bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABAB and mGlu2/3 receptors
Authors: Kupferschmidt David A. , Lovinger David M. 
Published: March 2015

Key points
Plastic changes at cortical inputs to the dorsolateral striatum (DLS) underlie skill learning and habit formation, so characterizing the mechanisms by which these inputs are regulated is important for understanding the neural basis of action control.
We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 and brain slice photometry to assess evoked presynaptic Ca2+ transients in cortical inputs to the DLS and study their regulation by GABAB and mGlu2/3 receptors.
GABAB and mGlu2/3 receptor activation caused clear reductions in electrical stimulus‐evoked presynaptic Ca2+ transients in corticostriatal inputs to the DLS.
Functional P/Q‐type voltage‐gated Ca2+ channels were required for the normal inhibitory action of corticostriatal mGlu2/3 receptors.
We provide direct evidence of presynaptic Ca2+ inhibition by G protein‐coupled receptors at corticostriatal projections.
AbstractCortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS‐associated circuit function, behaviour and pathology. Presynaptic GABAB and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 to assess presynaptic Ca2+ in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca2+ and striatal field potential recordings, we report that relative to P/Q‐type Ca2+ channels, N‐type channels preferentially contributed to evoked presynaptic Ca2+ influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABAB or mGlu2/3 receptors inhibited both evoked presynaptic Ca2+ transients and striatal field potentials. mGlu2/3 receptor‐mediated depression did not require functional N‐type Ca2+ channels, but was attenuated by blockade of P/Q‐type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires.
Decreases in mitochondrial reactive oxygen species initiate GABAA receptor‐mediated electrical suppression in anoxia‐tolerant turtle neurons
Authors: Hogg David W. , Pamenter Matthew E. , Dukoff David J. , Buck Leslie T. 
Published: March 2015

Key points
Anoxia induces hyper‐excitability and cell death in mammalian brain but in the western painted turtle (Chrysemys picta bellii) enhanced GABA transmission prevents injury.
The mechanism responsible for increased GABA transmission is unknown; however, reactive oxygen species (ROS) generated by mitochondria may play a role because this is an oxygen‐sensitive process.
In this study, we show that inhibition of mitochondrial ROS production is sufficient to initiate a redox‐sensitive GABA signalling cascade that suppresses pyramidal neuron action potential frequency.
These results further our understanding of the turtle's unique strategy for reducing ATP consumption during anoxia and highlights a natural mechanism in which to explore therapies to protect mammalian brain from low‐oxygen insults (e.g. cerebral stroke).
AbstractAnoxia induces hyper‐excitability and cell death in mammalian brain but in the anoxia‐tolerant western painted turtle (Chrysemys picta bellii) neuronal electrical activity is suppressed (i.e. spike arrest), adenosine triphosphate (ATP) consumption is reduced, and cell death does not occur. Electrical suppression is primarily the result of enhanced γ‐aminobutyric acid (GABA) transmission; however, the underlying mechanism responsible for initiating oxygen‐sensitive GABAergic spike arrest is unknown. In turtle cortical pyramidal neurons there are three types of GABAA receptor‐mediated currents: spontaneous inhibitory postsynaptic currents (IPSCs), giant IPSCs and tonic currents. The aim of this study was to assess the effects of reactive oxygen species (ROS) scavenging on these three currents since ROS levels naturally decrease with anoxia and may serve as a redox signal to initiate spike arrest. We found that anoxia, pharmacological ROS scavenging, or inhibition of mitochondrial ROS generation enhanced all three types of GABA currents, with tonic currents comprising ∼50% of the total current. Application of hydrogen peroxide inhibited all three GABA currents, demonstrating a reversible redox‐sensitive signalling mechanism. We conclude that anoxia‐mediated decreases in mitochondrial ROS production are sufficient to initiate a redox‐sensitive inhibitory GABA signalling cascade that suppresses electrical activity when oxygen is limited. This unique strategy for reducing neuronal ATP consumption during anoxia represents a natural mechanism in which to explore therapies to protect mammalian brain from low‐oxygen insults.
Models for predicting objective function weights in prostate cancer IMRT
Authors: Boutilier Justin J. , Lee Taewoo , Craig Tim , Sharpe Michael B. , Chan Timothy C. Y. 
Published: March 2015

Purpose:To develop and evaluate the clinical applicability of advanced machine learning models that simultaneously predict multiple optimization objective function weights from patient geometry for intensity‐modulated radiation therapy of prostate cancer.Methods:A previously developed inverse optimization method was applied retrospectively to determine optimal objective function weights for 315 treated patients. The authors used an overlap volume ratio (OV) of bladder and rectum for different PTV expansions and overlap volume histogram slopes (OVSR and OVSB for the rectum and bladder, respectively) as explanatory variables that quantify patient geometry. Using the optimal weights as ground truth, the authors trained and applied three prediction models: logistic regression (LR), multinomial logistic regression (MLR), and weighted K‐nearest neighbor (KNN). The population average of the optimal objective function weights was also calculated.Results:The OV at 0.4 cm and OVSR at 0.1 cm features were found to be the most predictive of the weights. The authors observed comparable performance (i.e., no statistically significant difference) between LR, MLR, and KNN methodologies, with LR appearing to perform the best. All three machine learning models outperformed the population average by a statistically significant amount over a range of clinical metrics including bladder/rectum V53Gy, bladder/rectum V70Gy, and dose to the bladder, rectum, CTV, and PTV. When comparing the weights directly, the LR model predicted bladder and rectum weights that had, on average, a 73% and 74% relative improvement over the population average weights, respectively. The treatment plans resulting from the LR weights had, on average, a rectum V70Gy that was 35% closer to the clinical plan and a bladder V70Gy that was 29% closer, compared to the population average weights. Similar results were observed for all other clinical metrics.Conclusions:The authors demonstrated that the KNN and MLR weight prediction methodologies perform comparably to the LR model and can produce clinical quality treatment plans by simultaneously predicting multiple weights that capture trade‐offs associated with sparing multiple OARs.
Patch‐based generation of a pseudo CT from conventional MRI sequences for MRI‐only radiotherapy of the brain
Authors: Andreasen Daniel , Van Leemput Koen , Hansen Rasmus H. , Andersen Jon A. L. , Edmund Jens M. 
Published: March 2015

Purpose:In radiotherapy (RT) based on magnetic resonance imaging (MRI) as the only modality, the information on electron density must be derived from the MRI scan by creating a so‐called pseudo computed tomography (pCT). This is a nontrivial task, since the voxel‐intensities in an MRI scan are not uniquely related to electron density. To solve the task, voxel‐based or atlas‐based models have typically been used. The voxel‐based models require a specialized dual ultrashort echo time MRI sequence for bone visualization and the atlas‐based models require deformable registrations of conventional MRI scans. In this study, we investigate the potential of a patch‐based method for creating a pCT based on conventional T1‐weighted MRI scans without using deformable registrations. We compare this method against two state‐of‐the‐art methods within the voxel‐based and atlas‐based categories.Methods:The data consisted of CT and MRI scans of five cranial RT patients. To compare the performance of the different methods, a nested cross validation was done to find optimal model parameters for all the methods. Voxel‐wise and geometric evaluations of the pCTs were done. Furthermore, a radiologic evaluation based on water equivalent path lengths was carried out, comparing the upper hemisphere of the head in the pCT and the real CT. Finally, the dosimetric accuracy was tested and compared for a photon treatment plan.Results:The pCTs produced with the patch‐based method had the best voxel‐wise, geometric, and radiologic agreement with the real CT, closely followed by the atlas‐based method. In terms of the dosimetric accuracy, the patch‐based method had average deviations of less than 0.5% in measures related to target coverage.Conclusions:We showed that a patch‐based method could generate an accurate pCT based on conventional T1‐weighted MRI sequences and without deformable registrations. In our evaluations, the method performed better than existing voxel‐based and atlas‐based methods and showed a promising potential for RT of the brain based only on MRI.
X‐ray computed tomography using curvelet sparse regularization
Authors: Wieczorek Matthias , Frikel Jürgen , Vogel Jakob , Eggl Elena , Kopp Felix , Noël Peter B. , Pfeiffer Franz , Demaret Laurent , Lasser Tobias 
Published: March 2015

Purpose:Reconstruction of x‐ray computed tomography (CT) data remains a mathematically challenging problem in medical imaging. Complementing the standard analytical reconstruction methods, sparse regularization is growing in importance, as it allows inclusion of prior knowledge. The paper presents a method for sparse regularization based on the curvelet frame for the application to iterative reconstruction in x‐ray computed tomography.Methods:In this work, the authors present an iterative reconstruction approach based on the alternating direction method of multipliers using curvelet sparse regularization.Results:Evaluation of the method is performed on a specifically crafted numerical phantom dataset to highlight the method's strengths. Additional evaluation is performed on two real datasets from commercial scanners with different noise characteristics, a clinical bone sample acquired in a micro‐CT and a human abdomen scanned in a diagnostic CT. The results clearly illustrate that curvelet sparse regularization has characteristic strengths. In particular, it improves the restoration and resolution of highly directional, high contrast features with smooth contrast variations. The authors also compare this approach to the popular technique of total variation and to traditional filtered backprojection.Conclusions:The authors conclude that curvelet sparse regularization is able to improve reconstruction quality by reducing noise while preserving highly directional features.
Noninvasive differential diagnosis of dental periapical lesions in cone‐beam CT scans
Authors: Okada Kazunori , Rysavy Steven , Flores Arturo , Linguraru Marius George 
Published: March 2015

Purpose:This paper proposes a novel application of computer‐aided diagnosis (CAD) to an everyday clinical dental challenge: the noninvasive differential diagnosis of periapical lesions between periapical cysts and granulomas. A histological biopsy is the most reliable method currently available for this differential diagnosis; however, this invasive procedure prevents the lesions from healing noninvasively despite a report that they may heal without surgical treatment. A CAD using cone‐beam computed tomography (CBCT) offers an alternative noninvasive diagnostic tool which helps to avoid potentially unnecessary surgery and to investigate the unknown healing process and rate for the lesions.Methods:The proposed semiautomatic solution combines graph‐based random walks segmentation with machine learning‐based boosted classifiers and offers a robust clinical tool with minimal user interaction. As part of this CAD framework, the authors provide two novel technical contributions: (1) probabilistic extension of the random walks segmentation with likelihood ratio test and (2) LDA‐AdaBoost: a new integration of weighted linear discriminant analysis to AdaBoost.Results:A dataset of 28 CBCT scans is used to validate the approach and compare it with other popular segmentation and classification methods. The results show the effectiveness of the proposed method with 94.1% correct classification rate and an improvement of the performance by comparison with the Simon's state‐of‐the‐art method by 17.6%. The authors also compare classification performances with two independent ground‐truth sets from the histopathology and CBCT diagnoses provided by endodontic experts.Conclusions:Experimental results of the authors show that the proposed CAD system behaves in clearer agreement with the CBCT ground‐truth than with histopathology, supporting the Simon's conjecture that CBCT diagnosis can be as accurate as histopathology for differentiating the periapical lesions.
Incorporating multislice imaging into x‐ray CT polymer gel dosimetry
Authors: Johnston H. , Hilts M. , Jirasek A. 
Published: March 2015

Purpose:To evaluate multislice computed tomography (CT) scanning for fast and reliable readout of radiation therapy (RT) dose distributions using CT polymer gel dosimetry (PGD) and to establish a baseline assessment of image noise and uniformity in an unirradiated gel dosimeter.Methods:A 16‐slice CT scanner was used to acquire images through a 1 L cylinder filled with water. Additional images were collected using a single slice machine. The variability in CT number (NCT) associated with the anode heel effect was evaluated and used to define a new slice‐by‐slice background subtraction artifact removal technique for CT PGD. Image quality was assessed for the multislice system by evaluating image noise and uniformity. The agreement in NCT for slices acquired simultaneously using the multislice detector array was also examined. Further study was performed to assess the effects of increasing x‐ray tube load on the constancy of measured NCT and overall scan time. In all cases, results were compared to the single slice machine. Finally, images were collected throughout the volume of an unirradiated gel dosimeter to quantify image noise and uniformity before radiation is delivered.Results:Slice‐by‐slice background subtraction effectively removes the variability in NCT observed across images acquired simultaneously using the multislice scanner and is the recommended background subtraction method when using a multislice CT system. Image noise was higher for the multislice system compared to the single slice scanner, but overall image quality was comparable between the two systems. Further study showed NCT was consistent across image slices acquired simultaneously using the multislice detector array for each detector configuration of the slice thicknesses examined. In addition, the multislice system was found to eliminate variations in NCT due to increasing x‐ray tube load and reduce scanning time by a factor of 4 when compared to imaging a large volume using a single slice scanner. Images acquired through an unirradiated, active gel revealed NCT varies between the top and bottom of the 1 L cylinder as well as across the diameter of the cylinder by up to 7 HU.Conclusions:Multislice CT imaging has been evaluated for CT PGD and found to be the superior technique compared to single slice imaging in terms of the time required to complete a scan and the tube load characteristics associated with each scanning method. The implementation of multislice scanning is straightforward and expected to facilitate routine gel dosimetry measurements for complex dose distributions in modern RT centers.
Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents
Authors: Neely Michael , Margol Ashley , Fu Xiaowei , van Guilder Michael , Bayard David , Schumitzky Alan , Orbach Regina , Liu Siyu , Louie Stan , Hope William 
Published: March 2015

ABSTRACT

Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiple-model Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study. Using all available samples to estimate the individual Bayesian posterior parameter values, the median percent prediction bias relative to a measured target trough concentration in the patients was 1.1% (interquartile range, −17.1 to 10%). Compared to the actual dose that resulted in the target concentration, the percent bias of the predicted dose was −0.7% (interquartile range, −7 to 20%). Using only trough concentrations to generate the Bayesian posterior parameter values, the target bias was 6.4% (interquartile range, −1.4 to 14.7%;
P
= 0.16 versus the full posterior parameter value) and the dose bias was −6.7% (interquartile range, −18.7 to 2.4%;
P
= 0.15). Use of a sample collected at an optimal time of 4 h after a dose, in addition to the trough concentration, resulted in a nonsignificantly improved target bias of 3.8% (interquartile range, −13.1 to 18%;
P
= 0.32) and a dose bias of −3.5% (interquartile range, −18 to 14%;
P
= 0.33). With the nonparametric population model and trough concentrations, our control algorithm can accurately manage voriconazole therapy in children independently of steady-state conditions, and it is generalizable to any drug with a nonparametric pharmacokinetic model. (This study has been registered at ClinicalTrials.gov under registration no. NCT01976078.)
Tenofovir versus Entecavir in Treatment of Chronic Hepatitis B Virus with Severe Acute Exacerbation
Authors: Hung Chao-Hung , Hu Tsung-Hui , Lu Sheng-Nan , Lee Chuan-Mo , Chen Chih-Hung , Kee Kwong-Ming , Wang Jing-Houng , Tsai Ming-Chao , Kuo Yuan-Hung , Chang Kuo-Chin , Chiu Yi-Chun , Chen Chien-Hung 
Published: March 2015

ABSTRACTTenofovir disoproxil fumarate (TDF) and entecavir (ETV) are effective antivirals recommended as first-line monotherapies for treatment of chronic hepatitis B (CHB) infection. This study aimed to compare the short-term efficacies of TDF and ETV in the treatment of CHB with severe acute exacerbation. From 2008 to 2013, 189 consecutive treatment-naive CHB patients receiving TDF (n= 41) or ETV (n= 148) for severe acute exacerbation were enrolled. The primary endpoint was overall mortality or receipt of liver transplantation by week 24. The baseline characteristics were comparable between these two groups. By week 24, 8 (19% [95% confidence interval {CI}, 7% to 32%]) patients in the TDF group and 26 (18% [95% CI, 11 to 24%]) patients in the ETV group died (n= 30) or received liver transplantation (n= 4) (P= 0.749). The two groups of patients developed similar rates of liver-related complications and achieved comparable biochemical and virological responses at week 24. Cox regression analysis showed that baseline viral DNA level (P= 0.002), hypertension (P= 0.002), model for end-stage liver disease (MELD) score (P= 0.01), platelet count (P= 0.005), early presence (within 4 weeks) of ascites (P= 0.005), hepatic encephalopathy (P= 0.002), and hepatorenal syndrome (P< 0.001) were independent factors for mortality or liver transplantation. Among the patients who survived by week 24, there was no difference between the two groups in the percentage of patients who had a serum creatinine increase of ≥0.5 mg/dl from baseline (6.7% [95% CI, 0% to 16%] versus 2.0% [95% CI, 0% to 4.8%] in the TDF and ETV groups, respectively;P= 0.231), whereas a significant reduction in the estimated glomerular filtration rate (eGFR) was found in the two groups (P= 0.001 for both). In conclusion, TDF and ETV produce a similar treatment response and clinical outcome in patients with severe acute exacerbation of CHB.
In Vitro
Antimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics
Authors: Sharma Indu , Sullivan Margery , McCutchan Thomas F. 
Published: March 2015

ABSTRACT

Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of
Plasmodium falciparum
. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The
in vitro
growth inhibition assay was done using three laboratory strains of
P. falciparum
displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC
50
s) of 51.55 nM for
P. falciparum
3D7 (CQ susceptible), 85.67 nM for
P. falciparum
Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for
P. falciparum
K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC
50
s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC
50
, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation.
Squalestatin Is an Inhibitor of Carotenoid Biosynthesis in Plasmodium falciparum
Authors: Gabriel Heloisa B. , Silva Marcia F. , Kimura Emília A. , Wunderlich Gerhard , Katzin Alejandro M. , Azevedo Mauro F. 
Published: March 2015

ABSTRACT

The increasing resistance of malaria parasites to almost all available drugs calls for the characterization of novel targets and the identification of new compounds. Carotenoids are polyisoprenoids from plants, algae, and some bacteria, and they are biosynthesized by
Plasmodium falciparum
but not by mammalian cells. Biochemical and reverse genetics approaches were applied to demonstrate that phytoene synthase (PSY) is a key enzyme for carotenoid biosynthesis in
P. falciparum
and is essential for intraerythrocytic growth. The known PSY inhibitor squalestatin reduces biosynthesis of phytoene and kills parasites during the intraerythrocytic cycle. PSY-overexpressing parasites showed increased biosynthesis of phytoene and its derived product phytofluene and presented a squalestatin-resistant phenotype, suggesting that this enzyme is the primary target of action of this drug in the parasite.