr, 2011  |  Pubmed ID: 21281935

The electrokinetic properties of suspended spherical particles are examined using a modified standard electrokinetic model, which takes into account the finite ion size and considers that the minimum approach distance of ions to the particle surface need not be equal to their effective radius in the bulk solution. We calculate the conductivity increment and the electrophoretic mobility and present a detailed interpretation of the obtained results, based on the analysis of the equilibrium and field-induced ion concentrations, as well as the convective fluid flow in the neighborhood of the particle surface. We show that when charge reversal takes place, the sign of the concentration polarization remains unchanged while the sign of the electrophoretic mobility only changes under favorable circumstances.

Altered Cerebrovenous Drainage in Patients with Migraine As Assessed by Phase-contrast Magnetic Resonance Imaging

Investigative Radiology. Jul, 2011  |  Pubmed ID: 21317790

We aimed to assess whether migraine is associated with changes in the distribution of the venous drainage through primary and secondary pathways by using phase-contrast magnetic resonance imaging (MRI).

Nucleating Actin for Invasion

Nature Reviews. Cancer. Mar, 2011  |  Pubmed ID: 21326322

The invasion of cancer cells into the surrounding tissue is a prerequisite and initial step in metastasis, which is the leading cause of death from cancer. Invasive cell migration requires the formation of various structures, such as invadopodia and pseudopodia, which require actin assembly that is regulated by specialized actin nucleation factors. There is a large variety of different actin nucleators in human cells, such as formins, spire and Arp2/3-regulating proteins, and the list is likely to grow. Studies of the mechanisms of various actin nucleation factors that are involved in cancer cell function may ultimately provide new treatments for invasive and metastatic disease.

An Efficient Method of Modeling Material Properties Using a Thermal Diffusion Analogy: an Example Based on Craniofacial Bone

PloS One. 2011  |  Pubmed ID: 21347288

The ability to incorporate detailed geometry into finite element models has allowed researchers to investigate the influence of morphology on performance aspects of skeletal components. This advance has also allowed researchers to explore the effect of different material models, ranging from simple (e.g., isotropic) to complex (e.g., orthotropic), on the response of bone. However, bone's complicated geometry makes it difficult to incorporate complex material models into finite element models of bone. This difficulty is due to variation in the spatial orientation of material properties throughout bone. Our analysis addresses this problem by taking full advantage of a finite element program's ability to solve thermal-structural problems. Using a linear relationship between temperature and modulus, we seeded specific nodes of the finite element model with temperatures. We then used thermal diffusion to propagate the modulus throughout the finite element model. Finally, we solved for the mechanical response of the finite element model to the applied loads and constraints. We found that using the thermal diffusion analogy to control the modulus of bone throughout its structure provides a simple and effective method of spatially varying modulus. Results compare favorably against both experimental data and results from an FE model that incorporated a complex (orthotropic) material model. This method presented will allow researchers the ability to easily incorporate more material property data into their finite element models in an effort to improve the model's accuracy.

De-novo Discovery of Differentially Abundant Transcription Factor Binding Sites Including Their Positional Preference

PLoS Computational Biology. 2011  |  Pubmed ID: 21347314

Transcription factors are a main component of gene regulation as they activate or repress gene expression by binding to specific binding sites in promoters. The de-novo discovery of transcription factor binding sites in target regions obtained by wet-lab experiments is a challenging problem in computational biology, which has not been fully solved yet. Here, we present a de-novo motif discovery tool called Dispom for finding differentially abundant transcription factor binding sites that models existing positional preferences of binding sites and adjusts the length of the motif in the learning process. Evaluating Dispom, we find that its prediction performance is superior to existing tools for de-novo motif discovery for 18 benchmark data sets with planted binding sites, and for a metazoan compendium based on experimental data from micro-array, ChIP-chip, ChIP-DSL, and DamID as well as Gene Ontology data. Finally, we apply Dispom to find binding sites differentially abundant in promoters of auxin-responsive genes extracted from Arabidopsis thaliana microarray data, and we find a motif that can be interpreted as a refined auxin responsive element predominately positioned in the 250-bp region upstream of the transcription start site. Using an independent data set of auxin-responsive genes, we find in genome-wide predictions that the refined motif is more specific for auxin-responsive genes than the canonical auxin-responsive element. In general, Dispom can be used to find differentially abundant motifs in sequences of any origin. However, the positional distribution learned by Dispom is especially beneficial if all sequences are aligned to some anchor point like the transcription start site in case of promoter sequences. We demonstrate that the combination of searching for differentially abundant motifs and inferring a position distribution from the data is beneficial for de-novo motif discovery. Hence, we make the tool freely available as a component of the open-source Java framework Jstacs and as a stand-alone application at http://www.jstacs.de/index.php/Dispom.

Measuring Health and Well-being Effects in Family Caregivers of Children with Craniofacial Malformations

Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. Nov, 2011  |  Pubmed ID: 21347570

This research explores the sensitivity of three generic instruments for preference-weighting health states of family caregivers of children with craniofacial malformations (CFM). We also examine the construct validity of the new CarerQol instrument measuring caregiver burden and general quality of life.

Reversible Shape Memory of Nanoscale Deformations in Inherently Conducting Polymers Without Reprogramming

The Journal of Physical Chemistry. B. Apr, 2011  |  Pubmed ID: 21401135

By using inherently conducting polymers, we introduce new shape memory functionality for stimuli-responsive polymers. The shape memory process is unique in that it utilizes electrochemical control of the polymer redox state to conceal, and temporarily store, preformed nanoscale surface patterns, which can later be recalled. Unlike classical thermoset and thermoplastic shape memory polymers, the electrochemical control does not completely perturb the low entropy state of the deformed polymer chains, thus enabling the concept of reversible transition between the permanent and temporary shapes. This is demonstrated using electrochemical-atomic force microscopy/quartz crystal microbalance to characterize the modulation of nanoscale deformations in electroactive polybithiophene films. Experimental results reveal that cation/solvent exchange with the electrolyte and its effect on reconfiguration of the film structure is the mechanism behind the process. In addition to incorporating conductive properties into shape-memory polymers, the ability to reversibly modulate surface nanopatterns in a liquid environment is also of significant interest in tribology and biointerface applications.

Chemoselective Reduction of 2-acyl-N-sulfonylpyrroles: Synthesis of 3-pyrrolines and 2-alkylpyrroles

Organic & Biomolecular Chemistry. May, 2011  |  Pubmed ID: 21445438

The partial reduction of pyrroles is not a common practice even though it offers a potential route to pyrroline building blocks, commonly used for synthesis. We have investigated the reduction of 2-acyl-N-sulfonylpyrroles and by varying the hydride source and solvent, achieved a chemoselective reduction, leading to 3-pyrrolines and alkyl pyrroles in high yield.

High Extinction Ratio 10 Gbit/s Silicon Optical Modulator

Optics Express. Mar, 2011  |  Pubmed ID: 21451607

High speed and high extinction ratio silicon optical modulator using carrier depletion is experimentally demonstrated. The phase-shifter is a 1.8 mm-long PIPIN diode which is integrated in a Mach Zehnder interferometer. 8.1 dB Extinction Ratio at 10 Gbit/s is obtained simultaneously with optical loss as low as 6 dB.

Meganuclease-mediated Inhibition of HSV1 Infection in Cultured Cells

Molecular Therapy : the Journal of the American Society of Gene Therapy. Apr, 2011  |  Pubmed ID: 21224832

Herpes simplex virus type 1 (HSV1) is a major health problem. As for most viral diseases, current antiviral treatments are based on the inhibition of viral replication once it has already started. As a consequence, they impair neither the viral cycle at its early stages nor the latent form of the virus, and thus cannot be considered as real preventive treatments. Latent HSV1 virus could be addressed by rare cutting endonucleases, such as meganucleases. With the aim of a proof of concept study, we generated several meganucleases recognizing HSV1 sequences, and assessed their antiviral activity in cultured cells. We demonstrate that expression of these proteins in African green monkey kidney fibroblast (COS-7) and BSR cells inhibits infection by HSV1, at low and moderate multiplicities of infection (MOIs), inducing a significant reduction of the viral load. Furthermore, the remaining viral genomes display a high rate of mutation (up to 16%) at the meganuclease cleavage site, consistent with a mechanism of action based on the cleavage of the viral genome. This specific mechanism of action qualifies meganucleases as an alternative class of antiviral agent, with the potential to address replicative as well as latent DNA viral forms.

Prevention of Intellectual Disability Through Screening for Congenital Hypothyroidism: How Much and at What Level?

Archives of Disease in Childhood. Apr, 2011  |  Pubmed ID: 21242230

Congenital hypothyroidism (CHT) is a common cause of preventable mental retardation, and the quantification of intellectual disability due to CHT is needed to assess the public health benefit of newborn screening.

Medical Expenditures of Children in the United States with Fetal Alcohol Syndrome

Neurotoxicology and Teratology. Mar-Apr, 2011  |  Pubmed ID: 21073947

This paper calculates the medical expenditures for pediatric Medicaid enrollees with fetal alcohol syndrome (FAS), those with and those without reported intellectual disability (ID). The pediatric portion of the MarketScan® Medicaid Multi-State databases for the years 2003-2005 was used. Children with FAS were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Children without FAS formed the comparison group. Annual mean, median, and 95(th) percentile total expenditures were calculated for those continuously enrolled during 2005. Children with FAS incurred annual mean medical expenditures that were nine times as high as those of children without FAS during 2005 ($16,782 vs. $1,859). ID more commonly was listed as a medical diagnosis among children with FAS than among children in the comparison group (12% vs. 0.5%), and mean expenditures of children with FAS and ID were 2.8 times those of children with FAS but without reported ID. Children with FAS incurred higher medical expenditures compared with children without FAS. A subset of children with FAS who had ID sufficiently serious to be recorded in medical records increased those expenditures still further. Our estimate of mean expenditures for children with FAS was several times higher than previous estimates in the United States.

Integrin-targeted Nanocomplexes for Tumour Specific Delivery and Therapy by Systemic Administration

Biomaterials. Feb, 2011  |  Pubmed ID: 21074847

Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.

Do Changes in Dynamic Plantar Pressure Distribution, Strength Capacity and Postural Control After Intra-articular Calcaneal Fracture Correlate with Clinical and Radiological Outcome?

Injury. Oct, 2011  |  Pubmed ID: 21075372

Fractures of the calcaneus are often associated with serious permanent disability, a considerable reduction in quality of life, and high socio-economic cost. Although some studies have already reported changes in plantar pressure distribution after calcaneal fracture, no investigation has yet focused on the patient's strength and postural control.

Nanoscale Joule Heating, Peltier Cooling and Current Crowding at Graphene-metal Contacts

Nature Nanotechnology. May, 2011  |  Pubmed ID: 21460825

The performance and scaling of graphene-based electronics is limited by the quality of contacts between the graphene and metal electrodes. However, the nature of graphene-metal contacts remains incompletely understood. Here, we use atomic force microscopy to measure the temperature distributions at the contacts of working graphene transistors with a spatial resolution of ~ 10 nm (refs 5-8), allowing us to identify the presence of Joule heating, current crowding and thermoelectric heating and cooling. Comparison with simulation enables extraction of the contact resistivity (150-200 Ω µm²) and transfer length (0.2-0.5 µm) in our devices; these generally limit performance and must be minimized. Our data indicate that thermoelectric effects account for up to one-third of the contact temperature changes, and that current crowding accounts for most of the remainder. Modelling predicts that the role of current crowding will diminish and the role of thermoelectric effects will increase as contacts improve.

Strategies and Perspectives in Ion-channel Engineering

Chembiochem : a European Journal of Chemical Biology. Apr, 2011  |  Pubmed ID: 21472911

Membranes form natural barriers that need to be permeable to diverse matter like ions and substrates. This permeability is controlled by ion-channel proteins, which have attracted great interest for pharmaceutical applications. Ion-channel engineering (ICE) modifies biological ion channels by chemical/biological synthetis means. The goal is to obtain ion channels with modified or novel functionality. Three functional strategies exist. The first is the manipulation of the wider pores with robust β-barrel structures, such as those of α-hemolysin and porins. The second engineering approach focuses on the modification of narrow (mostly α-helical) pores to understand selectivity and modes of action. A third functional approach addresses channel gating by (photo)triggering the biological receptor that controls the channel. Several synthetis strategies have been developed and successfully utilized for the synthetic modification of biological ion-channels: the S-alkylation of specifically introduced Cys, protein semisynthesis by native chemical ligation, protein semisynthesis by protein trans-splicing, as well as nonsense-suppression methods. Structural studies (X-ray crystallography, NMR spectroscopy) are necessary to support the functional studies and to afford predictable engineering. The reprogramming and re-engineering of channels can be used for sensing applications, treatment of channelopathies, chemical neurobiology, and providing novel lead compounds for targeting ion channels.

[Job Satisfaction of Radiologists in Germany - Status Quo]

RöFo : Fortschritte Auf Dem Gebiete Der Röntgenstrahlen Und Der Nuklearmedizin. Aug, 2011  |  Pubmed ID: 21506073

The aim of this study was to identify and evaluate the work-related satisfaction of radiologists and its influencing factors in Germany.

Development of a Shear Stress Sensor to Analyse the Influence of Polymers on the Turbulent Wall Shear Stress

Journal of Physics. Condensed Matter : an Institute of Physics Journal. May, 2011  |  Pubmed ID: 21508484

The drag reducing effect of polymers in a channel flow is well known and it is assumed that the polymer filaments interfere with the turbulent structures in the very near-wall flow. To analyse their precise effect, a micro-pillar shear stress sensor (MPS³) measurement system is developed which allows the detection of wall shear stress at high spatial and temporal resolutions. Different manufacturing techniques for the required micro-pillars are discussed and their influence on the flow is investigated evidencing the non-intrusive character of the pillars. Subsequently, a complete calibration is presented to relate the recorded deflection to wall shear stress values and to assure the correct detection over the whole expected frequency spectrum. A feasibility study about the ability to visualize the two-dimensional wall shear stress distribution completes the discussion about the validity of MPS³. In the last step, the drag reduction of a polymer filament grafted on a micro-pillar compared to a plain pillar and the application of MPS³ in an ocean-type polymer solution are investigated. The results confirm the expected behaviour found in the literature.

Exploiting Prior Knowledge and Gene Distances in the Analysis of Tumor Expression Profiles with Extended Hidden Markov Models

Bioinformatics (Oxford, England). Jun, 2011  |  Pubmed ID: 21511716

Changes in gene expression levels play a central role in tumors. Additional information about the distribution of gene expression levels and distances between adjacent genes on chromosomes should be integrated into the analysis of tumor expression profiles.

Automated Volumetric Assessment of the Achilles Tendon (AVAT) Using a 3D T2 Weighted SPACE Sequence at 3T in Healthy and Pathologic Cases

European Journal of Radiology. May, 2011  |  Pubmed ID: 21543175

PURPOSE: Achilles tendinopathy has been reported to be frequently associated with increasing volume of the tendon. This work aims at reliable and accurate volumetric quantification of the Achilles tendon using a newly developed contour detection algorithm applied on high resolution MRI data sets recorded at 3T. MATERIALS AND METHODS: A total of 26 healthy tendons and 4 degenerated tendons were examined for this study. Automated identification (AI) of tendon boundaries was performed in transverse slices with isotropic resolution (0.8mm) gained with a T2-weighted SPACE sequence at 3T. For AI a snake algorithm was applied and compared to manual tracing (MT). RESULTS: AI was feasible in all examined tendons without further correction. AI of both tendons was performed in each participant within 2min (2×37 slices) compared to MT lasting 20min. MT and AI showed excellent agreement and correlation (R(2)=0.99, p<0.0001). AI provided a reduction of measurement error (0.4cm(3) vs. 0.5cm(3)) and coefficient of variation (1% vs. 2%). DISCUSSION: Compared to MT the AI allows assessment of tendon volumes in highly resolved MRI data in a more accurate and reliable time-saving way. Therefore automated volume detection is seen as a helpful clinical tool for evaluation of small volumetric changes of the Achilles tendon.

Human DHX9 Helicase Preferentially Unwinds RNA-containing Displacement Loops (R-loops) and G-quadruplexes

DNA Repair. Jun, 2011  |  Pubmed ID: 21561811

Human DHX9 helicase, also known as nuclear DNA helicase II (NDH II) and RNA helicase A (RHA), belongs to the SF2 superfamily of nucleic acid unwinding enzymes. DHX9 melts simple DNA-DNA, RNA-RNA, and DNA-RNA strands with a 3'-5' polarity; despite this little is known about its substrate specificity. Here, we used partial duplex DNA consisting of M13mp18 DNA and oligonucleotide-based replication and recombination intermediates. We show that DHX9 unwinds DNA- and RNA-containing forks, DNA- and RNA-containing displacement loops (D- and R-loops), and also G-quadruplexes. With these substrates, DHX9 behaved similarly as the RecQ helicase WRN. In contrast to WRN, DHX9 melted RNA-hybrids considerably faster than the corresponding DNA-DNA strands. DHX9 preferably unwound R-loops and DNA-based G-quadruplexes indicating that these structures may be biologically relevant. DHX9 also unwound RNA-based G-quadruplexes that have been reported to occur in human transcripts. It is believed that an improper dissolution of co-transcriptionally formed D-loops, R-loops, and DNA- or RNA-based G-quadruplexes represent potential roadblocks for transcription and thereby enhance transcription associated recombination events. By unwinding these structures, DHX9 may significantly contribute to transcriptional activation and also to the maintenance of genomic stability.

The Effects of Modeling Simplifications on Craniofacial Finite Element Models: the Alveoli (tooth Sockets) and Periodontal Ligaments

Journal of Biomechanics. Jul, 2011  |  Pubmed ID: 21592483

Several finite element models of a primate cranium were used to investigate the biomechanical effects of the tooth sockets and the material behavior of the periodontal ligament (PDL) on stress and strain patterns associated with feeding. For examining the effect of tooth sockets, the unloaded sockets were modeled as devoid of teeth and PDL, filled with teeth and PDLs, or simply filled with cortical bone. The third premolar on the left side of the cranium was loaded and the PDL was treated as an isotropic, linear elastic material using published values for Young's modulus and Poisson's ratio. The remaining models, along with one of the socket models, were used to determine the effect of the PDL's material behavior on stress and strain distributions under static premolar biting and dynamic tooth loading conditions. Two models (one static and the other dynamic) treated the PDL as cortical bone. The other two models treated it as a ligament with isotropic, linear elastic material properties. Two models treated the PDL as a ligament with hyperelastic properties, and the other two as a ligament with viscoelastic properties. Both behaviors were defined using published stress-strain data obtained from in vitro experiments on porcine ligament specimens. Von Mises stress and strain contour plots indicate that the effects of the sockets and PDL material behavior are local. Results from this study suggest that modeling the sockets and the PDL in finite element analyses of skulls is project dependent and can be ignored if values of stress and strain within the alveolar region are not required.

Carcinogenicity of Chemicals in Industrial and Consumer Products, Food Contaminants and Flavourings, and Water Chlorination Byproducts

The Lancet Oncology. Apr, 2011  |  Pubmed ID: 21598447

The Continuing Health Burden of Congenital Hypothyroidism in the Era of Neonatal Screening

The Journal of Clinical Endocrinology and Metabolism. Jun, 2011  |  Pubmed ID: 21602460

Pathogenesis of Candida Albicans Infections in the Alternative Chorio-allantoic Membrane Chicken Embryo Model Resembles Systemic Murine Infections

PloS One. 2011  |  Pubmed ID: 21603634

Alternative models of microbial infections are increasingly used to screen virulence determinants of pathogens. In this study, we investigated the pathogenesis of Candida albicans and C. glabrata infections in chicken embryos infected via the chorio-allantoic membrane (CAM) and analyzed the virulence of deletion mutants. The developing immune system of the host significantly influenced susceptibility: With increasing age, embryos became more resistant and mounted a more balanced immune response, characterized by lower induction of proinflammatory cytokines and increased transcription of regulatory cytokines, suggesting that immunopathology contributes to pathogenesis. While many aspects of the chicken embryo response resembled murine infections, we also observed significant differences: In contrast to systemic infections in mice, IL-10 had a beneficial effect in chicken embryos. IL-22 and IL-17A were only upregulated after the peak mortality in the chicken embryo model occurred; thus, the role of the Th17 response in this model remains unclear. Abscess formation occurs frequently in murine models, whereas the avian response was dominated by granuloma formation. Pathogenicity of the majority of 15 tested C. albicans deletion strains was comparable to the virulence in mouse models and reduced virulence was associated with significantly lower transcription of proinflammatory cytokines. However, fungal burden did not correlate with virulence and for few mutants like bcr1Δ and tec1Δ different outcomes in survival compared to murine infections were observed. C. albicans strains locked in the yeast stage disseminated significantly more often from the CAM into the embryo, supporting the hypothesis that the yeast morphology is responsible for dissemination in systemic infections. These data suggest that the pathogenesis of C. albicans infections in the chicken embryo model resembles systemic murine infections but also differs in some aspects. Despite its limitations, it presents a useful alternative tool to pre-screen C. albicans strains to select strains for subsequent testing in murine models.

Using Occlusal Wear Information and Finite Element Analysis to Investigate Stress Distributions in Human Molars

Journal of Anatomy. Sep, 2011  |  Pubmed ID: 21615398

Simulations based on finite element analysis (FEA) have attracted increasing interest in dentistry and dental anthropology for evaluating the stress and strain distribution in teeth under occlusal loading conditions. Nonetheless, FEA is usually applied without considering changes in contacts between antagonistic teeth during the occlusal power stroke. In this contribution we show how occlusal information can be used to investigate the stress distribution with 3D FEA in lower first molars (M(1)). The antagonistic crowns M(1) and P(2)-M(1) of two dried modern human skulls were scanned by μCT in maximum intercuspation (centric occlusion) contact. A virtual analysis of the occlusal power stroke between M(1) and P(2)-M(1) was carried out in the Occlusal Fingerprint Analyser (OFA) software, and the occlusal trajectory path was recorded, while contact areas per time-step were visualized and quantified. Stress distribution of the M(1) in selected occlusal stages were analyzed in strand7, considering occlusal information taken from OFA results for individual loading direction and loading area. Our FEA results show that the stress pattern changes considerably during the power stroke, suggesting that wear facets have a crucial influence on the distribution of stress on the whole tooth. Grooves and fissures on the occlusal surface are seen as critical locations, as tensile stresses are concentrated at these features. Properly accounting for the power stroke kinematics of occluding teeth results in quite different results (less tensile stresses in the crown) than usual loading scenarios based on parallel forces to the long axis of the tooth. This leads to the conclusion that functional studies considering kinematics of teeth are important to understand biomechanics and interpret morphological adaptation of teeth.

[Pulmonary Graft Versus Host Disease]

RöFo : Fortschritte Auf Dem Gebiete Der Röntgenstrahlen Und Der Nuklearmedizin. Jun, 2011  |  Pubmed ID: 21618168

Electrically Driven Hybrid Si/III-V Fabry-Pérot Lasers Based on Adiabatic Mode Transformers

Optics Express. May, 2011  |  Pubmed ID: 21643289

We report the first demonstration of an electrically driven hybrid silicon/III-V laser based on adiabatic mode transformers. The hybrid structure is formed by two vertically superimposed waveguides separated by a 100-nm-thick SiO2 layer. The top waveguide, fabricated in an InP/InGaAsP-based heterostructure, serves to provide optical gain. The bottom Si-waveguides system, which supports all optical functions, is constituted by two tapered rib-waveguides (mode transformers), two distributed Bragg reflectors (DBRs) and a surface-grating coupler. The supermodes of this hybrid structure are controlled by an appropriate design of the tapers located at the edges of the gain region. In the middle part of the device almost all the field resides in the III-V waveguide so that the optical mode experiences maximal gain, while in regions near the III-V facets, mode transformers ensure an efficient transfer of the power flow towards Si-waveguides. The investigated device operates under quasi-continuous wave regime. The room temperature threshold current is 100 mA, the side-mode suppression ratio is as high as 20 dB, and the fiber-coupled output power is ~7 mW.

Extension of a Classic Thin Double Layer Polarization Theory of Colloidal Suspensions to Include the Stagnant Layer Conductivity

The Journal of Physical Chemistry. B. Jul, 2011  |  Pubmed ID: 21648948

A rigorous extension of the classic Dukhin-Shilov thin double layer polarization theory including the stagnant layer conductivity is presented. Precisely the same assumptions and approximations made in the original theory are maintained, and the same adsorption isotherms are used as in most of the existing numerical calculations. The obtained analytical results improve upon existing approximate extensions, mainly for low surface conductivities and high surface potentials and for high surface conductivities and low surface potentials. Moreover, they avoid the assumption that all the adsorbed ions in the stagnant layer must have a single sign. Finally, they present a very good agreement with numerical calculations specifically made using the same system parameters.

Pancreatic Exocrine Function and Cardiac Iron in Patients with Iron Overload and with Thalassemia

Pediatric Blood & Cancer. Oct, 2011  |  Pubmed ID: 21671371

Patients with β-thalassemia major at risk of cardiac iron overload have to be identified to undergo myocardial iron measurements by magnetic resonance imaging (MRI), especially, in areas and centers with restricted access to MRI. Measurements of heart iron, liver iron, and pancreatic exocrine function were performed in 44 patients by MRI-R2* [the transverse relaxation rate R2* (= 1/T2*) characterizes the magnetic resonance decay from protons not being in phase with each other in contrast to R2 (= 1/T2)], biomagnetic liver susceptometry (LIC), and pancreatic serum amylase (PAM) and lipase (LIP), respectively. ROC analysis (area: 0.88) for detecting patients with cardiac R2* > 50 sec(-1) (T2* < 20 msec) by LIP revealed a cut-off level of 19 U/L. In conclusion, patients at risk of elevated cardiac iron levels could be identified by the exocrine pancreatic lipase and amylase function parameters.

A Randomized, Parallel Group, Double-blind, Multicentre Study Comparing the Efficacy and Safety of Avandamet (rosiglitazone/metformin) and Metformin on Long-term Glycaemic Control and Bone Mineral Density After 80 Weeks of Treatment in Drug-naïve Type 2 Diabetes Mellitus Patients

Diabetes, Obesity & Metabolism. Nov, 2011  |  Pubmed ID: 21682834

The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients.

Gastric Tuft Cells Express DCLK1 and Are Expanded in Hyperplasia

Histochemistry and Cell Biology. Aug, 2011  |  Pubmed ID: 21688022

Epithelial tuft cells are named after their characteristic microtubule bundles located at the cell apex where these are exposed to the luminal environment. As such, tuft cells are found in multiple organs, including the gastrointestinal (GI) tract where the apical "tuft" is hypothesized to detect and transmit environmental signals. Thus, the goal of our study was to characterize gastric tuft cells during GI tract development, then subsequently in the normal and metaplastic adult stomach. GI tracts from mouse embryos, and newborn and postnatal mice were analyzed. Tuft cells were identified by immunohistochemistry using acetylated-α-tubulin (acTub) antibody to detect the microtubule bundle. Additional tuft cell markers, e.g., doublecortin-like kinase 1 (DCLK1), were used to co-localize with acTub. Tuft cells were quantified in human gastric tissue arrays and in mouse stomachs with or without inflammation. In the developing intestine, tuft cells in both the crypts and villi expressed all markers by E18.5. In the stomach, acTub co-localized with DCLK1 and other established tuft cell markers by E18.5 in the antrum, but not until postnatal day 7 in the corpus, with the highest density of tuft cells clustered at the forestomach ridge. Tuft cell numbers increased in hyperplastic human and mouse stomachs. In the adult GI tract, the tuft cell marker acTub co-expressed with DCKL1 and chemosensory markers, e.g.,TRPM5. In summary, tuft cells appear in the gastric antrum and intestine at E18.5, but their maximal numbers in the corpus are not achieved until after weaning. Tuft cell numbers increase with inflammation, hyperplasia, and metaplasia.

High Contrast 40Gbit/s Optical Modulation in Silicon

Optics Express. Jun, 2011  |  Pubmed ID: 21716382

Data interconnects are on the verge of a revolution. Electrical links are increasingly being pushed to their limits with the ever increasing demand for bandwidth. Data transmission in the optical domain is a leading candidate to satisfy this need. The optical modulator is key to most applications and increasing the data rate at which it operates is important for reducing power consumption, increasing channel bandwidth limitations and improving the efficiency of infrastructure usage. In this work silicon based devices of lengths 3.5mm and 1mm operating at 40Gbit/s are demonstrated with extinction ratios of up to 10dB and 3.5dB respectively. The efficiency and optical loss of the phase shifter is 2.7V.cm and 4dB/mm (or 4.5dB/mm including waveguide loss) respectively.

Excitability and Recruitment Patterns of Spinal Motoneurons in Human Sleep As Assessed by F-wave Recordings

Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale. Aug, 2011  |  Pubmed ID: 21717101

This study examines the excitability and recruitment of spinal motoneurons in human sleep. The main objective was to assess whether supraspinal inhibition affects the different subpopulations of the compound spinal motoneuron pool in the same way or rather in a selective fashion in the various sleep stages. To this end, we studied F-conduction velocities (FCV) and F-tacheodispersion alongside F-amplitudes and F-persistence in 22 healthy subjects in sleep stages N2, N3 (slow-wave sleep), REM and in wakefulness. Stimuli were delivered on the ulnar nerve, and F-waves were recorded from the first dorsal interosseus muscle. Repeated sets of stimuli were stored to obtain at least 15 F-waves for each state of vigilance. F-tacheodispersion was calculated based on FCVs using the modified Kimura formula. Confirming the only previous study, excitability of spinal motoneurons was generally decreased in all sleep stages compared with wakefulness as indicated by significantly reduced F-persistence and F-amplitudes. More importantly, F-tacheodispersion showed a narrowed range of FCV in all sleep stages, most prominently in REM. In non-REM, this narrowed range was associated with a shift towards significantly decreased maximal FCV and mean FCV as well as with a trend towards lower minimal FCV. In REM, the lowering of mean FCV was even more pronounced, but contrary to non-REM sleep without a shift of minimal and maximal FCV. Variations in F-tacheodispersion between sleep stages suggest that different supraspinal inhibitory neuronal circuits acting on the spinal motoneuron pool may contribute to muscle hypotonia in human non-REM sleep and to atonia in REM sleep.

Integration of Detailed Modules in a Core Model of Body Fluid Homeostasis and Blood Pressure Regulation

Progress in Biophysics and Molecular Biology. Oct, 2011  |  Pubmed ID: 21729716

This paper presents a contribution to the definition of the interfaces required to perform heterogeneous model integration in the context of integrative physiology. A formalization of the model integration problem is proposed and a coupling method is presented. The extension of the classic Guyton model, a multi-organ, integrated systems model of blood pressure regulation, is used as an example of the application of the proposed method. To this end, the Guyton model has been restructured, extensive sensitivity analyses have been performed, and appropriate transformations have been applied to replace a subset of its constituting modules by integrating a pulsatile heart and an updated representation of the renin-angiotensin system. Simulation results of the extended integrated model are presented and the impacts of their integration within the original model are evaluated.

The Effect of Simulating Leg Length Inequality on Spinal Posture and Pelvic Position: a Dynamic Rasterstereographic Analysis

European Spine Journal : Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. Jul, 2011  |  Pubmed ID: 21769443

INTRODUCTION: Leg length inequalities (LLI) are a common finding. Rasterstereography offers a non-invasive, contact-free and reliable method to detect the effects of LLIs on spinal posture and pelvic position. MATERIALS AND METHODS: A total of 115 subjects were rasterstereographically examined during different artificially created leg length inequalities (5-15 mm) using a platform. The pelvic obliquity and torsion and the lateral and frontal deviation of the spine, as well as the surface rotation, were measured. RESULTS: Changes in platform height led to an increase of the pelvic tilt and torsion. Only minor changes in the spinal posture were found by different simulated leg length inequalities. CONCLUSIONS: Our study showed that there was a correlation between an artificial leg length inequality up to 15 mm and pelvic tilt or torsion, but only minor changes in the spinal posture were measured. Further studies should investigate the effects of greater leg length inequalities on spine and pelvis.

Human Regulatory T Cells in Allogeneic Stem Cell Transplantation

Blood. Sep, 2011  |  Pubmed ID: 21778340

GVHD is still one of the major complications after allogeneic stem cell transplantation. Whereas murine data have clearly shown the beneficial effects of regulatory T cells (Tregs) on the prevention of GVHD, data from the human system are rare. Here, we present a comparative dynamic analysis of CD4(+)CD25(hi)CD127(lo/-) Tregs from patients with and without GVHD analyzing the whole genome profile over the first 6 months after stem cell transplantation, representing the most sensitive time window for tolerance induction. The Treg transcriptome showed a high stability. However, the comparison of Treg transcriptomes from patients with and without GVHD uncovered regulated gene transcripts highly relevant for Treg cell function. The confirmative protein analyses demonstrated a significantly higher expression of granzyme A, CXCR3, and CCR5 in Tregs of immune tolerant patients. These results point to a reduced suppressive function of Tregs from GVHD patients with diminished migration capacity to the target organs.

Finite Element Analysis of Performance in the Skulls of Marmosets and Tamarins

Journal of Anatomy. Jan, 2011  |  Pubmed ID: 20572898

Reliance on plant exudates is a relatively rare dietary specialization among mammals. One well-studied example of closely related exudate feeders is the New World marmosets and tamarins. Whereas marmosets actively gouge tree bark with their incisors to stimulate the flow of sap, tamarins are opportunistic exudate feeders that do not gouge bark. Several studies of the dentaries and jaw adductors indicate that marmosets exhibit specializations for increased gape at the expense of bite force. Few studies, however, have looked to the cranium of marmosets for evidence of functional specializations. Using 3D finite element models of the marmoset Callithrix jacchus and the tamarin Saguinus fuscicollis, we investigated the performance of the cranium under loading regimes that mimicked unilateral molar biting and bark-gouging. We investigated three measures of performance: the efficiency with which muscle force is transferred to bite force, the extent to which the models are stressed (a predictor of failure), and the work expended by muscles as they deform the skull (total strain energy). We found that during molar biting the two models exhibited similar levels of performance, though the Saguinus model had slightly higher mechanical efficiency, a slightly lower state of stress, and expended more energy on deformation. In contrast, under the bark-gouging load, Callithrix exhibited much higher mechanical efficiency than Saguinas, but did so at the expense of more work and higher levels of von Mises stress. This analysis illustrates that differences in the shapes of the skulls of Callithrix and Saguinus confer differences in performance. Whether these aspects of performance are targets of selection awaits broader comparative analyses.

Microstructure and Cytocompatibility of Collagen Matrices for Urological Tissue Engineering

BJU International. Jun, 2011  |  Pubmed ID: 20840325

• To analyse the in vitro cytocompatibility of several engineered collagen-based biomaterials for tissue engineering of the urinary tract. • Tissue-engineered implants for the reconstruction of the urinary tract are of major interest for urological researchers as well as clinicians. Although several materials have been investigated, the ideal replacement has still to be identified.

Variation in Immunoreactive Trypsinogen Concentrations Among Michigan Newborns and Implications for Cystic Fibrosis Newborn Screening

Pediatric Pulmonology. Feb, 2011  |  Pubmed ID: 20848586

To investigate variation in immunoreactive trypsinogen (IRT) concentrations by race, sex, birth weight, and gestational age and their implications for the use of percentile-based cutoffs for cystic fibrosis (CF) newborn screening (NBS) programs.

Acute but Not Chronic Graft-versus-host Disease is Associated with a Reduction of Circulating CD4(+)CD25 (high)CD127 (low/-) Regulatory T Cells

Annals of Hematology. Feb, 2011  |  Pubmed ID: 20859740

Defects in central and peripheral tolerance are thought to contribute to life-threatening graft-versus-host disease (GvHD), a severe complication following allogeneic stem cell transplantation (SCT). Recent investigations have demonstrated regulatory T cells (Tregs) to suppress allogeneic immune reactions. Therefore, SCT patients with no or critically low numbers of Tregs may have an increased risk of GvHD. To address this hypothesis, we analyzed the recovery of CD4(+)CD25(high)CD127(low/-) Tregs in the peripheral blood of patients who have never developed GvHD (n = 6), patients who developed acute/chronic GvHD (n = 18), and patients who developed chronic GvHD without an earlier acute manifestation (n = 5) every 30 days for the first 6 months after peripheral blood SCT (PBSCT). The number of Tregs continuously improved in acute/chronic GvHD patients, but always remained lower than Tregs quantified in patients who never developed a GvHD. In contrast, chronic GvHD patients who did not develop acute GvHD earlier displayed significantly increased Treg cell numbers at the timepoint of chronic inflammation. These results indicate that numerically deficient Tregs following PBSCT are associated with the development of acute but not chronic GvHD.

Using Parasitic Trematode Larvae to Quantify an Elusive Vertebrate Host

Conservation Biology : the Journal of the Society for Conservation Biology. Feb, 2011  |  Pubmed ID: 21029163

Digenean trematode parasites require multiple host species to complete their life cycles, and their abundance can often be strongly correlated with the abundance of their host species. Species richness and abundance of parasites in easily sampled host species may yield an accurate estimate of the species richness and abundance of other hosts in a parasite's life cycle that are difficult to survey directly. Accordingly, we investigated whether prevalence and mean abundance of trematodes could be used to estimate the abundance of one of their host species, diamondback terrapins (Malaclemys terrapin), which are difficult to sample and are designated as near threatened (by the International Union for Conservation of Nature [IUCN Red List]) along some U.S. coasts. As an adult the trematode Pleurogonius malaclemys is specific to terrapins. Its larval stages live first inside mud snails (Ilyanassa obsoleta) and are subsequently shed into the environment where they form external metacercarial cysts on hard surfaces such as snail opercula. The life cycle of P. malaclemys is completed when terrapins ingest these cysts. At 12 sites along the coast of Georgia (U.S.A.), we determined the prevalence of internal P. malaclemys larvae in mud snails (proportion of infected snails in a population) and the prevalence and mean abundance of external trematode cysts. We examined whether these data were correlated with terrapin abundance, which we estimated with mark-recapture methods. The abundance of external cysts and salinity explained ≥59% of the variability in terrapin abundance. We suggest that dependent linkages between the life stages of multihost parasites make them reliable predictors of host species' abundance, including hosts with abundances that are challenging to quantify directly.

Nef Does Not Inhibit F-actin Remodelling and HIV-1 Cell-cell Transmission at the T Lymphocyte Virological Synapse

European Journal of Cell Biology. Nov, 2011  |  Pubmed ID: 21044805

Nef, a HIV-1 pathogenesis factor, elevates virus replication in vivo and thus progression to AIDS by incompletely defined mechanisms. As one of its biological properties, Nef enhances the infectivity of cell-free HIV-1 particles in single round infections, however it fails to provide a significant and amplifying growth advantage for HIV-1 on such virus producing cells. A major difference between HIV-1 cell-free single round infections and virus replication kinetics on T lymphocytes consists in the predominant role of cell-associated virus transmission rather than cell-free infection during multiple round virus replication. HIV-1 cell-to-cell transmission occurs across close cell contacts also referred to as virological synapse (VS) and involves polarization of the F-actin cytoskeleton, formation of F-actin rich membrane bridges as well as virus budding to cell-cell contacts. Since Nef potently interferes with triggered actin remodelling in several cell systems to reduce e.g. cell motility and signal transduction, we set out here to address whether Nef also affects organization and possibly function of the T lymphocyte VS. We find that in addition to increasing infectivity of cell-free virions, Nef can also moderately enhance single rounds of HIV-1 cell-cell transmission between Jurkat T lymphocytes. This occurs without affecting cell conjugation efficiencies or polarization of F-actin and HIV-1 p24Gag at the VS, identifying actin remodelling at the VS as an example of Nef-insensitive host cell actin rearrangements. However, Nef-mediated enhancement of single round cell-free infection or cell-to-cell transmission does not potentiate over multiple rounds of infection. These results suggest that Nef affects cell-free and cell-associated HIV-1 infection by the same mechanism acting on the intrinsic infectivity of HIV-1 particles. They further indicate that the high efficacy of cell-to-cell transmission can compensate such infectivity defects. Nef therefore selectively interferes with actin remodelling processes involved in antiviral host cell defense while actin driven processes that promote virus propagation remain unaltered.

Androgen Receptor-mediated Gene Repression

Molecular and Cellular Endocrinology. Apr, 2012  |  Pubmed ID: 21784131

Androgens have an essential role in inducing the genetic program for masculinization during development. Androgens mediate their effect through the androgen receptor (AR), a ligand-controlled transcription factor and regulator of rapid signaling. Inactivated AR results in complete feminization. Androgens are also essential in later life for reproduction, behavior, muscle development, breast, and prostate growth. In general, androgens inhibit breast and promote prostate growth. In the latter context the AR is a major drug target. On the one hand, many insights have been obtained how the AR mediates gene activation on a molecular level. Gene activation is mediated by a battery of factors including coactivators, chromatin remodeling complex proteins and transcription factors which either directly or indirectly interact with the AR at DNA binding sites. On the other hand, there are important AR target genes that are repressed by androgen-bound AR. However, the underlying molecular mechanisms are poorly understood although genes repressed by AR are key factors involved in cell proliferation and invasion. Here, we summarize molecular mechanisms of AR-mediated gene repression, thereby differentiating between direct and indirect DNA/chromatin recruitment and between genomic and non-genomic effects.

Two-year-old Children Differentiate Test Questions from Genuine Questions

Journal of Child Language. Jan, 2012  |  Pubmed ID: 21457590

Children are frequently confronted with so-called 'test questions'. While genuine questions are requests for missing information, test questions ask for information obviously already known to the questioner. In this study we explored whether two-year-old children respond differentially to one and the same question used as either a genuine question or as a test question based on the situation (playful game versus serious task) and attitude (playful ostensive cues versus not). Results indicated that children responded to questions differently on the basis of the situation but not the expressed attitude of the questioner. Two-year-old children thus understand something of the very special communicative intentions behind test questions.

Health Utility Elicitation: is There Still a Role for Direct Methods?

PharmacoEconomics. Feb, 2012  |  Pubmed ID: 22185185

Health Care Expenditures for Medicaid-covered Males with Haemophilia in the United States, 2008

Haemophilia : the Official Journal of the World Federation of Hemophilia. Mar, 2012  |  Pubmed ID: 22188641

Although haemophilia is an expensive disorder, no studies have estimated health care costs for Americans with haemophilia enrolled in Medicaid as distinct from those with employer-sponsored insurance (ESI). The objective of this study is to provide information on health care utilization and expenditures for publicly insured people with haemophilia in the United States in comparison with people with haemophilia who have ESI. Data from the MarketScan Medicaid Multi-State, Commercial and Medicare Supplemental databases were used for the period 2004-2008 to identify cases of haemophilia and to estimate medical expenditures during 2008. A total of 511 Medicaid-enrolled males with haemophilia were identified, 435 of whom were enrolled in Medicaid for at least 11 months during 2008. Most people with haemophilia qualified for Medicaid based on 'disability'. Average Medicaid expenditures in 2008 were $142,987 [median, $46,737], similar to findings for people with ESI. Average costs for males with haemophilia A and an inhibitor were 3.6 times higher than those for individuals without an inhibitor. Average costs for 56 adult Medicaid enrollees with HCV or HIV infection were not statistically different from those for adults without the infection, but median costs were 1.6 times higher for those treated for blood-borne infections. Haemophilia treatment can lead to high costs for payers. Further research is needed to understand the effects of public health insurance on haemophilia care and expenditures, to evaluate treatment strategies and to implement strategies that may improve outcomes and reduce costs of care.

The Role of the Sutures in Biomechanical Dynamic Simulation of a Macaque Cranial Finite Element Model: Implications for the Evolution of Craniofacial Form

Anatomical Record (Hoboken, N.J. : 2007). Feb, 2012  |  Pubmed ID: 22190334

The global biomechanical impact of cranial sutures on the face and cranium during dynamic conditions is not well understood. It is hypothesized that sutures act as energy absorbers protecting skulls subjected to dynamic loads. This hypothesis predicts that sutures have a significant impact on global patterns of strain and cranial structural stiffness when analyzed using dynamic simulations; and that this global impact is influenced by suture material properties. In a finite element model developed from a juvenile Rhesus macaque cranium, five different sets of suture material properties for the zygomaticotemporal sutures were tested. The static and dynamic analyses produced similar results in terms of strain patterns and reaction forces, indicating that the zygomaticotemporal sutures have limited impact on global skull mechanics regardless of loading design. Contrary to the functional hypothesis tested in this study, the zygomaticotemporal sutures did not absorb significant amounts of energy during dynamic simulations regardless of loading speed. It is alternatively hypothesized that sutures are mechanically significant only insofar as they are weak points on the cranium that must be shielded from unduly high stresses so as not to disrupt vitally important growth processes. Thus, sutural and overall cranial form in some vertebrates may be optimized to minimize or otherwise modulate sutural stress and strain.

Notch Signaling Modulates Proliferation and Differentiation of Intestinal Crypt Base Columnar Stem Cells

Development (Cambridge, England). Feb, 2012  |  Pubmed ID: 22190634

Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, whereas Notch regulation of Olfm4 gene expression was Atoh1 independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice to control epithelial cell homeostasis.

Short-chain Fatty Acids Stimulate Glucagon-like Peptide-1 Secretion Via the G-protein-coupled Receptor FFAR2

Diabetes. Feb, 2012  |  Pubmed ID: 22190648

Interest in how the gut microbiome can influence the metabolic state of the host has recently heightened. One postulated link is bacterial fermentation of "indigestible" prebiotics to short-chain fatty acids (SCFAs), which in turn modulate the release of gut hormones controlling insulin release and appetite. We show here that SCFAs trigger secretion of the incretin hormone glucagon-like peptide (GLP)-1 from mixed colonic cultures in vitro. Quantitative PCR revealed enriched expression of the SCFA receptors ffar2 (grp43) and ffar3 (gpr41) in GLP-1-secreting L cells, and consistent with the reported coupling of GPR43 to Gq signaling pathways, SCFAs raised cytosolic Ca2+ in L cells in primary culture. Mice lacking ffar2 or ffar3 exhibited reduced SCFA-triggered GLP-1 secretion in vitro and in vivo and a parallel impairment of glucose tolerance. These results highlight SCFAs and their receptors as potential targets for the treatment of diabetes.

Healthcare Expenditures for Males with Haemophilia and Employer-sponsored Insurance in the United States, 2008

Haemophilia : the Official Journal of the World Federation of Hemophilia. Mar, 2012  |  Pubmed ID: 22151000

Although hemophilia has a potentially high economic impact, published estimates of health care costs for Americans with hemophilia are sparse and non-specific as to the non-bleeding complications of the disease. The objective of this study is to estimate average annual health care expenditures for people with hemophilia covered by employer-sponsored insurance, stratified according to the influence of age, type of hemophilia [A (factor VIII deficiency) versus B (factor IX)], presence of neutralizing alloantibody inhibitors and exposure to blood-borne viral infections. Data from the MarketScan Commercial and Medicare Research Databases were used for the period 2002-2008 to identify cases of hemophilia and to estimate mean and median medical expenditures during 2008. A total of 1,164 males with hemophilia were identified with continuous enrollment during 2008, 933 with hemophilia A and 231 with hemophilia B. Mean health care expenditures were $155,136 [median $73,548]. Mean costs for 30 (3%) males with an inhibitor were 5 times higher than for males without an inhibitor, approximately $697,000 [median $330,835] and $144,000 [median $73,321], respectively. Clotting factor concentrate accounted for 70%-82% of total costs. Average costs for 207 adults with HCV or HIV infection were 1.5 times higher than those for adults without infection. Hemophilia treatment is costly, particularly for individuals with neutralizing alloantibody inhibitors who require bypassing agents. Efforts to understand the cause of inhibitors are needed so that prevention strategies can be implemented and the excess costs resulting from this serious complication of hemophilia care can be avoided.

Autism Spectrum Disorders and Health Care Expenditures: the Effects of Co-occurring Conditions

Journal of Developmental and Behavioral Pediatrics : JDBP. Jan, 2012  |  Pubmed ID: 22157409

Children with autism spectrum disorders (ASDs) often have co-occurring conditions, but little is known on the effect of those conditions on their medical care cost. Medical expenditures attributable to ASDs among Medicaid-enrolled children were calculated, and the effects of 3 commonly co-occurring conditions-intellectual disability (ID), attention deficit/hyperactivity disorder (ADHD), and epilepsy-on those expenditures were analyzed.

Revival of the Intrauterine Device: Increased Insertions Among US Women with Employer-sponsored Insurance, 2002-2008

Contraception. Feb, 2012  |  Pubmed ID: 22067778

Use of the intrauterine device (IUD) in the United States has recently increased. New evidence for women with employer-sponsored health insurance permits analysis of variation and trends in such use.

Microwear, Mechanics and the Feeding Adaptations of Australopithecus Africanus

Journal of Human Evolution. Jan, 2012  |  Pubmed ID: 22130183

Recent studies of dental microwear and craniofacial mechanics have yielded contradictory interpretations regarding the feeding ecology and adaptations of Australopithecus africanus. As part of this debate, the methods used in the mechanical studies have been criticized. In particular, it has been claimed that finite element analysis has been poorly applied to this research question. This paper responds to some of these mechanical criticisms, highlights limitations of dental microwear analysis, and identifies avenues of future research.

Separate and Distinctive Roles for Wnt5a in Tongue, Lingual Tissue and Taste Papilla Development

Developmental Biology. Jan, 2012  |  Pubmed ID: 22024319

Although canonical Wnt signaling is known to regulate taste papilla induction and numbers, roles for noncanonical Wnt pathways in tongue and taste papilla development have not been explored. With mutant mice and whole tongue organ cultures we demonstrate that Wnt5a protein and message are within anterior tongue mesenchyme across embryo stages from the initiation of tongue formation, through papilla placode appearance and taste papilla development. The Wnt5a mutant tongue is severely shortened, with an ankyloglossia, and lingual mesenchyme is disorganized. However, fungiform papilla morphology, number and innervation are preserved, as is expression of the papilla marker, Shh. These data demonstrate that the genetic regulation for tongue size and shape can be separated from that directing lingual papilla development. Preserved number of papillae in a shortened tongue results in an increased density of fungiform papillae in the mutant tongues. In tongue organ cultures, exogenous Wnt5a profoundly suppresses papilla formation and simultaneously decreases canonical Wnt signaling as measured by the TOPGAL reporter. These findings suggest that Wnt5a antagonizes canonical Wnt signaling to dictate papilla number and spacing. In all, distinctive roles for Wnt5a in tongue size, fungiform papilla patterning and development are shown and a necessary balance between non-canonical and canonical Wnt paths in regulating tongue growth and fungiform papillae is proposed in a model, through the Ror2 receptor.

Influence of the Anatomic Characteristics of the Pulmonary Vein Ostium, the Learning Curve, and the Use of a Steerable Sheath on Success of Pulmonary Vein Isolation with a Novel Multielectrode Ablation Catheter

Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. Mar, 2012  |  Pubmed ID: 22024599

Anatomic variability of the pulmonary vein (PV) ostium may adversely affect isolation rates with the circular fixed-size pulmonary vein ablation catheter (PVAC). We wanted to assess the influence on PV isolation rates of anatomic characteristics of the ostium, increasing experience of four different operators, and additional use of a steerable sheath.

Short-term Weightlessness Produced by Parabolic Flight Maneuvers Altered Gene Expression Patterns in Human Endothelial Cells

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Feb, 2012  |  Pubmed ID: 22024737

This study focused on the effects of short-term microgravity (22 s) on the gene expression and morphology of endothelial cells (ECs) and evaluated gravisensitive signaling elements. ECs were investigated during four German Space Agency (Deutsches Zentrum für Luft- und Raumfahrt) parabolic flight campaigns. Hoechst 33342 and acridine orange/ethidium bromide staining showed no signs of cell death in ECs after 31 parabolas (P31). Gene array analysis revealed 320 significantly regulated genes after the first parabola (P1) and P31. COL4A5, COL8A1, ITGA6, ITGA10, and ITGB3 mRNAs were down-regulated after P1. EDN1 and TNFRSF12A mRNAs were up-regulated. ADAM19, CARD8, CD40, GSN, PRKCA (all down-regulated after P1), and PRKAA1 (AMPKα1) mRNAs (up-regulated) provide a very early protective mechanism of cell survival induced by 22 s microgravity. The ABL2 gene was significantly up-regulated after P1 and P31, TUBB was slightly induced, but ACTA2 and VIM mRNAs were not changed. β-Tubulin immunofluorescence revealed a cytoplasmic rearrangement. Vibration had no effect. Hypergravity reduced CARD8, NOS3, VASH1, SERPINH1 (all P1), CAV2, ADAM19, TNFRSF12A, CD40, and ITGA6 (P31) mRNAs. These data suggest that microgravity alters the gene expression patterns and the cytoskeleton of ECs very early. Several gravisensitive signaling elements, such as AMPKα1 and integrins, are involved in the reaction of ECs to altered gravity.

Persistent Chlamydia Trachomatis Infection of HeLa Cells Mediates Apoptosis Resistance Through a Chlamydia Protease-like Activity Factor-independent Mechanism and Induces High Mobility Group Box 1 Release

Infection and Immunity. Jan, 2012  |  Pubmed ID: 22025513

Intracellular persistence of Chlamydia trachomatis has been implicated in the development of chronic infection that can result in pelvic inflammatory disease and tubal sterility. By inhibition of host cell apoptosis, chlamydiae have evolved a strategy to maintain the intracellular environment for replication and persistence. Both antiapoptotic host cell-derived factors and the chlamydial protease-like activity factor (CPAF) are involved in Chlamydia-mediated apoptosis resistance. Here, we show that in HeLa cells infected with gamma interferon (IFN-γ)-induced persistent C. trachomatis serovar D, the expression of CPAF is downregulated, and proapoptotic protease substrates are not cleaved. Persistent infection protected HeLa cells from apoptosis when they were exposed to staurosporine. Small-interfering RNA-mediated inhibition of myeloid cell leukemia 1 (Mcl-1) protein upregulation sensitized persistently infected cells for apoptosis. The inhibitor of apoptosis protein 2 (IAP-2) seems not to be relevant in this context because IAP-2 protein was not induced in response to IFN-γ treatment. Although apoptosis was inhibited, persistent infection caused cell membrane disintegration, as measured by the increased release of cytokeratin 18 from HeLa cells. Moreover, persistently infected cells released significantly increased amounts of high mobility group box 1 (HMGB1) protein which represents a proinflammatory damage-associated pattern molecule. The data of this study suggest that cells infected with persistent C. trachomatis are protected from apoptosis independently of CPAF but may promote chronic inflammation through HMGB1 release.

Claudin-1 Involved in Neonatal Ichthyosis Sclerosing Cholangitis Syndrome Regulates Hepatic Paracellular Permeability

Hepatology (Baltimore, Md.). Apr, 2012  |  Pubmed ID: 22030598

Neonatal ichthyosis and sclerosing cholangitis (NISCH) syndrome is a liver disease caused by mutations of CLDN1 encoding Claudin-1, a tight-junction (TJ) protein. In this syndrome, it is speculated that cholestasis is caused by Claudin-1 absence, leading to increased paracellular permeability and liver injuries secondary to paracellular bile regurgitation. We studied the role of claudin-1 in hepatic paracellular permeability. A NISCH liver and polarized rat cell lines forming TJs, the hepatocellular Can 10 and the cholangiocellular normal rat choloangiocyte (NRC), were used. In contrast to NRC, Can 10 does not express claudin-1. Can 10 cells were transfected with a plasmid encoding Claudin-1, and stable Claudin-1-expressing clones were isolated. Claudin-1 expression was silenced by transfection with short interfering RNA in Can 10 clones and with short hairpin RNA in NRC. Claudin-1 expression was evaluated by quantitative reverse-transcriptase polymerase chain reaction, immunoblotting, and immunolocalization. Paracellular permeability was assessed by fluorescein isothiocyanate-dextran passage in both lines and by transepithelial resistance measurements in NRC. In the NISCH liver, Claudin-1 was not detected in hepatocytes or cholangiocytes. In Claudin-1 expressing Can 10 clones, Claudin-1 was localized at the TJ and paracellular permeability was decreased, compared to parental Can 10 cells, this decrease correlating with claudin-1 levels. Silencing of Claudin-1 in Can 10 clones increased paracellular permeability to a level similar to that of parental cells. Similarly, we observed an increase of paracellular permeability in NRC cells silenced for claudin-1 expression. Conclusion: Defect in claudin-1 expression increases paracellular permeability in polarized hepatic cell lines, supporting the hypothesis that paracellular bile leakage through deficient TJs is involved in liver pathology observed in NISCH syndrome. (Hepatology 2012).

Brief Communication: Comparing Loading Scenarios in Lower First Molar Supporting Bone Structure Using 3D Finite Element Analysis

American Journal of Physical Anthropology. Jan, 2012  |  Pubmed ID: 21952986

Finite element analysis (FEA) is a widespread technique to evaluate the stress/strain distributions in teeth or dental supporting tissues. However, in most studies occlusal forces are usually simplified using a single vector (i.e., point load) either parallel to the long tooth axis or oblique to this axis. In this pilot study we show how lower first molar occlusal information can be used to investigate the stress distribution with 3D FEA in the supporting bone structure. The LM(1) and the LP(2) -LM(1) of a dried modern human skull were scanned by μCT in maximum intercuspation contact. A kinematic analysis of the surface contacts between LM(1) and LP(2) -LM(1) during the power stroke was carried out in the occlusal fingerprint analyzer (OFA) software to visualize contact areas during maximum intercuspation contact. This information was used for setting the occlusal molar loading to evaluate the stress distribution in the supporting bone structure using FEA. The output was compared to that obtained when a point force parallel to the long axis of the tooth was loaded in the occlusal basin. For the point load case, our results indicate that the buccal and lingual cortical plates do not experience notable stresses. However, when the occlusal contact areas are considered, the disto-lingual superior third of the mandible experiences high tensile stresses, while the medio-lingual cortical bone is subjected to high compressive stresses. Developing a more realistic loading scenario leads to better models to understand the relationship between masticatory function and mandibular shape and structures. Am J Phys Anthropol, 2012. © 2011 Wiley Periodicals, Inc.

Medical Expenditures Attributable to Cerebral Palsy and Intellectual Disability Among Medicaid-enrolled Children

Research in Developmental Disabilities. May, 2012  |  Pubmed ID: 22245730

This study estimated medical expenditures attributable to cerebral palsy (CP) among children enrolled in Medicaid, stratified by the presence of co-occurring intellectual disability (ID), relative to children without CP or ID. The MarketScan(®) Medicaid Multi-State database was used to identify children with CP for 2003-2005 by using the International Classification of Diseases, Ninth Revision; Clinical Modification (ICD-9-CM) code 343.xx. Children with ID were identified for 2005 by using ICD-9-CM code 317.xx-319.xx. Children without CP or ID during the same period served as control subjects. Medical expenditures were estimated for case and control children for 2005. The difference between the average expenditures for children with and without CP was used as a proxy for attributable expenditures for the condition. The attributable expenditures of co-occurring ID were calculated similarly as the difference in average expenditures among children with CP with and without ID. A total of 9927 children with CP were identified. Among them, 2022 (20.3%) children had co-occurring ID recorded in medical claims. Children with CP but without ID incurred medical expenditures that were $15,047 higher than those of control children without CP or ID. By contrast, children with CP and co-occurring ID incurred costs that were $41,664 higher, compared with control children, and $26,617 more than children with CP but without ID. Administrative data from a large, multistate database demonstrated high medical expenditures for publicly insured children with CP. Expenditures approximately tripled for children with CP and co-occurring ID.

Parsimonious Higher-order Hidden Markov Models for Improved Array-CGH Analysis with Applications to Arabidopsis Thaliana

PLoS Computational Biology. Jan, 2012  |  Pubmed ID: 22253580

Array-based comparative genomic hybridization (Array-CGH) is an important technology in molecular biology for the detection of DNA copy number polymorphisms between closely related genomes. Hidden Markov Models (HMMs) are popular tools for the analysis of Array-CGH data, but current methods are only based on first-order HMMs having constrained abilities to model spatial dependencies between measurements of closely adjacent chromosomal regions. Here, we develop parsimonious higher-order HMMs enabling the interpolation between a mixture model ignoring spatial dependencies and a higher-order HMM exhaustively modeling spatial dependencies. We apply parsimonious higher-order HMMs to the analysis of Array-CGH data of the accessions C24 and Col-0 of the model plant Arabidopsis thaliana. We compare these models against first-order HMMs and other existing methods using a reference of known deletions and sequence deviations. We find that parsimonious higher-order HMMs clearly improve the identification of these polymorphisms. Moreover, we perform a functional analysis of identified polymorphisms revealing novel details of genomic differences between C24 and Col-0. Additional model evaluations are done on widely considered Array-CGH data of human cell lines indicating that parsimonious HMMs are also well-suited for the analysis of non-plant specific data. All these results indicate that parsimonious higher-order HMMs are useful for Array-CGH analyses. An implementation of parsimonious higher-order HMMs is available as part of the open source Java library Jstacs (www.jstacs.de/index.php/PHHMM).

Cloning, Baeyer-Villiger Biooxidations, and Structures of the Camphor Pathway 2-Oxo-{Delta}3-4,5,5-Trimethylcyclopentenylacetyl-Coenzyme A Monooxygenase of Pseudomonas Putida ATCC 17453

Applied and Environmental Microbiology. Apr, 2012  |  Pubmed ID: 22267661

A dimeric Baeyer-Villiger monooxygenase (BVMO) catalyzing the lactonization of 2-oxo-Δ(3)-4,5,5-trimethylcyclopentenylacetyl-coenzyme A (CoA), a key intermediate in the metabolism of camphor by Pseudomonas putida ATCC 17453, had been initially characterized in 1983 by Ougham and coworkers (H. J. Ougham, D. G. Taylor, and P. W. Trudgill, J. Bacteriol. 153:140-152, 1983). Here we cloned and overexpressed the 2-oxo-Δ(3)-4,5,5-trimethylcyclopentenylacetyl-CoA monooxygenase (OTEMO) in Escherichia coli and determined its three-dimensional structure with bound flavin adenine dinucleotide (FAD) at a 1.95-Å resolution as well as with bound FAD and NADP(+) at a 2.0-Å resolution. OTEMO represents the first homodimeric type 1 BVMO structure bound to FAD/NADP(+). A comparison of several crystal forms of OTEMO bound to FAD and NADP(+) revealed a conformational plasticity of several loop regions, some of which have been implicated in contributing to the substrate specificity profile of structurally related BVMOs. Substrate specificity studies confirmed that the 2-oxo-Δ(3)-4,5,5-trimethylcyclopentenylacetic acid coenzyme A ester is preferred over the free acid. However, the catalytic efficiency (k(cat)/K(m)) favors 2-n-hexyl cyclopentanone (4.3 × 10(5) M(-1) s(-1)) as a substrate, although its affinity (K(m) = 32 μM) was lower than that of the CoA-activated substrate (K(m) = 18 μM). In whole-cell biotransformation experiments, OTEMO showed a unique enantiocomplementarity to the action of the prototypical cyclohexanone monooxygenase (CHMO) and appeared to be particularly useful for the oxidation of 4-substituted cyclohexanones. Overall, this work extends our understanding of the molecular structure and mechanistic complexity of the type 1 family of BVMOs and expands the catalytic repertoire of one of its original members.

Functional MicroRNA Targets in Protein Coding Sequences

Bioinformatics (Oxford, England). Mar, 2012  |  Pubmed ID: 22285563

Experimental evidence has accumulated showing that microRNA (miRNA) binding sites within protein coding sequences (CDSs) are functional in controlling gene expression.

Probabilistic Finite Element Analysis of a Craniofacial Finite Element Model

Journal of Theoretical Biology. Jan, 2012  |  Pubmed ID: 22306513

We employed a probabilistic finite element analysis (FEA) method to determine how variability in material property values affects stress and strain values in a finite model of a Macaca fascicularis cranium. The material behavior of cortical bone varied in three ways: isotropic homogeneous, isotropic non-homogeneous, and orthotropic non-homogeneous. The material behavior of the trabecular bone and teeth was always treated as isotropic and homogeneous. All material property values for the cranium were randomized with a Gaussian distribution with either coefficients of variation (CVs) of 0.2 or with CVs calculated from empirical data. Latin hypercube sampling was used to determine the values of the material properties used in the finite element models. In total, four hundred and twenty six separate deterministic FE simulations were executed. We tested four hypotheses in this study: (1) uncertainty in material property values will have an insignificant effect on high stresses and a significant effect on high strains for homogeneous isotropic models; (2) the effect of variability in material property values on the stress state will increase as non-homogeneity and anisotropy increase; (3) variation in the in vivo shear strain values reported by Strait et al. (2005) and Ross et al. (2011) is not only due to variations in muscle forces and cranial morphology, but also due to variation in material property values; (4) the assumption of a uniform coefficient of variation for the material property values will result in the same trend in how moderate-to-high stresses and moderate-to-high strains vary with respect to the degree of non-homogeneity and anisotropy as the trend found when the coefficients of variation for material property values are calculated from empirical data. Our results supported the first three hypotheses and falsified the fourth. When material properties were varied with a constant CV, as non-homogeneity and anisotropy increased the level of variability in the moderate-to-high strains decreased while the level of variability in the moderate-to-high stresses increased. However, this is not the pattern observed when CVs calculated from empirical data were applied to the material properties where the lowest level of variability in both stresses and strains occurred when the cranium was modeled with a low level of non-homogeneity and anisotropy. Therefore, when constant material property variability is assumed, inaccurate trends in the level of variability present in modest-to-high magnitude stresses and strains are produced. When the cranium is modeled with the highest level of accuracy (high non-homogeneity and anisotropy) and when randomness in the material properties is calculated from empirical data, there is a large level of variability in the significant strains (CV=0.369) and a low level of variability in the modest-to-high magnitude stresses (CV=0.150). This result may have important implications with regard to the mechanical signals driving bone remodeling and adaptation through natural selection.

CRM1-Dependent Trafficking of Retroviral Gag Proteins Revisited

Journal of Virology. Apr, 2012  |  Pubmed ID: 22318151

We analyzed the nuclear trafficking ability of Gag proteins from six retroviral genera. Contrary to a previous report, human immunodeficiency virus type 1 (HIV-1) Gag showed no propensity to cycle through the nucleus. The only Gag protein that displayed CRM1-dependent nuclear cycling was that of Rous sarcoma virus (RSV). Surprisingly, this cycling could be eliminated without compromising infectivity by replacing the RSV Gag N-terminal matrix (MA) domain with HIV MA.

Embryonated Chicken Eggs As Alternative Infection Model for Pathogenic Fungi

Methods in Molecular Biology (Clifton, N.J.). 2012  |  Pubmed ID: 22328397

Embryonated eggs have been used as infection models for decades in virology and bacteriology. However, they can also be used as an attractive alternative infection model for studying fungal pathogenesis. Here, we discuss some general aspects which need to be considered when working with embryonated eggs as infection models. Furthermore, we provide detailed protocols and technical tips for infection of embryonated eggs with Aspergillus fumigatus and Candida albicans via the chorioallantois membrane, as well as sampling methods for downstream analyses.

Response to the Comment by Gröning and Fagan on "The Effects of Modeling Simplifications on Craniofacial Finite Element Models: The Alveoli (tooth Sockets) and Periodontal Ligaments" (volume 44, Issue 10, Pages 1831-1838)

Journal of Biomechanics. Feb, 2012  |  Pubmed ID: 22349117

On the Inter-instrument and the Inter-laboratory Transferability of a Tandem Mass Spectral Reference Library. 3. Focus on Ion Trap and Upfront CID

Journal of Mass Spectrometry : JMS. Feb, 2012  |  Pubmed ID: 22359338

Mass spectral libraries represent versatile tools for the identification of small bioorganic molecules. Libraries based on electron impact spectra are rated robust and transferable. Tandem mass spectral libraries are often considered to work properly only on the instrument that has been used to build the library. An exception from that rule is the 'Wiley Registry of Tandem Mass Spectral Data, MSforID'. In various studies with data sets from different kinds of tandem mass spectrometric instruments, the outstanding sensitivity and robustness of this tandem mass spectral library search approach was demonstrated. The instrumental platforms tested, however, mainly included various tandem-in-space instruments. Herein, the results of a multicenter study with a focus on upfront and tandem-in-time fragmentation are presented. Five laboratories participated and provided fragment ion mass spectra from the following types of mass spectrometers: time-of-flight (TOF), quadrupole-hexapole-TOF, linear ion trap (LIT), 3-D ion trap and LIT-Orbitrap. A total number of 1231 fragment ion mass spectra were collected from 20 test compounds (amiloride, buphenin, cinchocaine, cyclizine, desipramine, dihydroergotamine, dyxirazine, dosulepin, ergotamine, ethambutol, etofylline, mefruside, metoclopramide, phenazone, phentermine, phenytoin, sulfamethoxazole, sulfamoxole, sulthiame and tetracycline) on seven electrospray ionization instruments using 18 different instrumental configurations for fragmentation. For 1222 spectra (99.3%), the correct compound was retrieved as the best matching compound. Classified matches (matches with 'relative average match probability' >40.0) were obtained for 1207 spectra (98.1%). This high percentage of correct identifications clearly supports the hypothesis that the tandem mass spectral library approach tested is a robust and universal identification tool.

Study of the Retention Behavior in Zwitterionic Hydrophilic Interaction Chromatography of Isomeric Hydroxy- and Aminobenzoic Acids

Journal of Chromatography. A. Feb, 2012  |  Pubmed ID: 22417889

The retention behavior of fifteen isomeric hydroxy- and aminobenzoic acids in zwitterionic hydrophilic interaction chromatography was studied using a sulfobetaine phase (ZIC-HILIC). By an inspection of their molecular structures, the retention was related to the number, the position and hydrogen bond properties of the functional groups. The effect of the chromatographic conditions was analyzed in order to investigate the retention mechanism of the stationary phase. The increased retention observed for negative charged compounds when the mobile phase pH decreased was ascribed to a diminishing of the electrostatic repulsion with the underivatized silanol groups. Also the salt buffer concentration in the mobile was proved to have a great influence in the modulation of the electrostatic interactions. However, the retention behavior of the benzoic acids was not described by conventional ion-exchange models. Subsequently, a systematical analysis of partition, adsorption, and hydrophilic chromatographic models was presented. The results from the fittings indicated that partition processes govern mainly the ZIC-HILIC separation, but also adsorption processes via hydrogen bonds occurred for hydrogen donor analytes. Finally, the influence of the chromatographic conditions on the water enriched layer in which partition takes place has been evaluated by the elution behavior of toluene.

The Novel Candida Albicans Transporter Dur31 Is a Multi-Stage Pathogenicity Factor

PLoS Pathogens. Mar, 2012  |  Pubmed ID: 22438810

Candida albicans is the most frequent cause of oral fungal infections. However, the exact pathogenicity mechanisms that this fungus employs are largely unknown and many of the genes expressed during oral infection are uncharacterized. In this study we sought to functionally characterize 12 previously unknown function genes associated with oral candidiasis. We generated homozygous knockout mutants for all 12 genes and analyzed their interaction with human oral epithelium in vitro. Eleven mutants caused significantly less epithelial damage and, of these, deletion of orf19.6656 (DUR31) elicited the strongest reduction in pathogenicity. Interestingly, DUR31 was not only involved in oral epithelial damage, but in multiple stages of candidiasis, including surviving attack by human neutrophils, endothelial damage and virulence in vivo. In silico analysis indicated that DUR31 encodes a sodium/substrate symporter with 13 transmembrane domains and no human homologue. We provide evidence that Dur31 transports histatin 5. This is one of the very first examples of microbial driven import of this highly cytotoxic antimicrobial peptide. Also, in contrast to wild type C. albicans, dur31Δ/Δ was unable to actively increase local environmental pH, suggesting that Dur31 lies in the extracellular alkalinization hyphal auto-induction pathway; and, indeed, DUR31 was required for morphogenesis. In agreement with this observation, dur31Δ/Δ was unable to assimilate the polyamine spermidine.

Incidence-based Cost Estimates Require Population-based Incidence Data. A Critique of Mahan Et Al

Thrombosis and Haemostasis. Jan, 2012  |  Pubmed ID: 22159589

Differential Expression of the Androgen-Conjugating UGT2B15 and UGT2B17 Enzymes in Prostate Tumor Cells During Cancer Progression

The Journal of Clinical Endocrinology and Metabolism. Mar, 2012  |  Pubmed ID: 22170718

Context: Androgens play major roles in prostate cancer initiation and development. In prostate cells, the human uridine diphosphate-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes inactivate androgens. Objective: We investigated in vivo how UGT2B15 and UGT2B17 expressions are affected during prostate cancer development. Design: We conducted an observational study of the UGT2B15 and UGT2B17 mRNA and protein levels. Setting: The study was conducted at Laval University (Québec, Canada) and at the University of British Columbia (Vancouver, Canada). Patients/Participants: Participants were from a cohort of prostate cancer patients from the Hôtel-Dieu de Québec hospital (Québec; mRNA analyses) and from the Vancouver Prostate Centre tissue bank (Vancouver; tissue microarray experiments). Main Outcome Measures: UGT mRNA and protein levels were determined using real-time PCR and immunohistochemical analyses, respectively. Results: Both UGT2B15 and UGT2B17 mRNA and protein levels were not significantly associated with Gleason score stratification. However, when protein levels were compared to benign prostatic hyperplasia, UGT2B17 was significantly more abundant in all Gleason-scored tumors. By contrast, UGT2B15 levels were significantly reduced in naive and castration-resistant tumors and undetectable in lymph node metastases. Finally, UGT2B17 proteins were 5-fold more abundant in metastases than in benign samples. Conclusions: The current study reveals that UGT2B15 and UGT2B17 are differentially regulated during prostate cancer progression. Furthermore, this study also identifies the UGT2B15 gene as a negatively regulated target gene in castration-resistant prostate cancer and lymph node metastases.