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Find video protocols related to scientific articles indexed in Pubmed.
G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-19-2014
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Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5'- and 3'-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5'-tiRNAs (e.g., tiRNA(Ala), tiRNA(Cys)) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNA(Ala) binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5'-tiDNA(Ala) (the DNA equivalent of 5'-tiRNA(Ala)) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5'-tiDNA(Ala) also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1-dependent manner. Remarkably, the ability of 5'-tiRNA(Ala) to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease.
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Discovery of BI 207524, an indole diamide NS5B thumb pocket 1 inhibitor with improved potency for the potential treatment of chronic HCV infection.
J. Med. Chem.
PUBLISHED: 11-14-2014
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The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.
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Modest, reliable spectral peaks in preceding sounds influence vowel perception.
J. Acoust. Soc. Am.
PUBLISHED: 11-07-2014
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When a spectral property is reliable across an acoustic context and subsequent vowel target, perception deemphasizes this cue and shifts toward less predictable, more informative cues. This phenomenon (auditory perceptual calibration) has been demonstrated for reliable spectral peaks +20?dB or larger, but psychoacoustic findings predict sensitivity to more modest spectral peaks. Listeners identified vowel targets following a sentence with a reliable +2 to +15?dB spectral peak centered at F2 of the vowel. Vowel identifications weighted F2 significantly less when reliable peaks were at least +5?dB. Results demonstrate high sensitivity to reliable acoustic properties in the sensory environment.
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Bone morphogenetic protein-associated complications in pediatric spinal fusion in the early postoperative period: an analysis of 4658 patients and review of the literature.
J Neurosurg Pediatr
PUBLISHED: 10-11-2014
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Object Use of recombinant human bone morphogenetic protein-2 has risen steadily since its approval by the FDA for use in anterior lumbar interbody fusion in 2002. The FDA has not approved the use of bone morphogenetic protein (BMP) in children. Age less than 18 years or lack of evidence of epiphyseal closure are considered by the manufacturer to be contraindications to BMP use. In light of this, the authors performed a query of the database of one of the nation's largest health insurance companies to determine the rate of BMP use and complications in pediatric patients undergoing spinal fusion. Methods The authors used the PearlDiver Technologies private payer database containing all records from United Health-Care from 2005 to 2011 to query all cases of pediatric spinal fusion with or without BMP use. A review of the literature was also performed to examine the complications associated with BMP use in pediatric spinal fusion. Results A total of 4658 patients underwent spinal fusion. The majority was female (65.4%), and the vast majority was age 10-19 years (94.98%) and underwent thoracolumbar fusion (93.13%). Bone morphogenetic protein was used in 1752 spinal fusions (37.61%). There was no difference in the rate of BMP use when comparing male and female patients or age 10 years or older versus less than 10 years. Anterior cervical fusions were significantly less likely to use BMP (7.3%). Complications occurred in 9.82% of patients treated with versus 9.88% of patients treated without BMP. The complication rate was nearly identical in male versus female patients and in patients older versus younger than 10 years. Comparison of systemic, wound-related, CNS, and other complications showed no difference between groups treated with and without BMP. The reoperation rate was also nearly identical. Conclusions Bone morphogenetic protein is used in a higher than expected percentage of pediatric spinal fusions. The rate of acute complications in these operations does not appear to be different in patients treated with versus those treated without BMP. Caution must be exercised in interpreting these data due to the many limitations of the administrative database as a data source, including the short length of follow-up.
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Androgen receptor action in osteoblasts in male mice is dependent on their stage of maturation.
J. Bone Miner. Res.
PUBLISHED: 10-08-2014
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Androgen action via the androgen receptor (AR) is essential for normal skeletal growth and bone maintenance post-puberty in males, however, the molecular and cellular mechanisms by which androgens exert their actions in osteoblasts remains relatively unexplored in vivo. To identify autonomous AR actions in osteoblasts independent of AR signalling in other tissues, we compared the extent to which the bone phenotype of the Global-ARKO mouse was restored by replacing the AR in osteoblasts commencing at either the 1) proliferative or 2) mineralization stage of their maturation. In trabecular bone, androgens stimulated trabecular bone accrual during growth via the AR in proliferating osteoblasts, and maintained trabecular bone post-puberty via the AR in mineralizing osteoblasts, with its predominant action being to inhibit bone resorption by decreasing the ratio of RANKL to OPG gene expression. During growth, replacement of the AR in proliferating but not mineralizing osteoblasts of Global-ARKOs was able to partially restore periosteal circumference, supporting the concept that androgen action in cortical bone to increase bone size during growth is mediated via the AR in proliferating osteoblasts. This study provides further significant insight into the mechanism of androgen action via the AR in osteoblasts, demonstrating that it is dependent on the stage of osteoblast maturation. This article is protected by copyright. All rights reserved.
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Vertebroplasty and Kyphoplasty for the Treatment of Osteoporotic Vertebral Compression Fractures.
J Am Acad Orthop Surg
PUBLISHED: 10-05-2014
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Vertebroplasty and kyphoplasty have been used to treat osteoporotic compression fractures for many years. In 2009, two randomized controlled trials demonstrated limited effectiveness of vertebroplasty over sham treatment; thus, the American Academy of Orthopaedic Surgeons published evidence-based guidelines recommending "against vertebroplasty for patients who present with an osteoporotic spinal compression fracture." However, several other trials have since been published that contradict these conclusions. A recent meta-analysis cited strong evidence in favor of cement augmentation in the treatment of symptomatic vertebral compression fractures.
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FLI1 Expression is Correlated with Breast Cancer Cellular Growth, Migration, and Invasion and Altered Gene Expression.
Neoplasia
PUBLISHED: 10-01-2014
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ETS factors have been shown to be dysregulated in breast cancer. ETS factors control the expression of genes involved in many biological processes, such as cellular proliferation, differentiation, and apoptosis. FLI1 is an ETS protein aberrantly expressed in retrovirus-induced hematological tumors, but limited attention has been directed towards elucidating the role of FLI1 in epithelial-derived cancers. Using data mining, we show that loss of FLI1 expression is associated with shorter survival and more aggressive phenotypes of breast cancer. Gain and loss of function cellular studies indicate the inhibitory effect of FLI1 expression on cellular growth, migration, and invasion. Using Fli1 mutant mice and both a transgenic murine breast cancer model and an orthotopic injection of syngeneic tumor cells indicates that reduced Fli1 contributes to accelerated tumor growth. Global expression analysis and RNA-Seq data from an invasive human breast cancer cell line with over expression of either FLI1 and another ETS gene, PDEF, shows changes in several cellular pathways associated with cancer, such as the cytokine-cytokine receptor interaction and PI3K-Akt signaling pathways. This study demonstrates a novel role for FLI1 in epithelial cells. In addition, these results reveal that FLI1 down-regulation in breast cancer may promote tumor progression.
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Cancer risk from bone morphogenetic protein exposure in spinal arthrodesis.
J Bone Joint Surg Am
PUBLISHED: 09-05-2014
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The U.S. Food and Drug Administration reported a higher incidence of cancer in patients who had spinal arthrodesis and were exposed to a high dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) compared with the control group in a randomized controlled trial. The purpose of this study was to determine the risk of cancer after spinal arthrodesis with BMP.
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tRNA fragments in human health and disease.
FEBS Lett.
PUBLISHED: 08-07-2014
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Transfer RNA (tRNA) is traditionally considered to be an adaptor molecule that helps ribosomes to decode messenger RNA (mRNA) and synthesize protein. Recent studies have demonstrated that tRNAs also serve as a major source of small non-coding RNAs that possess distinct and varied functions. These tRNA fragments are heterogeneous in size, nucleotide composition, biogenesis and function. Here we describe multiple roles that tRNA fragments play in cell physiology and discuss their relevance to human health and disease.
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Derivation of Human Health-Based Ambient Water Quality Criteria: A Consideration of Conservatism and Protectiveness Goals.
Integr Environ Assess Manag
PUBLISHED: 07-07-2014
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Under the terms of the Clean Water Act, criteria for the protection of human health [Human Health Ambient Water Quality Criteria (HHWQC)] are traditionally derived using United States Environmental Protection Agency (USEPA)-recommended equations that include parameters for exposure assessment. To derive "adequately protective" HHWQC, USEPA proposes the use of default values for these parameters that are a combination of medians, means and percentile estimates targeting the high end (90(th) percentile) of the general population. However, in practice, in nearly all cases, USEPA's recommended default assumptions represent upper percentiles. This paper considers the adequacy of the exposure assessment component of USEPA-recommended equations to yield criteria that are consistent with corresponding health protection targets established in USEPA recommendations or state policies and concludes that conservative selections for exposure parameters can result in criteria that are substantially more protective than the health protection goals for HHWQC recommended by USEPA, due in large part to the compounding effect that occurs when multiple conservative factors are combined. This situation may be mitigated by thoughtful selection of exposure parameter values when using a deterministic approach, or by using a probabilistic approach based on data distributions for many of these parameters. Integr Environ Assess Manag © 2014 SETAC.
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Use of computed tomography for assessing bone mineral density.
Neurosurg Focus
PUBLISHED: 07-02-2014
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Assessing local bone quality on CT scans with Hounsfield unit (HU) quantification is being used with increasing frequency. Correlations between HU and bone mineral density have been established, and normative data have been defined throughout the spine. Recent investigations have explored the utility of HU values in assessing fracture risk, implant stability, and spinal fusion success. The information provided by a simple HU measurement can alert the treating physician to decreased bone quality, which can be useful in both medically and surgically managing these patients.
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Influenza a virus host shutoff disables antiviral stress-induced translation arrest.
PLoS Pathog.
PUBLISHED: 07-01-2014
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Influenza A virus (IAV) polymerase complexes function in the nucleus of infected cells, generating mRNAs that bear 5' caps and poly(A) tails, and which are exported to the cytoplasm and translated by host machinery. Host antiviral defences include mechanisms that detect the stress of virus infection and arrest cap-dependent mRNA translation, which normally results in the formation of cytoplasmic aggregates of translationally stalled mRNA-protein complexes known as stress granules (SGs). It remains unclear how IAV ensures preferential translation of viral gene products while evading stress-induced translation arrest. Here, we demonstrate that at early stages of infection both viral and host mRNAs are sensitive to drug-induced translation arrest and SG formation. By contrast, at later stages of infection, IAV becomes partially resistant to stress-induced translation arrest, thereby maintaining ongoing translation of viral gene products. To this end, the virus deploys multiple proteins that block stress-induced SG formation: 1) non-structural protein 1 (NS1) inactivates the antiviral double-stranded RNA (dsRNA)-activated kinase PKR, thereby preventing eIF2? phosphorylation and SG formation; 2) nucleoprotein (NP) inhibits SG formation without affecting eIF2? phosphorylation; 3) host-shutoff protein polymerase-acidic protein-X (PA-X) strongly inhibits SG formation concomitant with dramatic depletion of cytoplasmic poly(A) RNA and nuclear accumulation of poly(A)-binding protein. Recombinant viruses with disrupted PA-X host shutoff function fail to effectively inhibit stress-induced SG formation. The existence of three distinct mechanisms of IAV-mediated SG blockade reveals the magnitude of the threat of stress-induced translation arrest during viral replication.
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Intervertebral disc and stem cells cocultured in biomimetic extracellular matrix stimulated by cyclic compression in perfusion bioreactor.
Spine J
PUBLISHED: 05-29-2014
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Intervertebral disc (IVD) degeneration often causes back pain. Current treatments for disc degeneration, including both surgical and nonsurgical approaches, tend to compromise the disc movement and cannot fully restore functions of the IVD. Instead, cell-based IVD tissue engineering seems promising as an ultimate therapy for IVD degeneration.
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Effects of aberrant gamma frequency oscillations on prepulse inhibition.
Int. J. Neuropsychopharmacol.
PUBLISHED: 05-15-2014
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Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased 'neural noise' in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.
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Dependence of anisotropy of human lumbar vertebral trabecular bone on quantitative computed tomography-based apparent density.
J Biomech Eng
PUBLISHED: 05-15-2014
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Most studies investigating human lumbar vertebral trabecular bone (HVTB) mechanical property-density relationships have presented results for the superior-inferior (SI), or "on-axis" direction. Equivalent, directly measured data from mechanical testing in the transverse (TR) direction are sparse and quantitative computed tomography (QCT) density-dependent variations in the anisotropy ratio of HVTB have not been adequately studied. The current study aimed to investigate the dependence of HVTB mechanical anisotropy ratio on QCT density by quantifying the empirical relationships between QCT-based apparent density of HVTB and its apparent compressive mechanical properties--elastic modulus (E(app)), yield strength (?(y)), and yield strain (?(y))--in the SI and TR directions for future clinical QCT-based continuum finite element modeling of HVTB. A total of 51 cylindrical cores (33 axial and 18 transverse) were extracted from four L1 human lumbar cadaveric vertebrae. Intact vertebrae were scanned in a clinical resolution computed tomography (CT) scanner prior to specimen extraction to obtain QCT density, ?(CT). Additionally, physically measured apparent density, computed as ash weight over wet, bulk volume, ?(app), showed significant correlation with ?(CT) [?(CT)?=?1.0568?×??(app), r?=?0.86]. Specimens were compression tested at room temperature using the Zetos bone loading and bioreactor system. Apparent elastic modulus (E(app)) and yield strength (?(y)) were linearly related to the ?(CT) in the axial direction [E(SI)?=?1493.8?×?(?(CT)), r?=?0.77, p?
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Adverse events recording and reporting in clinical trials of cervical total disk replacement.
Instr Course Lect
PUBLISHED: 04-12-2014
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Adverse events reporting in pivotal trials of new technologies, such as cervical total disk replacement, are essential to determine safety. Important questions concerning the adequacy of reporting about such new technologies in peer-reviewed publications have prompted this analysis to assess the safety of cervical disk replacement compared with fusion as presented in peer-reviewed publications and FDA summary reports. Identifying differences among these reports highlight the poor quality of adverse event reporting in the peer-reviewed literature. Nine peer-reviewed studies and five FDA summary reports documented excellent safety for both cervical fusion and disk arthroplasty. No differences in rates of adverse events were found to exist between the two treatments. The methods of recording and the actual reporting of adverse events were poor in peer-reviewed manuscripts, whereas they were comprehensive but difficult to clinically apply in the FDA summaries. Recommendations to improve documentation and reporting of adverse events are presented.
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Developing a toolkit for comparing safety in spine surgery.
Instr Course Lect
PUBLISHED: 04-12-2014
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Safety information in spine surgery is important for informed patient choice and performance-based payment incentives, but measurement methods for surgical safety assessment are not standardized. Published reports of complication rates for common spinal procedures show wide variation. Factors influencing variation may include differences in safety ascertainment methods and procedure types. In a prospective cohort study, adverse events were observed in all patients undergoing spine surgery at two hospitals during a 2-year period. Multiple processes for adverse occurrence surveillance were implemented, and the associations between surveillance methods, surgery invasiveness, and observed frequencies of adverse events were examined. The study enrolled 1,723 patients. Adverse events were noted in 48.3% of the patients. Reviewers classified 25% as minor events and 23% as major events. Of the major events, the daily rounding team reported 38.4% of the events using a voluntary reporting system, surgeons reported 13.4%, and 9.1% were identified during clinical conferences. A review of medical records identified 86.7% of the major adverse events. The adverse events occurred during the inpatient hospitalization for 78.1% of the events, within 30 days for an additional 12.5%, and within the first year for the remaining 9.4%. A unit increase in the invasiveness index was associated with an 8.2% increased risk of a major adverse event. A Current Procedural Terminology-based algorithm for quantifying invasiveness correlated well with medical records-based assessment. Increased procedure invasiveness is associated with an increased risk of adverse events. The observed frequency of adverse events is influenced by the ascertainment modality. Voluntary reports by surgeons and other team members missed more than 50% of the events identified through a medical records review. Increased surgery invasiveness, measured from medical records or billing codes, is quantitatively associated with an increased risk of adverse events.
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Alternative translation initiation in immunity: MAVS learns new tricks.
Trends Immunol.
PUBLISHED: 03-17-2014
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Translational control of gene expression contributes to various aspects of immune function [1]. Recent results by Brubaker et al. [2] show how alternative translation initiation produces distinct isoforms of Mitochondrial Antiviral Signaling (MAVS), an adaptor protein associated with RIG-I and MDA5 that possess unique immunomodulatory properties.
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Zeolites are no longer a challenge: Atomic resolution data by Aberration-corrected STEM.
Micron
PUBLISHED: 02-04-2014
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Transmission electron microscopy is undoubtedly an indispensable tool for materials characterization, which can currently reach sub-angstrom resolution down to the elemental building blocks of matter, isolated single atoms of most elements. In addition to the phenomenal image resolution, if the material is strong enough, it can be accompanied with chemical information, converting electron microscopy into a unique method for the analysis of a great variety of materials. Unfortunately, extracting all this valuable information is not simple as most materials in one way or another are affected by the strong and localized electron beam. Radiolysis is one kind of reaction between electrons and matter than can cause irreversible structural transformations in our materials. This effect is the predominant factor in zeolites, zeotypes and the majority of molecular sieves. In the present work some results, taken at high voltage (300kV) and minimizing the exposure to the beam, are presented proving the feasibility of the technique to obtain unprecedented atomic resolution information of different zeolites and microporous solids.
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Mechanisms of vitamin D? metabolite repression of IgE-dependent mast cell activation.
J. Allergy Clin. Immunol.
PUBLISHED: 01-22-2014
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Mast cells have gained notoriety based on their detrimental contributions to IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to what extent 1?,25-dihydroxyvitamin D3 (1?,25[OH]2D3) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo.
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Remote monitoring of the progression of primary pneumonic plague in Brown Norway rats in high-capacity, high-containment housing.
Pathog Dis
PUBLISHED: 01-06-2014
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Development of new vaccines, diagnostics, and therapeutics for biodefense or other relatively rare infectious diseases is hindered by the lack of naturally occurring human disease on which to conduct clinical trials of efficacy. To overcome this experimental gap, the U.S. Food and Drug Administration established the Animal Rule, in which efficacy testing in two well-characterized animal models that closely resemble human disease may be accepted in lieu of large-scale clinical trials for diseases with limited natural human incidence. In this report, we evaluated the Brown Norway rat as a model for pneumonic plague and describe the natural history of clinical disease following inhalation exposure to Yersinia pestis. In high-capacity, high-containment housing, we monitored temperature, activity, heart rate, and rhythm by capturing electronic impulses transmitted from abdominal telemeter implants. Using this system, we show that reduced activity and development of fever are sensitive indications of disease progression. Furthermore, we identified heart arrhythmias as contributing factors to the rapid progression to lethality following the fever response. Together, these data validate the Brown Norway rat as an experimental model for human pneumonic plague and provide new insight that may ultimately lead to novel approaches in postexposure treatment of this devastating infection.
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Vitamin D receptor overexpression in osteoblasts and osteocytes prevents bone loss during vitamin D-deficiency.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 01-02-2014
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There are several lines of evidence that demonstrate the ability of 1,25-dihydroxyvitamin D (1,25(OH)2D3), acting via the vitamin D receptor (VDR) to mediate negative or positive effects in bone. Transgenic over-expression of VDR in osteoblasts and osteocytes in a mouse model (OSVDR) has been previously shown to inhibit processes of bone resorption and enhance bone formation, under conditions of adequate calcium intake. While these findings suggest that vitamin D signalling in osteoblasts and osteocytes promotes bone mineral accrual, the vitamin D requirement for this action is not well understood. In this study, 4 week old female OSVDR and wild-type (WT) mice were fed either a vitamin D-replete (1000IU/kg diet, D+) or vitamin D-deficient (D-) diet for 4 months to observe changes to bone mineral homeostasis. Tibial bone mineral volume was analysed by micro-CT and changes to bone cell activities were measured using standard dynamic histomorphometric techniques. While vitamin D-deplete WT mice demonstrated a reduction in periosteal bone accrual and overall bone mineral volume, OSVDR mice, however, displayed increased cortical and cancellous bone volume in mice which remained higher during vitamin D-depletion due to a reduced osteoclast number and increased bone formation rate. These data suggest that increased VDR-mediated activity in osteoblast and osteocytes prevents bone loss due to vitamin D-deficiency. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
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Recovery of crystallographic texture in remineralized dental enamel.
PLoS ONE
PUBLISHED: 01-01-2014
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Dental caries is the most prevalent disease encountered by people of all ages around the world. Chemical changes occurring in the oral environment during the caries process alter the crystallography and microstructure of dental enamel resulting in loss of mechanical function. Little is known about the crystallographic effects of demineralization and remineralization. The motivation for this study was to develop understanding of the caries process at the crystallographic level in order to contribute towards a long term solution. In this study synchrotron X-ray diffraction combined with scanning electron microscopy and scanning microradiography have been used to correlate enamel crystallography, microstructure and mineral concentration respectively in enamel affected by natural caries and following artificial demineralization and remineralization regimes. In particular, the extent of destruction and re-formation of this complex structure has been measured. 2D diffraction patterns collected at the European Synchrotron Radiation Facility were used to quantify changes in the preferred orientation (crystallographic texture) and position of the (002) Bragg reflection within selected regions of interest in each tooth slice, and then correlated with the microstructure and local mineral mass. The results revealed that caries and artificial demineralization cause a large reduction in crystallographic texture which is coupled with the loss of mineral mass. Remineralization restores the texture to the original level seen in healthy enamel and restores mineral density. The results also showed that remineralization promotes ordered formation of new crystallites and growth of pre-existing crystallites which match the preferred orientation of healthy enamel. Combining microstructural and crystallographic characterization aids the understanding of caries and erosion processes and assists in the progress towards developing therapeutic treatments to allow affected enamel to regain structural integrity.
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Application of 1H-NMR Metabolomic Profiling for Reef-Building Corals.
PLoS ONE
PUBLISHED: 01-01-2014
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In light of global reef decline new methods to accurately, cheaply, and quickly evaluate coral metabolic states are needed to assess reef health. Metabolomic profiling can describe the response of individuals to disturbance (i.e., shifts in environmental conditions) across biological models and is a powerful approach for characterizing and comparing coral metabolism. For the first time, we assess the utility of a proton-nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomics approach in characterizing coral metabolite profiles by 1) investigating technical, intra-, and inter-sample variation, 2) evaluating the ability to recover targeted metabolite spikes, and 3) assessing the potential for this method to differentiate among coral species. Our results indicate 1H-NMR profiling of Porites compressa corals is highly reproducible and exhibits low levels of variability within and among colonies. The spiking experiments validate the sensitivity of our methods and showcase the capacity of orthogonal partial least squares discriminate analysis (OPLS-DA) to distinguish between profiles spiked with varying metabolite concentrations (0 mM, 0.1 mM, and 10 mM). Finally, 1H-NMR metabolomics coupled with OPLS-DA, revealed species-specific patterns in metabolite profiles among four reef-building corals (Pocillopora damicornis, Porites lobata, Montipora aequituberculata, and Seriatopora hystrix). Collectively, these data indicate that 1H-NMR metabolomic techniques can profile reef-building coral metabolomes and have the potential to provide an integrated picture of the coral phenotype in response to environmental change.
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Auditory/visual distance estimation: accuracy and variability.
Front Psychol
PUBLISHED: 01-01-2014
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Past research has shown that auditory distance estimation improves when listeners are given the opportunity to see all possible sound sources when compared to no visual input. It has also been established that distance estimation is more accurate in vision than in audition. The present study investigates the degree to which auditory distance estimation is improved when matched with a congruent visual stimulus. Virtual sound sources based on binaural room impulse response (BRIR) measurements made from distances ranging from approximately 0.3 to 9.8 m in a concert hall were used as auditory stimuli. Visual stimuli were photographs taken from the participant's perspective at each distance in the impulse response measurement setup presented on a large HDTV monitor. Participants were asked to estimate egocentric distance to the sound source in each of three conditions: auditory only (A), visual only (V), and congruent auditory/visual stimuli (A+V). Each condition was presented within its own block. Sixty-two participants were tested in order to quantify the response variability inherent in auditory distance perception. Distance estimates from both the V and A+V conditions were found to be considerably more accurate and less variable than estimates from the A condition.
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Effect of machined interfacet allograft spacers on cervical foraminal height and area.
J Neurosurg Spine
PUBLISHED: 12-13-2013
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Object Iatrogenic foraminal stenosis is a well-known complication in cervical spine surgery. Machined interfacet allograft spacers can provide a large surface area, which ensures solid support, and could potentially increase foraminal space. The authors tested the hypothesis that machined interfacet allograft spacers increase cervical foraminal height and area. Methods The C4-5, C5-6, and C6-7 facets of 4 fresh adult cadavers were exposed, and the cartilage was removed from each facet using customized rasps. Machined allograft spacers were tamped into the joints. The spines were scanned with the O-arm surgical imaging system before and after placement of the spacers. Two individuals independently measured foraminal height and area on obliquely angled sagittal images. Results Foraminal height and area were significantly greater following placement of the machined interfacet spacers at all levels. The Pearson correlation between the 2 radiographic reviewers was very strong (r = 0.971, p = 0.0001), as was the intraclass correlation coefficient (ICC = 0.907, p = 0.0001). The average increase in foraminal height was 1.38 mm. The average increase in foraminal area was 18.4% (0.097 mm(2)). Conclusions Modest distraction of the facets using machined interfacet allograft spacers can increase foraminal height and area and therefore indirectly decompress the exiting nerve roots. This technique can be useful in treating primary foraminal stenosis and also for preventing iatrogenic foraminal stenosis that may occur when the initially nonlordotic spine is placed into lordosis either with repositioning after central canal decompression or with correction using instrumentation. These grafts may be a useful adjunct to the surgical treatment of cervical spine disease.
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Oral contraceptive use and acute mountain sickness in South Pole workers.
Aviat Space Environ Med
PUBLISHED: 11-28-2013
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Progesterone has a number of properties that could influence the development of acute mountain sickness (AMS), including anti-inflammation, respiratory smooth muscle relaxation, ventilatory stimulation, and antidiuretic characteristics. Oral contraceptive (OC) use decreases levels of circulating progesterone by preventing ovulation. We hypothesized rates of AMS development would be significantly higher in OC users as compared to Non-OC users in a population traveling rapidly to the South Pole.
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Amplitude modulation detection by human listeners in reverberant sound fields: Effects of prior listening exposure.
Proc Meet Acoust
PUBLISHED: 10-29-2013
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Previous work [Zahorik et al., POMA, 15, 050002 (2012)] has reported that for both broadband and narrowband noise carrier signals in a simulated reverberant sound field, human sensitivity to amplitude modulation (AM) is higher than would be predicted based on the acoustical modulation transfer function (MTF) of the listening environment. These results may be suggestive of mechanisms that functionally enhance modulation in reverberant listening, although many details of this enhancement effect are unknown. Given recent findings that demonstrate improvements in speech understanding with prior exposure to reverberant listening environments, it is of interest to determine whether listening exposure to a reverberant room might also influence AM detection in the room, and perhaps contribute to the AM enhancement effect. Here, AM detection thresholds were estimated (using an adaptive 2-alternative forced-choice procedure) in each of two listening conditions: one in which consistent listening exposure to a particular room was provided, and a second that intentionally disrupted listening exposure by varying the room from trial-to-trial. Results suggest that consistent prior listening exposure contributes to enhanced AM sensitivity in rooms. [Work supported by the NIH/NIDCD.].
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Effects of Fluoride Concentration on Enamel Demineralization Kinetics in vitro.
J Dent
PUBLISHED: 10-16-2013
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The aim of the present study was to measure the effects of fluoride concentration on the real-time in vitro demineralization of enamel during exposure to caries-simulating conditions using Scanning Microradiography (SMR).
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Simulated spinal cerebrospinal fluid leak repair: an educational model with didactic and technical components.
Neurosurgery
PUBLISHED: 09-21-2013
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In the era of surgical resident work hour restrictions, the traditional apprenticeship model may provide fewer hours for neurosurgical residents to hone technical skills. Spinal dura mater closure or repair is 1 skill that is infrequently encountered, and persistent cerebrospinal fluid leaks are a potential morbidity.
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QPLOT: A Quality Assessment Tool for Next Generation Sequencing Data.
Biomed Res Int
PUBLISHED: 09-13-2013
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Background. Next generation sequencing (NGS) is being widely used to identify genetic variants associated with human disease. Although the approach is cost effective, the underlying data is susceptible to many types of error. Importantly, since NGS technologies and protocols are rapidly evolving, with constantly changing steps ranging from sample preparation to data processing software updates, it is important to enable researchers to routinely assess the quality of sequencing and alignment data prior to downstream analyses. Results. Here we describe QPLOT, an automated tool that can facilitate the quality assessment of sequencing run performance. Taking standard sequence alignments as input, QPLOT generates a series of diagnostic metrics summarizing run quality and produces convenient graphical summaries for these metrics. QPLOT is computationally efficient, generates webpages for interactive exploration of detailed results, and can handle the joint output of many sequencing runs. Conclusion. QPLOT is an automated tool that facilitates assessment of sequence run quality. We routinely apply QPLOT to ensure quick detection of diagnostic of sequencing run problems. We hope that QPLOT will be useful to the community as well.
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Cost-effectiveness of single-level anterior cervical discectomy and fusion five years after surgery.
Spine
PUBLISHED: 09-07-2013
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Longitudinal cohort. OBJECTIVE.: The purpose of this study is to determine the cost per quality-adjusted life year (cost/QALY) gained for single-level instrumented anterior cervical discectomy and fusion (ACDF) over 5 years.
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Mechanical properties of sand tiger shark (Carcharias taurus) vertebrae in relation to spinal deformity.
J. Exp. Biol.
PUBLISHED: 08-30-2013
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Approximately 35% of sand tiger sharks (Carcharias taurus) in public aquaria exhibit spinal deformities ranging from compressed vertebrae and loss of intervertebral space to dislocated spines with vertebral degeneration and massive spondylosis caused by excessive mineralization both within vertebrae and outside the notochordal sheath. To identify the mechanical basis of these deformities, vertebral centra from affected (N=12) and non-affected (N=9) C. taurus were subjected to axial compression tests on an MTS 858 Bionix material testing system, after which mineral content was determined. Vertebral centra from affected sharks had significantly lower mineral content and material behavior in nearly all variables characterizing elasticity, plasticity and failure. These mechanical deficiencies are correlated with size at capture, capture method, vitamin C and zinc deficiency, aquarium size and swimming behavior in public aquaria. Non-affected C. taurus had greater stiffness and toughness even though these properties are generally incompatible in mineralized structures, suggesting that the biphasic (mineralized, unmineralized phases) nature of chondrichthyan vertebrae yields material behavior not otherwise observed in vertebrate skeletons. However, vertebral centra from non-affected sharks had lower mineral content (33%), stiffness (167 MPa), yield strain (14%) and ultimate strength (16 MPa) than other species of sharks and bony vertebrates, indicating that biomechanical precautions must be taken in the husbandry of this species.
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The paired-box homeodomain transcription factor Pax6 binds to the upstream region of the TRAP gene promoter and suppresses receptor activator of NF-?B ligand (RANKL)-induced osteoclast differentiation.
J. Biol. Chem.
PUBLISHED: 08-29-2013
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Osteoclast formation is regulated by balancing between the receptor activator of nuclear factor-?B ligand (RANKL) expressed in osteoblasts and extracellular negative regulatory cytokines such as interferon-? (IFN-?) and interferon-? (IFN-?), which can suppress excessive bone destruction. However, relatively little is known about intrinsic negative regulatory factors in RANKL-mediated osteoclast differentiation. Here, we show the paired-box homeodomain transcription factor Pax6 acts as a negative regulator of RANKL-mediated osteoclast differentiation. Electrophoretic mobility shift and reporter assays found that Pax6 binds endogenously to the proximal region of the tartrate acid phosphatase (TRAP) gene promoter and suppresses nuclear factor of activated T cells c1 (NFATc1)-induced TRAP gene expression. Introduction of Pax6 retrovirally into bone marrow macrophages attenuates RANKL-induced osteoclast formation. Moreover, we found that the Groucho family member co-repressor Grg6 contributes to Pax6-mediated suppression of the TRAP gene expression induced by NFATc1. These results suggest that Pax6 interferes with RANKL-mediated osteoclast differentiation together with Grg6. Our results demonstrate that the Pax6 pathway constitutes a new aspect of the negative regulatory circuit of RANKL-RANK signaling in osteoclastogenesis and that the augmentation of Pax6 might therefore represent a novel target to block pathological bone resorption.
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Adequate dietary vitamin D and calcium are both required to reduce bone turnover and increased bone mineral volume.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 08-01-2013
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Clinical studies indicate that the combination of vitamin D and dietary calcium supplementation is more effective for reducing fracture risk than either supplement alone. Our previous dietary studies demonstrated that an adequate serum 25-hydroxyvitamin D3 (25D) of 80nmol/L or more reduces bone RANKL expression, osteoclastogenesis and maintains the optimal levels of trabecular bone volume (BV/TV%) in young rats. The important clinical question of the interaction between vitamin D status, dietary calcium intake and age remains unclear. Hence, 9 month-old female Sprague-Dawley rats (n=5-6/group) were pair-fed a semi-synthetic diet containing varying levels of vitamin D (0, 2, 12 or 20IU/day) and dietary calcium (0.1% or 1%) for 6 months. At 15 months of age, animals were killed, for biochemical and skeletal analyses. While changes to serum 25D were determined by both dietary vitamin D and calcium levels, changes to serum 1,25-dihydroxyvitamin D3 (1,25D) were consistently raised in animals fed 0.1% Ca regardless of dietary vitamin D or vitamin D status. Importantly, serum cross-laps levels were significantly increased in animals fed 0.1% Ca only when combined with 0 or 2 IUD/day of vitamin D, suggesting a contribution of both dietary calcium and vitamin D in determining bone resorption activity. Serum 25(OH)D3 levels were positively correlated with both femoral mid-diaphyseal cortical bone volume (R(2)=0.24, P<0.01) and metaphyseal BV/TV% (R(2)=0.23, P<0.01, data not shown). In multiple linear regressions, serum 1,25(OH)2D3 levels were a negative determinant of CBV (R(2)=0.24, P<0.01) and were not a determinant of metaphyseal BV/TV% levels. These data support clinical data that reduced bone resorption and increased bone volume can only be achieved with adequate 25D levels in combination with high dietary calcium and low serum 1,25D levels. This article is part of a Special Issue entitled 16th Vitamin D Workshop.
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The local production of 1,25(OH)2D3 promotes osteoblast and osteocyte maturation.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 07-31-2013
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Maintenance of an adequate vitamin D status, as indicated by the level of circulating 25-hydroxyvitamin D (25(OH)D), is associated with higher bone mass and decreased risk of fracture. However, the molecular actions of vitamin D hormone (1,25(OH)2D3) in bone are complex, and include stimulation of osteoclastogenesis via RANK-ligand up-regulation, as well as the inhibition of mineralisation. We hypothesise that these divergent data may be reconciled by autocrine actions of 1,25(OH)2D3 which effect skeletal maintenance, as opposed to endocrine 1,25(OH)2D3 which acts to maintain serum calcium homeostasis. We have previously described local metabolism of 1,25(OH)2D3 within osteoblasts, with effects on gene expression and cell function. The aim of the current study was to investigate potential autocrine actions of 1,25(OH)2D3 within cells that exhibit osteocyte-like properties. Late osteoblastic MLO-A5 cells were cultured in the presence of 25(OH)D for 9 days with gene expression analysed pre- and post-mineralisation. Gene expression analysis revealed maturation within this time frame to an osteocyte-like stage, evidenced by increased Dmp1 and Phex mRNA expression. Expression of Cyp27b1 in 25(OH)D treated MLO-A5 cells was associated with elevated media levels of 1,25(OH)2D3 (p<0.05), induction of Cyp24a1 (p<0.001) and elevated ratios of Opg:Rankl mRNA (p<0.01). Chronic 25(OH)D exposure also increased osteocalcin mRNA in MLO-A5 cells, which contrasted with the dose-dependent inhibition of osteocalcin mRNA observed with acute treatment in MLO-Y4 cells (p<0.01). Treatment of MLO-Y4 cells with 25(OH)D also inhibited Phex mRNA expression (p<0.05), whilst Enpp1 gene expression was induced (p<0.01). Overall, the current study demonstrates that osteocyte-like cells convert physiological levels of 25(OH)D to 1,25(OH)2D3, with changes in gene expression that are consistent with increased osteocyte maturation. Although the physiological role of local metabolism of 1,25(OH)2D3 within osteocytes requires further investigation, the abundance and diverse functions of this cell type within bone underscore its potential importance. This article is part of a Special Issue entitled 16th Vitamin D Workshop.
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Analysis of vitamin D metabolism gene expression in human bone: Evidence for autocrine control of bone remodelling.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 07-31-2013
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The metabolism of 25-hydroxyvitamin D (25D) to active 1?,25-dihydroxyvitamin D (1,25D) by endogenous expression of 25D 1-? hydroxylase (CYP27B1) in bone cells appears to have functional effects in both osteoclasts and osteoblasts. To examine relationships between CYP27B1 expression in bone and its potential function in vivo, we examined the expression of vitamin D metabolism genes (CYP27B1, CYP24A1, VDR) in human trabecular bone samples and compared them by linear regression analysis with the expression of osteoclast (TRAP, CA2, CATK, NFATC1), osteoblast (TNAP, COL1A1, OCN, MEPE, BRIL), osteocyte (DMP1, SOST, PHEX, MEPE, FGF23)-related gene markers, genes associated with osteoblast/osteocyte control of osteoclastogenesis (RANKL, M-CSF, OPG, IL-8, TWEAK) and transcription factors (NFATC1, RUNX2, OSX, MSX2, HIF1A). This revealed multiple significant gene expression relationships between CYP27B1 and the transcription factors RUNX2, NFATC1, consistent with the coordinated expression of this gene by both osteoblast and osteoclast-lineage cells, and with MSX2 and the hypoxia-inducible transcription factor, HIF1A. CYP27B1 expression associated mainly with gene markers of bone resorption. VDR mRNA expression was also associated with resorption-related genes. Against expectations, CYP27B1 expression did not associate with bone expressed genes known to be 1,25D responsive, such as OCN, RANKL and DMP1. The major implication of these relationships in gene expression is that endogenous 1,25D synthesis and the response to 1,25D in human trabecular bone is linked with coordinated functions in both the osteoclastic and osteoblastic compartments towards the control of bone remodelling. This article is part of a Special Issue entitled 16th Vitamin D Workshop.
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Novel targets of vitamin d activity in bone: action of the vitamin d receptor in osteoblasts, osteocytes and osteoclasts.
Curr Drug Targets
PUBLISHED: 07-26-2013
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The active form of vitamin D, 1,25-dihydroxyvitamin D3, carries out its diverse range of biological activities by binding to the nuclear vitamin D receptor, present in almost every cell of the body. It is well established that adequate serum 25-hydroxyvitamin D levels correlate with a reduction in the incidence of osteoporosis; however, the physiological basis for this relationship remains elusive. Although, the endocrine actions of vitamin D are thoroughly appreciated, the effect of vitamin D on bone tissue and bone cells is yet to be completely understood. There exists a wealth of literature that suggests the VDR within the three major bone cell types, osteoblasts, osteocytes and osteoclasts, is responsible for the regulation of bone homeostasis. The circumstances, under which the action of 1,25-dihydroxyvitamin D3 elicits an anabolic or catabolic role have not been elucidated. However, it would seem that vitamin D can evoke both of these effects and that this is partly mediated by calcium homeostasis. This raises the possibility that dietary calcium intake and vitamin D metabolism act concomitantly at the kidney, intestine and the bone in a coordinated response. Thus, to maintain adequate bone homeostasis and reduce the risk of metabolic bone disease via the diet, it is important to consider this duality of vitamin D action in relation to the overall calcium economy.
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Vitamin D activities and metabolic bone disease.
Clin. Chim. Acta
PUBLISHED: 06-29-2013
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Vitamin D activity requires an adequate vitamin D status as indicated by the serum level of 25-hydroxyvitamin D and appropriate expression of genes coding for vitamin D receptor and 25-hydroxyvitamin D 1?-hydroxylase, the enzyme which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Vitamin D deficiency contributes to the aetiology of osteomalacia and osteoporosis. The key element of osteomalacia, or rickets in children, is a delay in mineralization. It can be resolved by normalisation of plasma calcium and phosphate homeostasis independently of vitamin D activity. The well characterised endocrine pathway of vitamin D metabolism generates plasma 1,25-dihydroxyvitamin D and these endocrine activities are solely responsible for vitamin D regulating plasma calcium and phosphate homeostasis and protection against osteomalacia. In contrast, a large body of clinical data indicate that an adequate serum 25-hydroxyvitamin D level improves bone mineral density protecting against osteoporosis and reducing fracture risk. Recent research demonstrates that the three major bone cell types have the capability to metabolise 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D to activate the vitamin D receptor and modulate gene expression. Dietary calcium intake interacts with vitamin D metabolism at both the renal and bone tissue levels to direct either a catabolic action on bone through the endocrine system when calcium intake is inadequate or an anabolic action through a bone autocrine or paracrine system when calcium intake is sufficient.
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Meta-analysis of vertebral augmentation compared with conservative treatment for osteoporotic spinal fractures.
J. Bone Miner. Res.
PUBLISHED: 06-28-2013
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Cement augmentation is a controversial treatment for painful vertebral compression fractures (VCF). Our research questions for the meta-analysis were: Is there a clinical and statistical difference in pain relief, functional improvement, and quality of life between conservative care and cement augmentation for VCF and, if so, are they maintained at longer time points? We conducted a search of MEDLINE from January 1980 to July 2011 using PubMed, Cochrane Database of Systematic Reviews and Controlled Trials, CINAHL, and EMBASE. Searches were performed from medical subject headings. Terms "vertebroplasty" and "compression fracture" were used. The outcome variables of pain, functional measures, health-related quality of life (HRQOL), and new fracture risk were analyzed. A random effects model was chosen. Continuous variables were calculated using the standardized mean difference comparing improvement from baseline of the experimental group with the control group. New vertebral fracture risk was calculated using log odds ratio. Six studies met the criteria. The pain visual analog scale (VAS) mean difference was 0.73 (confidence interval [CI] 0.35, 1.10) for early (<12 weeks) and 0.58 (CI 0.19, 0.97) for late time points (6 to 12 months), favoring vertebroplasty (p?
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Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2.
J. Bone Miner. Res.
PUBLISHED: 05-06-2013
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The osteocyte product sclerostin is emerging as an important paracrine regulator of bone mass. It has recently been shown that osteocyte production of receptor activator of NF-?B ligand (RANKL) is important in osteoclastic bone resorption, and we reported that exogenous treatment of osteocytes with sclerostin can increase RANKL-mediated osteoclast activity. There is good evidence that osteocytes can themselves liberate mineral from bone in a process known as osteocytic osteolysis. In the current study, we investigated sclerostin-stimulated mineral dissolution by human primary osteocyte-like cells (hOCy) and mouse MLO-Y4 cells. We found that sclerostin upregulated osteocyte expression of carbonic anhydrase 2 (CA2/Car2), cathepsin K (CTSK/Ctsk), and tartrate-resistant acid phosphatase (ACP5/Acp5). Because acidification of the extracellular matrix is a critical step in the release of mineral from bone, we further examined the regulation by sclerostin of CA2. Sclerostin stimulated CA2 mRNA and protein expression in hOCy and in MLO-Y4 cells. Sclerostin induced a decrease in intracellular pH (pHi) in both cell types as well as a decrease in extracellular pH (pHo) and the release of calcium ions from mineralized substrate. These effects were reversed in the co-presence of the carbonic anhydrase inhibitor, acetozolamide. Car2-siRNA knockdown in MLO-Y4 cells significantly inhibited the ability of sclerostin to both reduce the pHo and release calcium from a mineralized substrate. Knockdown in MLO-Y4 cells of each of the putative sclerostin receptors, Lrp4, Lrp5 and Lrp6, using siRNA, inhibited the sclerostin induction of Car2, Catk and Acp5 mRNA, as well as pHo and calcium release. Consistent with this activity of sclerostin resulting in osteocytic osteolysis, human trabecular bone samples treated ex vivo with recombinant human sclerostin for 7 days exhibited an increased osteocyte lacunar area, an effect that was reversed by the co-addition of acetozolamide. These findings suggest a new role for sclerostin in the regulation of perilacunar mineral by osteocytes. © 2013 American Society for Bone and Mineral Research.
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Stress granules and cell signaling: more than just a passing phase?
Trends Biochem. Sci.
PUBLISHED: 05-02-2013
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Stress granules (SGs) contain translationally-stalled mRNAs, associated preinitiation factors, and specific RNA-binding proteins. In addition, many signaling proteins are recruited to SGs and/or influence their assembly, which is transient, lasting only until the cells adapt to stress or die. Beyond their role as mRNA triage centers, we posit that SGs constitute RNA-centric signaling hubs analogous to classical multiprotein signaling domains such as transmembrane receptor complexes. As signaling centers, SG formation communicates a state of emergency, and their transient existence alters multiple signaling pathways by intercepting and sequestering signaling components. SG assembly and downstream signaling functions may require a cytosolic phase transition facilitated by intrinsically disordered, aggregation-prone protein regions shared by RNA-binding and signaling proteins.
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Comparison of dural repair techniques.
Spine J
PUBLISHED: 04-14-2013
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Incidental durotomy occurs in 1% to 17% of lumbar spine surgery. This is treated with watertight suture repair, often combined with a sealant.
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Smartphone medication adherence apps: potential benefits to patients and providers.
J Am Pharm Assoc (2003)
PUBLISHED: 04-11-2013
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To provide an overview of medication adherence, discuss the potential for smartphone medication adherence applications (adherence apps) to improve medication nonadherence, evaluate features of adherence apps across operating systems (OSs), and identify future opportunities and barriers facing adherence apps.
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Post-transcriptional regulatory networks in immunity.
Immunol. Rev.
PUBLISHED: 04-05-2013
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Post-transcriptional mechanisms that modulate global and/or transcript-specific mRNA stability and translation contribute to the rapid and flexible control of gene expression in immune effector cells. These mechanisms rely on RNA-binding proteins (RBPs) that direct regulatory complexes (e.g. exosomes, deadenylases, decapping complexes, RNA-induced silencing complexes) to the 3-untranslated regions of specific immune transcripts. Here, we review the surprising variety of post-transcriptional control mechanisms that contribute to gene expression in the immune system and discuss how defects in these pathways can contribute to autoimmune disease.
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Prevention of orthopaedic implant infection in patients undergoing dental procedures.
J Am Acad Orthop Surg
PUBLISHED: 03-05-2013
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The Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures evidence-based clinical practice guideline was codeveloped by the American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association. This guideline replaces the previous AAOS Information Statement, "Antibiotic Prophylaxis in Bacteremia in Patients With Joint Replacement," published in 2009. Based on the best current evidence and a systematic review of published studies, three recommendations have been created to guide clinical practice in the prevention of orthopaedic implant infections in patients undergoing dental procedures. The first recommendation is graded as Limited; this recommendation proposes that the practitioner consider changing the long-standing practice of routinely prescribing prophylactic antibiotic for patients with orthopaedic implants who undergo dental procedures. The second, graded as Inconclusive, addresses the use of oral topical antimicrobials in the prevention of periprosthetic joint infections. The third recommendation, a Consensus statement, addresses the maintenance of good oral hygiene.
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An update on modifiable factors to reduce the risk of surgical site infections.
Spine J
PUBLISHED: 02-12-2013
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Despite an increase in physician and public awareness and advances in infection control practices, surgical site infection (SSI) remains to be one of the most common complications after an operation. Surgical site infections have been shown to decrease health-related quality of life, double the risk of readmission, prolong the length of hospital stay, and increase hospital costs.
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Reliability of the rabbit postero-lateral spinal fusion model: A meta-analysis.
J. Orthop. Res.
PUBLISHED: 02-07-2013
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The rabbit model of spinal fusion with the autogenous iliac crest bone graft (ICBG) control is widely used to evaluate bone graft substitutes and enhancers. This study examined the reliability of this model using meta-analysis. A systematic literature search from January 1995 to May 2011 identified 56 studies, involving 733 animals. The primary outcome was fusion success calculated as logit event rate. Study design, surgical technique, rabbit characteristics (gender, species, age, weight), and institution were analyzed. Overall fusion success was 52.4%. Important positive variables were time-point >4 weeks, ICBG dose >1?cm(3) , initial weight of animals ?3?kg, level at L4-5 or L5-6, and age ?6 months. Inter- and intra-institutional reliability was excellent. The rabbit model ICBG control group is reliable, although several factors can affect results. Fusion under normal handling occurs reliably in 5 weeks. The volume of bone graft should be >1?cm(3) but no benefits are present with >2?cm(3) . The animals should weigh a minimum of 3?kg and be at least 6 months old.
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Mixed metazoan and bacterial infection of the gas bladder of the lined seahorse-a case report.
J. Aquat. Anim. Health
PUBLISHED: 01-25-2013
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Five wild-caught Lined Seahorses Hippocampus erectus from an aquarium system presented with altered buoyancy and distended upper trunks. Radiography of one specimen revealed a reduced air volume in the gas bladder. Pneumocystocentesis revealed a brown exudate of numerous leukocytes, parasite ova, and Gram- and acid-fast-positive bacilli under wet mounts and stains. Necropsies revealed enlarged, friable kidneys and distended gas bladders containing copious purulent exudate, necrotic tissue, and adult digeneans Dictysarca virens. Bacterial isolates from exudate cultures grown on Lowenstein-Jensen medium were identified as Gordonia sp. and Mycobacterium poriferae by high-performance liquid chromatography and 16S ribosomal DNA sequencing. Histopathology demonstrated a histiocytic response in kidney and gas bladder exudate, inflammation of the gas bladder wall, and infection of the gas bladder lumen with parasite ova and acid-fast-positive and Gomoris methenamine silver-positive bacilli. Praziquantel is prescribed for digenean infections but dissolves incompletely in seawater and is toxic to this host. Eradication of intermediate host vectors is a management option. Treatment of Gordonia infection has not been addressed in nonhuman animals, and there is no known effective treatment for Mycobacterium spp. infection in fishes. This is the first case report of digenean infection of the gas bladder in a syngnathid, Gordonia sp. infection in a nonhuman animal, and M. poriferae infection in a fish.
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Physiological variables associated with the development of acute mountain sickness at the South Pole.
BMJ Open
PUBLISHED: 01-01-2013
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Exposure to altitudes >2500 m can result in acute mountain sickness (AMS), a mild and usually self-limiting condition. Research has attempted to identify factors associated with developing AMS without controlling important factors related to the ascent or collecting a comprehensive set of variables.
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An in vitro scanning microradiography study of the reduction in hydroxyapatite demineralization rate by statherin-like peptides as a function of increasing N-terminal length.
Eur. J. Oral Sci.
PUBLISHED: 12-21-2011
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Enamel demineralization is slowed by salivary proteins that inhibit calcium hydroxyapatite (HA) demineralization. Statherin (StN43), a 43-residue phosphorylated salivary protein with primary sequence similarities to osteopontin and caseins, binds calcium and HA. The aim of this study was to identify the minimum length of the functional domain of the statherin molecule required for cariostatic function by measuring the efficacy of peptides of progressively shorter length (i.e. containing only the N-terminal 21 (StN21), 15 (StN15), 10 (StN10), or 5 (StN5) residues) to reduce HA demineralization rates (RD(HA) ). Porous HA blocks were used as enamel analogues, and were exposed to 0.1 M acetic acid at pH 4 for 120 h, rinsed, and treated with StN21, StN15, StN10, or StN5 peptides (1.88 × 10(-5) M) for 24 h, then demineralized for a further 120 h. The RD(HA) was measured, before and after peptide treatment, using scanning microradiography. Hydroxyapatite blocks treated with StN21 and StN15 demonstrated a 50-60% reduction in the RD(HA) . However, no reduction in the RD(HA) was observed following treatment with either StN10, StN5, or buffer only. The mechanism by which statherin-like peptides reduce RD(HA) may be associated with their binding to HA surfaces. Comparisons with previously published binding energies of statherin to HA also suggest that statherin-like peptides containing 15 N-terminal residues or more, are required for binding, suggesting a link between binding and demineralization reduction.
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Decreased body weight in young Osterix-Cre transgenic mice results in delayed cortical bone expansion and accrual.
Transgenic Res.
PUBLISHED: 11-26-2011
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Conditional gene inactivation using the Cre/loxP system has lead to significant advances in our understanding of the function of genes in a wide range of disciplines. It is becoming increasingly apparent in the literature, that Cre transgenic mice may themselves have a phenotype. In the following study we describe the bone phenotype of a commonly used Cre transgenic mouse line to study osteoblasts, the Osx-GFP::Cre (Osx-Cre) mice. Cortical and trabecular bone parameters were determined in the femurs of Osx-Cre mice at 6 and 12 weeks of age by microtomography (?CT). At 6 weeks of age, Osx-Cre mice had reduced body weight by 22% (P < 0.0001) and delayed cortical bone expansion and accrual, characterized by decreases in periosteal circumference by 7% (P < 0.05) and cortical thickness by 11% (P < 0.01), compared to wild type controls. Importantly, the cortical bone phenotype of the skeletally immature Osx-Cre mice at 6 weeks of age could be accounted for by their low body weight. The delayed weight gain and cortical growth of Osx-Cre mice was overcome by 12 weeks of age, with no differences observed between Osx-Cre and wild type controls. In conclusion, Osx-Cre expressing mice display a delayed growth phenotype in the absence of doxycycline treatment, evidenced by decreased cortical bone expansion and accrual at 6 weeks of age, as an indirect result of decreased body weight. While this delay in growth is overcome by adulthood at 12 weeks of age, caution together with appropriate data analysis must be considered when assessing the experimental data from skeletally immature Cre/loxP knockout mice generated using the Osx-Cre mouse line to avoid misinterpretation.
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Amplitude modulation detection by human listeners in sound fields.
Proc Meet Acoust
PUBLISHED: 11-08-2011
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The temporal modulation transfer function (TMTF) approach allows techniques from linear systems analysis to be used to predict how the auditory system will respond to arbitrary patterns of amplitude modulation (AM). Although this approach forms the basis for a standard method of predicting speech intelligibility based on estimates of the acoustical modulation transfer function (MTF) between source and receiver, human sensitivity to AM as characterized by the TMTF has not been extensively studied under realistic listening conditions, such as in reverberant sound fields. Here, TMTFs (octave bands from 2 - 512 Hz) were obtained in 3 listening conditions simulated using virtual auditory space techniques: diotic, anechoic sound field, reverberant room sound field. TMTFs were then related to acoustical MTFs estimated using two different methods in each of the listening conditions. Both diotic and anechoic data were found to be in good agreement with classic results, but AM thresholds in the reverberant room were lower than predictions based on acoustical MTFs. This result suggests that simple linear systems techniques may not be appropriate for predicting TMTFs from acoustical MTFs in reverberant sound fields, and may be suggestive of mechanisms that functionally enhance modulation during reverberant listening.
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Stress puts TIA on TOP.
Genes Dev.
PUBLISHED: 10-21-2011
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Under conditions of limited nutrients, eukaryotic cells reprogram protein expression in a way that slows growth but enhances survival. Recent data implicate stress granules, discrete cytoplasmic foci into which untranslated mRNPs are assembled during stress, in this process. In the October 1, 2011, issue of Genes & Development, Damgaard and Lykke-Andersen (p. 2057-2068) provide mechanistic insights into the regulation of a specific subset of mRNAs bearing 5-terminal oligopyrimidine tracts (5TOPs) by the structurally related stress granule proteins TIA-1 and TIAR.
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Pediatric cervical spine trauma.
J Am Acad Orthop Surg
PUBLISHED: 10-08-2011
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Pediatric cervical spine injuries are rare and are associated with significant morbidity and mortality. Pediatric anatomy and physiology predispose to upper cervical spine injury and spinal cord injury without radiologic abnormality in contrast to lower cervical spine injury seen in adults. Care of pediatric patients is difficult because they have a greater head-to-body ratio than adults and may have difficulty cooperating with a history and physical examination. In evaluating a child with a suspected cervical spine injury, radiography may be supplemented with CT or MRI. Definitive management of pediatric cervical spine trauma must be adapted to the distinctive anatomy and growth potential of the patient. As with all injuries, prevention is necessary to reduce the incidence of trauma to the pediatric spine.
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Results of cervical arthroplasty compared with anterior discectomy and fusion: four-year clinical outcomes in a prospective, randomized controlled trial.
J Bone Joint Surg Am
PUBLISHED: 09-23-2011
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The published two-year results of the pivotal U.S. Food and Drug Administration investigational device exemption trial with the use of the Bryan cervical disc arthroplasty compared with anterior cervical discectomy with fusion for treating single-level degenerative cervical disc disease revealed a significantly superior overall success rate in the arthroplasty group. The purpose of this study was to evaluate the midterm safety and effectiveness of the Bryan disc as an alternative to arthrodesis following anterior cervical discectomy.
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Novel reduction technique for thoracolumbar fracture-dislocations.
J Neurosurg Spine
PUBLISHED: 09-16-2011
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Thoracolumbar fracture-dislocations are devastating injuries. They usually require surgical reduction and stabilization. The authors present a novel technique for reducing these injuries that is predictable and reproducible.
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Spinal duraplasty materials and hydrostasis: a biomechanical study: laboratory investigation.
J Neurosurg Spine
PUBLISHED: 06-24-2011
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Dural tears are a frequent complication of spinal surgery and contribute to significant morbidity. Occasionally, dural tears cannot be closed primarily and dural patch grafts must be utilized. No data exist on the comparative immediate hydrostatic strength of various patch materials used alone or with a biological adhesive in a spinal dural tear model. Thus, the authors conducted this study to determine the comparative effectiveness of various patch materials used with and without biological adhesive.
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Hounsfield units for assessing bone mineral density and strength: a tool for osteoporosis management.
J Bone Joint Surg Am
PUBLISHED: 06-10-2011
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Measurements obtained from clinical computed tomography examinations may yield information leading to the diagnosis of decreased bone mineral density, without added expense to the patient. The purpose of the present study was to determine if Hounsfield units, a standardized computed tomography attenuation coefficient, correlate with bone mineral density and compressive strength.
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Acute administration of typical and atypical antipsychotics reduces EEG ? power, but only the preclinical compound LY379268 reduces the ketamine-induced rise in ? power.
Int. J. Neuropsychopharmacol.
PUBLISHED: 06-09-2011
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A single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophrenia symptoms in patients. In conscious rats an equivalent dose of ketamine induces key features of animal models of acute psychosis, including hyperlocomotor activity, deficits in prepulse inhibition and gating of auditory evoked potentials, and concomitantly increases the power of ongoing spontaneously occurring gamma (30-80 Hz) oscillations in the neocortex. This study investigated whether NMDAR antagonist-induced aberrant gamma oscillations could be modulated by acute treatment with typical and atypical antipsychotic drugs. Extradural electrodes were surgically implanted into the skull of adult male Wistar rats. After recovery, rats were subcutaneously administered either clozapine (1-5 mg/kg, n=7), haloperidol (0.05-0.25 mg/kg; n=8), LY379268 (a preclinical agonist at mGluR2/3 receptors: 0.3-3 mg/kg; n=5) or the appropriate vehicles, and 30 min later received ketamine (5 mg/kg s.c.). Quantitative measures of EEG gamma power and locomotor activity were assessed throughout the experiment. All three drugs significantly reduced the power of baseline EEG gamma oscillations by 30-50%, an effect most prominent after LY379268, and all inhibited ketamine-induced hyperlocomotor activity. However, only pretreatment with LY379268 attenuated trough-to-peak ketamine-induced gamma hyperactivity. These results demonstrate that typical and atypical antipsychotic drugs acutely reduce cortical gamma oscillations, an effect that may be related to their clinical efficacy.
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The insertion of self expanding metal stents with flexible bronchoscopy under sedation for malignant tracheobronchial stenosis: a single-center retrospective analysis.
Arch. Bronconeumol.
PUBLISHED: 05-29-2011
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To describe a 10-year experience of inserting Ultraflex™ self-expanding metal stents (SEMS) under sedation using flexible bronchoscopy for the treatment of malignant tracheobronchial stenosis in a tertiary referral centre.
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Angiogenin-induced tRNA fragments inhibit translation initiation.
Mol. Cell
PUBLISHED: 04-05-2011
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Angiogenin is a stress-activated ribonuclease that cleaves tRNA within anticodon loops to produce tRNA-derived stress-induced fragments (tiRNAs). Transfection of natural or synthetic tiRNAs inhibits protein synthesis and triggers the phospho-eIF2?-independent assembly of stress granules (SGs), essential components of the stress response program. We show that selected tiRNAs inhibit protein synthesis by displacing eIF4G/eIF4A from uncapped > capped RNAs. tiRNAs also displace eIF4F, but not eIF4E:4EBP1, from isolated m(7)G cap. We identify a terminal oligoguanine motif that is required to displace the eIF4F complex, inhibit translation, and induce SG assembly. We show that the tiRNA-associated translational silencer YB-1 contributes to angiogenin-, tiRNA-, and oxidative stress-induced translational repression. Our data reveal some of the mechanisms by which stress-induced tRNA cleavage inhibits protein synthesis and activates a cytoprotective stress response program.
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Is there a beneficial role for a flexible bronchoscopic approach to oesophageal tumour-related tracheobronchial stenosis?
Lung
PUBLISHED: 04-04-2011
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Interventional pulmonology, in particular, tracheobronchial stent insertion, has been well described in the treatment of tracheobronchial malignant disease. Its benefits are particularly obvious in patients with inoperable malignancy or in those unfit for surgery and have been extensively described. Fewer data exist on the benefits of using self-expanding metal stents (SEMS) inserted via flexible bronchoscopy in the treatment of tracheobronchial stenosis due to extrinsic compression or infiltration from primary oesophageal malignancy.
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Efficacy and mechanisms of action of vitamin D in experimental polyarthritis.
Immunol. Cell Biol.
PUBLISHED: 03-29-2011
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Vitamin D (vit D) status has been linked to the occurrence and severity of auto-immune and inflammatory diseases. This study evaluates the effects of vit D status on adoptive transfer of adjuvant-induced arthritis (ATA). Rats maintained on diets replete or deficient in vit D3 received arthritogenic thoracic duct cells and were monitored for severity of arthritis. CD45(+) cells obtained by collagenase digestion of hind-paw synovium-rich tissues (SRTs) were analysed to observe the effects of dietary vit D3 on the inflammatory process. Arthritis was more severe in vitamin D-deficient (vit-D(-)) rats compared with vitamin D-replete (vit-D(+)) rats. Resolution was delayed in vit-D(-) rats compared with vit-D(+) rats, or rats fed standard chow. During the acute phase of ATA, numbers of CD45(+) cells were significantly increased in the SRTs of vit-D(-) rats compared with vit-D(+) rats. This increase involved T-cells, polymorphonuclear leukocytes, macrophages, dendritic cells (DCs) and MHC II(hi) cells that resemble activated monocytes. A major difference between the dietary groups was that most DCs at the peak of inflammation in vit-D(-) rats were CD4(-), whereas in convalescent vit-D(+) rats most expressed CD4. Multiple categories of genes expressed by DCs differed between deficient and replete rats, with deficiency being associated with relative upregulation of certain pro-inflammatory genes and replete status being associated with upregulation of genes associated with resolution of inflammation. The findings indicate that ATA is more severe and prolonged in vit-D deficiency, that vit-D deficiency promotes accumulation of CD4(-) DCs in synovium during ATA and that a gene-expression profile is likely to contribute to the observed increased severity and duration of arthritis.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.